Neuropeptides and the central regulation of body temperature during fever and hibernation

J. therm. Biol. Vol. 15, No. 3/4, pp. 329-347, 1990

0306-4565/90 $3.00 + 0.00 Copyright © 1990 PergamonPress plc

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NEUROPEPTIDES AND THE CENTRAL REGULATION OF BODY TEMPERATURE DURING FEVER AND HIBERNATION L. JANSK~" Department of Physiology and Developmental Biology, Faculty of Science, Charles University, 12800, Prague 2 (Received 21 October 1989; accepted in revised form 20 January 1990)

Abstract--Neuropeptides, acting on structures within the central nervous system influence body temperature. Non-opioid peptides induce hypothermia usually, while opioid peptides are mostly hyperthermic. Neuropeptides exert their effect only when injected into specific brain areas. Hypo- or hyperthermic effect of neuropeptides may be either due to changes in threshold body temperatures for induction of thermoregulatory effectors or due to changes in hypothalamic thermosensitivity. At the cellular level the opioid peptides also act differently than the non-opioid peptides. The opioid peptides mostly inhibit spontaneous neuronal firing, while the non-opioid peptides usually stimulate it. Neuropeptides exert their influence on all neurones in the hypothalamus, independently on their temperature characteristics. Neuropeptides may play a role in the regulation of body temperature under stressful conditions and during fever or hibernation, in particular. Some neuropeptides, namely AVP, ~t-MSH and ACTH, act as natural antipyretic substances by lowering the threshold for cold thermogenesis. Neuropeptides also modulate food intake, reproduction and many other functions which are substantially changed during hibernation. There appears to be a correlation between the effect of peptides on the control of food intake and on the control of body temperature. Opioid peptides, which increase food intake, induce hyperthermia, while non-opioid peptides, which are appetite inhibiting, induce hypothermia. The exact role of neuropeptides in the regulation of body temperature, food intake and gonadal activity of hibernators remains unclear, however. Key Word Index: Thermoregulation; neuropeptides; fever; thermosensitive neurones; hibernation

CENTRAL MECHANISMS REGULATING BODY TEMPERATURE

Hypothalamus is considered to be the main nervous centre regulating body temperature of homeotherms. However, in spite of great effort by many laboratories, the hypothalamic control functions have not been fully elucidated yet, mostly due to the fact that these structures are not freely accessible for direct studies under in vivo conditions. To clarify the role of the hypothalamus in body temperature control several thermoregulatory models have been suggested. The model of Bligh (Bligh et al., 1971) appears to be the most simple, and probably, most appropriate for elucidating basic hypothalamic processes controlling body temperature (Fig. 1). This model is based on the presumption that neurones in the preoptic area of the anterior hypothalamus (POAH) receive inputs from warm and cold sensors (thermoreceptors) located in the POAH or in other parts of the body. The model presumes that the warm or cold signals are transmitted by separate, but interconnected neural pathways, consisting of interneurones which are relatively temperature insensitive. The specific feature of this regulatory system is that the "warm" and "cold" pathways can reciprocally inhibit each other. As deep body temperature increases, activity of "warm" pathways is elevated and activity of "cold" pathways is depressed, the final 329

result being an activation of the heat loss mechanisms. In cold-exposed animals, in contrast, "cold" pathways are activated, while the "warm" ones are inhibited so that the heat production mechanisms are set into action, Through a balanced activation of "warm" and "cold" pathways heat production and heat loss are adequately controlled to yield a regulated and stable internal body temperature. Peripheral vasomotor tone (PVMT), which is controlled by the sympathetic nervous system, is presumably regulated through a separate neuronal pathway, which also integrates the activity of both "warm" and "cold" pathways. There is general consent that the weighted mean body temperature, rather than the hypothalamic temperature alone, represents the controlled variable in homeothermic temperature regulation. A certain balance between cold and warm receptor inputs seems to be associated with a minimal state of thermoregulatory effector activities. All body temperature profiles establishing this balance would represent set-point conditions. Figure 2 shows a simplified situation when the set-point is established as a consequence of interaction between activities of cold and warm receptors in the hypothalamus. Temperature changes that generate input imbalance in either direction will alter the state ofeffector activities to counteract these imbalance and thus are functional analogues of load errors (Simon, 1987).

330

L. JANSKY input

..............

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POAH............. +

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i

Fig. 1. Tentative scheme of thermoregulatory pathways in the preoptic area of the anterior hypothalamus (Bligh et al., 1971). Under normal physiological conditions, the thermo-effectors are driven by inputs from a multitude of body temperature sensors. The relative contribution of signals from the brain, skin and body core varies between species. The body core input, however, is being considered as the most powerful one (Simon et al., 1986). Although the preoptic area of the anterior hypothalamus is undoubtedly the main integrative centre of thermoregulation, some thermoregulatory responses can be induced at lower levels of the regulatory system (Simon, 1974). At all these sites the signals transmitted from one neurone to another can be modulated by chemical substances, namely by biological amines, amino acids and neuropeptides. Depending on their position in the thermoregulatory neuronal network, neurones releasing one or the other substance may alter the balance between cold and warm receptor inputs or the mode of signal processing at different levels of central integration. A clue, as to which action may be involved, could be derived from the evaluation of changes in thresholds and/or "gains" of individual thermoregulatory effectors.

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~$et point" P Fig. 2. Changes in activity of warm and cold receptors in the hypothalamus during normothermia ( ) and fever ( ). Equilibrium between activities of warm and cold receptors determine the set-point. During fever, presumably the activity of warm receptors is decreased and the activity of cold receptors is activated the final effect being an upward shift of the set-point.

EFFECT OF NEUROPEPTIDES ON BODY TEMPERATURE CONTROL

Evidence is accumulating that in the hypothalamus the activity of neural components involved in body temperature control can be modulated significantly by central (intrahypothalamic, intraventricular) administration of neuropeptides. Some neurpeptides, mostly those of opioid character (/3-endorphin, enkephalins) tend to increase body temperature, while mostly hypothermic actions have been reported for the non-opioid peptides (ACTH, ~-MSH, arginine-vasopressin, somatostatin, cholecystokinin, bombesin, calcitonin). However, some of these peptides, namely neurotensin, TRH, met-enkephalins and others, may elicit both hyper- and hypothermic effects depending on the experimental conditions and on the species used (Tables 1 and 2). Neuropeptides appear in large quantities in the preoptic area of the anterior hypothalamus. It can be expected, therefore, that they may be involved in processes regulating body temperature, especially under specific physiological situations, e.g. during fever or hibernation. Simple measurement of the core temperature response to central injection of a peptide in a thermoneutral environment provides only limited information about the physiological role of neuropeptides during thermoregulation, however. In order to conclude that neuropeptides participate in body temperature control under physiological conditions, it is necessary to obtain additional data about their specific effect on individual thermoregulatory effectors, namely on cold thermogenesis (CT), peripheral vasomotor tone (PVMT), respiratory evaporative heat loss (REHL), or sweating at different environmental temperatures, i.e. at different states of their activation. To shed more light on the mode of neuropeptide action upon control mechanisms of body temperature we have attempted to localize the site of their action and to disclose pathways involved in the control of individual thermoregutatory effectors, using the method of intestinal cooling and warming and of microinjections of neuropeptides into different brain stem areas (Inomoto et al., 1982; Jansk~, et al., 1986). This method makes it possible to manipulate the central body temperature, while leaving the peripheral body temperature relatively unaffected.

N e u r o p e p t i d e s a n d the central r e g u l a t i o n of b o d y t e m p e r a t u r e d u r i n g fever a n d h i b e r n a t i o n

331

Table 1. Peptides that decrease body temperature after central administration to nonfebrile animals Route of administration

Peptide Arginine-vasopressin Somatostatin TRH Kyotorphin Met-enkephalin o-Ala-leu-enkephalin Neurotensin

ICV ICV ICV ICV (in cold) ICV ICV ICV ICV (diphasic effect) ICV IC (in cold) IC IC (in cold) IC ICV IH (PA) ICV (in cold) ICV ICV I CV

Bombesin

ACTH ct-MSH Vasoactive intestinal polypeptide Cholecystokinin

Angiotensin II

ICV IC ICV IC (in cold) IC (in cold) IH (in cold) ICV, IH IH (PA) ICV I CV IH 1CV ICV (in cold) ICV (in cold)

Dose 1 ,ag 0.01 U 1-5/lg 0.1 #mol/kg 10/~g 142 nmol 242 nmol 400 #g 10 nmol 30 ng 250 ng-10 #g 10-30/~g 10-30/tg 0.1 10#g 2.5/~g 5-20 #g 1/~g 0.47-60/zg 1 - 10/~ g 1.5/~g 0.97 pg 0.25-2/ag 100 ng 1~500 ng 0.1-1/~g 1-100 ng 100 ng 50 ng-1 #g 250 ng I #g 1.25-5 #g 1.25-5 #g

ICV

1 10 #g

ICV ICV IH ICV IH ICV ICV ICV

25-250 ng 20-800/~g 20-60 ng 25 ng/min 0.05-15 # g 10-40/~g 5-50 ~g 5/~g

The advantage of the method is that it simplifies thermal input to the hypothalamic control centres and allows the expression of the activity of thermoregulatory effectors as a simple function of central body temperature. The method also allows the estimation of the intensity of responses of individual thermoregulatory effectors per unit core temperature change, as well as the threshold body core temperature for induction of these effector responses. Thermosensitivity of the body temperature controller can be also estimated from the slopes of the curves, steeper slopes indicating higher thermosensitivity and vice versa. Thus, by this method the central effect of neuropeptides on thermoregulation can be also analysed. Figure 3 schematically shows how changes in temperature of the body core during intestinal cooling or warming influence activity of individual thermoregulatory effectors in control rabbits. It is evident that deviations of temperatures from the threshold body temperature (which in this case, corresponds to 38.5°C) represent signals for activation of these effectors. Intensities of cold thermo-

Species

Reference

rat rat rat rat cat mouse mouse rat golden hamster mouse mouse mouse, hamster, guinea pig, rat, gerbil rat rat rat rat rat rat rabbit rat mouse rat rat rat rat rat rat rat rabbit rat rabbit rat rabbit rabbit

Naylor et al. (1986a, b) Kruk and Brittain (1972) Chandra et al. (1981) Prasad et al. (1978) Metcalf and Myers (1975) Sakurada et al. (1983) Sakurada et al. (1983) Ferri et aL (1978) Tseng et al. (1979) Bissette et al. (1976) Mason et al. (1982) Nemeroff et al. (1980a, b)

rat mouse rat rat rat sheep rabbit rat rabbit rat

Itoh and Hirata (1982) Zetler (1982) Morley et al. (I 981 ) Katsuura and ltoh (1981) Liu and Lin (1985) Huang et al. (1985) Sharpe et al. (I 978) Linet al. (1980) Lin (1980) Shido and Nagasaka (1985)

Loosen et al. (1978) Shido and Nagasaka (1985a, b) Kalivas et al. (1983) Chandra et al. (1981) Morley et al. (1982) Jolicoeur et al. (1984) Metcalf et al. (1980) Lee and Myers (1983) Mason et al. (1982) Avery and Calisher (1982) Brown et al. (1977) Rivier and Brown (1978) Pittman et al. (1980) Wunder et al. (1980) Lin and Lin (1986) Francesconi and Mager (I 981) Lipton and Glyn (1980) Tache et al. (1980) Jansk~' et al. (1987) Rasler (1983) Glyn and Lipton (1981) Glyn and Lipton (1981)

genesis, peripheral vasomotor tone and respiratory evaporative heat loss are related proportionally, in a first approximation to changes in body core temperature. With a temperature increase above 38.5 the heat loss mechanisms are activated to reach the maximal intensity at 40°C, the operational range for these thermoregulatory outputs thus being about 1.5°C. With a body temperature dropping below 38.5°C, the cold thermogenesis is activated to reach its maximal intensity at 37.5°C. The operational range for activating cold thermogenesis is, therefore, about I°C. Data so far obtained indicate that the intensities of thermoregulatory outputs, threshold temperatures and thermosensitivity of the controller can be markedly influenced by central administration of neuropeptides (Vybiral et al., 1986, 1987, 1988; Vybiral and Jansk~/, 1989; Jansk~ et al., 1987). Figure 4 summarizes our data by showing that neuropeptides, or related substances, when injected into the anterior hypothalamus of the rabbit in nanogram quantities induce consistent changes in threshold body temperatures and in hypothalamic

332

L. JANSKY Table 2. Peptides that increase body temperature after central administration Route of administration

Peptide TRH

Dose

ICV ICV, 1H ICV IH IH ICV ICV ICV IH ICV ICV IH ICV IH ICV 1CV

DADIE enkephalin Met-enkephalin Enkephalin analogue

Met-enkephalinamide FK33-824 //-Endorphin

ICV ICV ICV IH ICV ICV IH ICV ICV ICV IH ICV IH (PA) ICV ICV ( 2 2 C , 300 min) ICV (in warm) (in warm) IC, ICV

Neurotensin Calcitonin Arginine-vasopressin Cholecystokinin Bombesin

Somatostatin

0 . 2 5 4 ltg 0.1 10,ug 0.t l~g 0.7 7 mmol 7.5 ,ug 40 p g 1.4,uM 10 50/~g 0.625-5 p g 0.6-1.1 l~g 250 ng 0.02 U 100 ng 10 100,ug 100 ng 1 10 #g 1 10,ug

thermosensitivity. Three types of thermoregulatory responses can be distinguished: (1) Neurotensin, dopamine, apomorphin and substances released during the early phase of the fever induce a shift of the threshold for the induction of all thermoregulatory effectors to higher body core temperatures while leaving the thermosensitivity of the controller unchanged. (2) Bombesin shifts the threshold for the induction of all thermoregulatory effectors to lower body core 100

100

I

%

0

50-

fi L

y. 36

t

1

37

38

Species

0.01-1 p g 0.14-t4/~mol 0.1 ,umol kg 0.6-80 # g 50 500 ng 10 l~g 0.5 1 mg/kg 1- t 00 It g I 10/~g 10 # g 0.5 I m g 0.35 and 0.7 mmol 100 and 400/.tg 1 25/lg 100 1000 #g 240-300,ug

%

50

Reference

rat rat rat rat pigeon rabbit cat, rabbit rabbit rabbit rat cat rat rat cat rabbit rabbit

Brown et aL (1977) Cohn et al. (1980) Prasad et al. (1978) Boschi and Rips ( 1981 ) Lahti et al. (1983) Metcalf el at. (1980) Metcalf (1974) Horita and Carino (1976) Carino et al. (1976) Francesconi and M ager ( 1981) Clark (1977) Tepperman and Hirst (1983) Ferri et al. (1978) Stanton et ul. (1985) Kandasamy and Williams (1983) Konecka et al. (1982)

cat mouse mouse rat rat cat rabbit rabbit squirrel monkey rat rabbit rat rat guinea pig rat rat rabbit rat

Clark et aL (1982) Bloom and Tseng (1981) Huidobro-Toro et al. (1979) Martin and Bacino (1979) Holaday et al. (1978a, b) Clark and Bernardini (1981) Rezvani et al. (1982) Kandasmy and Williams (1983) Lipton and Murphy (1983) Tseng et aL (1979) Vybiral et al. (1986) Fargeas et al. (1985) Naylor et aL (1986a, b) Kandasamy and Williams (1983) Francesconi and Mager (1981) Tache et aL (1980) Lipton and Glyn (1980) Brown et al. (1981)

temperature and lowers the thermosensitivity of the controller. (3) The dopamine antagonist-haloperidol and substances released in the late phase of the fever (probably the ACTH) induce a dissociation of thresholds for the induction of the cold and warm defence, while leaving the thermosensitivity of the controller unchanged or slightly lowered. Effects of some neuropeptides (bombesin, neurotensin) are specific to the preoptic area of the anterior hypothalamus. Injections of peptides into the posterior hypothalamus are without effect on body temperature control. The data suggest that neuropeptides influence activities of hypothalamic integrative networks, which are specifically involved in the control of body temperature. Their function may be seen as that of messengers of central neuromodular system, which adjust thermal control to particular physiological or pathophysiological conditions. NEUROPEPTIDES AND FEVER

[ 39

40

41

42°C

Tcore

Fig. 3. Scheme of activation of thermoregulatory effectors (CT = cold thermogenesis, PVMT = peripheral vasomotor tone, REHL = respiratory evaporative heat loss) due to changes in central body temperature during intestinal cooling and warming.

Thermoregulation during fever Data of Vybiral e t al. (1987) and others indicate that in rabbits two phases of the fever can be distinguished after i.v. injection of the endotoxin (1/~g/kg). During the early phase occurring within the first 2 h after endotoxin injection, heat production increases, vasoconstriction appears and respiration rate decreases. Two hours after injection of endotoxin vasodilation appears again, heat production and

Neuropeptides and the central regulation of body temperature during fever and hibernation

333

OOPAMINi ( I l l ) APOMORPHINE ( 2 1 p l ) 1 NEUROTENSIN (250 n O) early phclse of endotoxin fever (1/zo/l(g i.v.)

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Fig. 4. Scheme of action of different neuropeptides and related substances on activity of hypotbalamic centres regulating body temperature. Based on data of Jansk~' et al., 1987; Vybiral and Jansk#, 1989; Vyblral et al., 1986, 1987, 1988.

respiration rate return to the normal level but animals still maintain an elevated body temperature for at least 5 h. The increase in body temperature during the early phase of the fever is due to the shift of the threshold for induction of shivering, panting and release of the peripheral vasomotor tone to higher body temperatures. No change in the thermosensitivity of the controller occurs during this phase. This effect may be due to action of prostaglandins as suggested by Stitt et al. (1974) and others. On the other hand, during the late phase of the fever a downward shift of the threshold for shivering occurs, while that for panting and vasodilation remains elevated, the consequence being a dissociation of thresholds for cold and warm defence. Thermosensitivity of the controller is not changed (Fig. 5). The data mean that animals in the late phase of the fever become insensitive to relatively large changes in their body temperature (37.0--39.5°C). The data complement earlier findings of Iriki et al. (1984) and Hashimoto et al. (1985) by documenting that the interthreshold zone is expanded and central thermosensitivity is not changed during the late phase of endotoxin fever. It further corresponds to observations of Riedel et al. (1982) according to which regional sympathetic outflow to the skin and visceral organs shows a distinct deviation from the regular thermoregulatory pattern in febrile animals.

Phases of the fever represent a specifically altered states of temperature regulation. The neural mechanisms and transmitters involved in the observed phenomena in the rabbit have not yet been identified. For the early phase of the endotoxin fever and for the prostaglandin fever it is assumed that the upward shift of the thermoregulatory threshold is due to an increased activity of central cold sensors and depressed activity of warm sensors (Cabanac et al., 1968; Stitt et al., 1974). Accordingly, it might be speculated that during the late phase of the endotoxin fever both cold and warm sensors are inhibited. However, there is a remarkable similarity between the thermoregulatory disturbances demonstrated in the late phase of endotoxin fever and those described for animals with hypothalamic lesions (Satinoff, 1978). The mode o f neuropeptide antipyretic action

Neuropeptides may play an important role in controlling fever. The antipyretic effect of peripherally administered ACTH in rabbits has been known for almost 40yr (Hench et al., 1949; Kass and Finland, 1950). The fact that ACTH also lowers body temperatures in nonfebrile rabbits, when given centrally (intrahypothalamically--i.h., or intracerebroventricularly--i.c.v.), has not been known until recently, however (Lipton and Glyn, 1980). Further it was found that smaller doses of ACTH, that do not

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influence normal body temperature, inhibited fever in rabbits (Glyn and Lipton, 1981) and in guinea pigs (Kandasamy and Williams, 1983), when centrally administered. This effect is independent of adrenal cortex (Zimmer and Lipton, 1981). Also in squirrel monkeys i.c.v, administrations of ACTH reduce fever (Lipton et al., 1984). On the other hand, in rats central administration of ACTH induces a slight hyperthermic response (Thornhill and Saunders, 1984) or is without effect (Thornhill and Wilfong, 1982). Peripheral (i.v.) administration of ACTH to normal rats is hyperthermic due to stimulation of heat production mechanisms (Bogtik et al., 1982). When analysing the antipyretic effect of ACTH by means of the method of intestinal cooling we found (Vybiral et al., 1988) that injections of ACTH into the anterior hypothalamus during the first phase of the fever induced a dissociation of the thresholds for warm and cold defence and, thus, transformed the first into the second phase of fever, thereby shortening the total time span of the fever. Thermosensitivity of the controller regulating shivering is lowered, however, and the maximal values are depressed to about 30% of those of control rabbits [Fig. 6(B)]. The heat defence mechanisms (PVMT, REHL) are not affected by ACTH. In the

- -

;f 2,

°C

Fig. 5. Effect of endotoxin on the relationship between hypothalamic temperature as a representative of central temperature and metabolic rate (CT), ear skin temperature (PVMT), and respiratory rate (REHL). Solid lines and solid symbols indicate the response of normal rabbits, interrupted lines and open symbols show response of rabbits 2 h after i.v. injections of endotoxin. The insets indicate the relationship between effector activity and central temperature of a representative experiment during the first 2 h following the endotoxin injections, with the numbers indicating the time elapsed. Vertical interrupted and dashed lines indicate central threshold temperatures in control conditions and during the late phase of fever respectively, and thereby indicate the extent of the interthreshold zone (Vybiral et al., 1987).

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Fig. 6. Scheme of ACTH action on body temperature control in normal rabbits (A), in rabbits during the early phase (B) and during the late phase (C) of the fever. Solid lines show the responses of ACTH-untreated rabbits. Interrupted lines show the responses of rabbits after injection of 5 ~g of ACTH into the anterior hypothalamus (according to Vybiral et al., 1988). late phase of the fever, ACTH induces a smaller effect than in the early phase. The downward shift of the temperature threshold for cold thermogenesis, which typically occurs during the late phase of the fever, becomes less evident after ACTH, the thermosensitivity of the controller remaining unchanged [Fig. 6(C)]. In contrast to that central injections of ACTH to nonfebrile rabbits are without effect on body temperature [Fig. 6(A)]. On the basis of these data it is speculated that the presumed activation of the pituitary-adrenal axis during the febrile state contributes to the termination of the fever by a negative feed-back mechanism. ACTH acting on hypothalamic control centres thus

Neuropeptides and the central regulation of body temperature during fever and hibernation appears to be a natural antipyretic substance, which eliminates the effects of prostaglandins on nervous pathways controlling shivering. ~t-MSH, when given intraventricularly is also very effective in inducing hypothermia or reducing fever in rabbits (Lipton and Glyn, 1980; Lipton et al., 1981). The hypothermic effect of ct-MSH is more prominent at lowered environmental temperatures (Glyn and Lipton, 1981). In rabbits injections of ct-MSH into the septal region (Glyn-Ballinger et al., 1983) as well as the peripheral administration of ct-MSH (Murphy and Lipton, 1982) are also antipyretic, i.c.v, administrations of ~-MSH reduce fever in squirrel monkeys (Lipton and Shih, 1985). In contrast to earlier data, Richards and Lipton (1984) produced evidence that ct-MSH is without effect on body temperature in febrile rabbits. In normothermic guinea pigs high doses of ~t-MSH into cerebral ventricle are required to produce hypothermia (Kandasamy and Williams, 1983). In rats peripheral administration of at-MSH also induces hypothermia (Yehuda and Carraso, 1983). Arginine-vasopressin (AVP) has also an antipyretic effect when injected intracerebroventricularly to rats (Kovacs and DeWied, 1983), or into the septal region of the sheep, rabbit, rat or cat (Kasting et al., 1979; Malkinson et al., 1987; Cooper et al., 1979, 1987; Naylor et al., 1986a, b; Wilkinson and Kasting, 1987; Kasting and Wilkinson, 1986). On the other hand, intrahypothalamic injections of this substance to febrile rabbits or monkeys are without effect or produce hyperthermia (Bernardini et al., 1983; Lee et al., 1985; Lipton and Glyn, 1980). Hypothermic effect of peripherally injected vasopressin to febrile rats was also observed (Okuno et al., 1965). This effect is due to inhibition of cold thermogenesis (Shido et al., 1984). Most recently this topic was reviewed by Naylor et al. (1987). Our recent experiments (Ehymayed and Jansk~,, 1990), show that AVP, when injected into the septum, has the same effect on thermoregulation during the first phase of the fever as ACTH, i.e. it induces dissociation of thresholds for cold and warm defence mechanisms.

335

C R F also reduces body temperature of febrile rabbits when given centrally. Intravenous administrations have no effect on fever (Bernardini et al., 1984). Further it was observed that neurotensin prevents hyperthermia induced by prostaglandin E2 in mice (Mason et al., 1982). Recently, Lin et al. (1989) presented evidence that hypothalamic somatostatin may be involved in induction of febrile processes. CELLULAR MECHANISMSOF NEUROPEPTIDE ACTION One of the most fascinating problems of modern physiology is the discrete mode of neuropeptides action on individual neurones. Neuropeptides evidently influence both thermosensitive and thermoinsensitive neurones and their effect is different in opioid and nonopioid peptides. Two of the most commonly observed effects of opioid peptides are a depression of neural firing (North, 1979) and an inhibition of neurotransmitter release (Miller, 1984). The following hypothesis were suggested to explain the mechanism of opiate action which are based on the assumption that different Ca 2+ distribution is responsible for the acute effect of opiates (North, 1986): (1) Opiates act directly on intracellular Ca 2÷ content by modulating voltage sensitive Ca 2÷ channels via K-receptors (Werz and MacDonald, 1983, 1984). (2) Opiates act indirectly on intracellular Ca 2+ content by mobilizing intracellular calcium via/~ and receptors. This could increase the Ca 2÷ dependent K ÷ conductance (North and Williams, 1985) and hyperpolarize the cell membrane (Pepper and Henderson, 1980). Such an action could reduce probability of the generation and propagation of action potentials and shorten their duration and, subsequently, modulate the voltage dependent Ca 2÷ influx. The mode of non-opioid peptides action appears to be different from that of opioid peptides. Under in vitro conditions, administration of neuropeptides

Table 3. Effect of neuropeptidesand other substanceson the activityof central thermosensors (measured under in vivo conditions)

w~ Pyrogen Prostaglandins

w~ TRH Bombesin Neurotensin

Wl'

ct (Cabanac et al., 1968;Witt and Wang, 1968; Eisenman, 1969;Nakayamaand Hori, 1973; Sakata, 1979;Schoenerand Wang, 1975) (Ford, 1974;Stitt and Hardy, 1975; Jell and Sweatman, 1977; Gordon and Heath, 1980; Schoener and Wang, 1976)

c~

Morphine Angiotensin Cholecystokinin Serotonin Dopamine Bombesin

w1"

(Salzman and Beckman, 1981) (Hori et al., 1986)

Noradrenalin

c~ [ (Baldino et al., 1980) (Kioharaet al., 1984) (Shianand Lin, 1985) (Hori and Nakayama, 1973;Murakami, 1973; Bligh et al., 1971;Gordon and Heath, 1981) (Scott and Boulant, 1984) (Lin and Lin, 1986)

cT I (Beckmanand Eisenman, 1970; Hori and Nakayama, 1973;Murakami, 1973)

fl-Endorphin(Gordon and Heath, 1981)--inconsistentdata w = warm sensitiveneurones. c = Cold sensitiveneurones.

336

L. JANSKY

to thermosensitive neurones at different brain sites of both anaesthetized or nonanaesthetized animals gives inconsistent data. Both activation or depression of activity of warm-sensitive and cold-sensitive neurones was observed. Data are summarized in Table 3. Extracellular recordings from neural slices in vitro generally show activation of spontaneous firing (substance P - - N a y a r et al., 1987: Pierau et al., 1989; cholecystokinin--Pan et al., 1986; Boden and Hill, 1987~ Kow and Pfaff, 1986a; AVP Kow and Pfaff, 1986b; bombesin--Pierau et al., 1989) Pyretic substances (LPS, leukopyrogen, prostaglandins, interleukin 1), when applied to hypothalamic slices usually depress spontaneous activity of warm-sensitive neurones, activate cold-sensitive neurones and have no effect on thermoinsensitive neurones (Boulant and Scott, 1983, 1986; Hori et al., 1984; Nakashima et al., 1985: Hori et al., 1988; Ono et al., 1987; Watanabe et al., 1987). The data obtained are rather inconsistent, however, especially as far as the effect of prostaglandins is concerned. Morimoto et al. (1988) have found that the responses to prostaglandin E 2 did not depend on their thermoresponsiveness, but rather on the sites of action. Neurones in the ventromedial hypothalamic region showed a decrease in their firing rate, while those in the preoptic area showed an increase in firing rate after prostaglandin E 2. Our unpublished observations (Jansk~ et al., unpublished) indicate a longlasting inhibition of activity of both thermosensitive and thermoinsensitive neurones after prostaglandin E2, independently on its site of action within the hypothalamus. Intracellular recordings after iontophoretic administration of non-opioid peptides show depolarization and excitation of neurones in different parts of the central nervous system (neurotensin--Nicoll, 1978; Baldino and Wolfson 1985; Stanzione and Zieglgfinsberger, 1983; cholecystokinin--Phillis and Kirkpatrick, 1979: Dodd and Kelly, 1981; Bunney et al., 1982: AVP and D S I ~ N o r m a n t o n and Gent, 1983; TRH--NicoI1, 1978; Ozawa, 1985). The discrete mode of action of non-opioid peptides on thermosensitive neurones in the brain has not been explained entirely yet. Some experiments were performed, however, concerning the mode of action of bombesin on cultured tumour, hypothalamic and pancreatic cells (Isacke et al., 1986; Muir and Murray 1987: Mendoza et al., 1986; Brown et al., 1987; Moody et aL, 1987; Bjoro et al., 1987; Swope and Schonbrunn, 1988a, b). Bombesin induces a shortlasting hyperpolarization, followed by a long-lasting depolarization and by an increased spontaneous activity (Bjoro et al., 1987). Ozawa (1985) has concluded that the short lasting hyperpolarization after bombesin may be due to its effect on Ca 2+ dependent K + channels. The data obtained can be summarized in the following way: (1) Bombesin acts on specific receptors at the cell membrane (Westendorf and Schonbrunn, 1983; Erne and Schwyer, 1987) (2) The first 8 amino acids in its C-terminal part are important for its action (Orloff et al., 1984; Broccardo et al., 1975)

(3) Bombesin increases intracellular concentration of phosphoinositols (IP + 40%: IP 2 + 300%: IP 3 + 800%; diacylglycerol + 4 0 % ) (Swope and Schonbrunn, 1988a) (4) IP 3 increases intracellular Ca:' by releasing it from the endoplasmic reticulum (Moody et al., 1987) (5) Diacylglycerol activates proteinkinase C, which acts the same was as IP 3 (Bjoro et al., 1987). To analyse the action of neuropeptides on hypothalamic thermosensitive neurones extracellular recordings of spontaneous activity of thermosensitive and thermoinsensitive neurones in slices from the anterior hypothalamus of the rat were performed (Pierau et al., 1989; Schmid et al., 1987a, b). It was found that bombesin (1 l~g in the perfusion chamber; 0.5 ml vol, perfusion rate 3 ml/min) consistently increased spontaneous activity in most of the hypothalamic neurones at the temperatures of 3TC. Activity was increased in 24 out of 35 warm-sensitive, in 24 out of 39 thermoinsensitive and in 1 out of 2 cold-sensitive neurones. In the remaining neurones activity was not affected. No inhibition of neural activity was observed. It is important to note that bombesin not only increased neural activity at 37°C, but also induced changes of the thermosensitivity of hypothalamic neurones. Nineteen out of 21 temperature-insensitive neurones became warmsensitive and temperature sensitivity of 7 out of 11 warm-sensitive neurones was enhanced for time periods exceeding 20min after the end of slice perfusion with bombesin. It can be concluded that neuropeptides stimulate both thermosensors and thermoinsensitive elements. Thus, the hypothalamic thermosensitivity does not appear to be a fixed property of individual neurones, but it is rather variable and can be changed due to different interactions of neural networks during temperature stimulation. N E U R O P E P T I D E S AND HIBERNATION

E f f e c t on t h e r m o r e g u l a t i o n

Hibernation represents a specialized model of body temperature control. There are data indicating that specific changes in body temperature during hibernation may be induced by peptides. Dawe and Spurrier (1969) presented the first evidence for the presence of a hibernation trigger factor in the blood of hibernating woodchucks and ground squirrels. They demonstrated that whole plasma obtained from the animal during the phase of winter hibernation, induces hibernation when is injected into an active squirrel or woodchuck during the summer months. Attempts to characterize the hibernation trigger molecule biochemically show that the factor is bound to, or closely associated with the plasma albumin fraction (Oeltgen et al., 1978), is a protein (Oeltgen and Spurrier, 1981) and exerts a profound effect on blood constituents (Oeltgen et al., 1979; Spurrier and Dawe, 1973). Infusion of the hibernation trigger into the cerebral ventricle of the monkey produces a transient fall in body temperature, a long-term reduction of the animal's intake of food (Myers et al., 1981), bradycardia and an opiate-like modification in behaviour (Adler, 1980; Oeltgen et al., 1982). Opiate

Neuropeptides and the central regulation of body temperature during fever and hibernation antagonists reverse these behavioural and physiological signs. Hibernation trigger also alters renal functions in the monkey by depressing urine production and creatinine clearance (Oeltgen et al., 1985). The effect of the hibernation trigger on individual hibernation parameters (durations of prehibernation period, hibernation season, hibernation bout) has not been studied in detail, however. Morphine induces depression of metabolic respiratory, gastrointestinal, endocrine and neural activities. It is reasonable to expect that the endogenous opioid systems may exert similar effects in hibernators (Margules et al., 1977). Continuous microinfusions of a specific opioid antagonist, naloxone, into the cerebral ventricle produced a dose-related decrease in duration of hibernation bouts (Beckman and Llados-Eckman, 1985) and naltrexone decreases the length of sleeping behaviour in the garden mouse (Kromer, 1980). Beckman et al. (1981) and Wang et aL (1987) published data showing that there are quantitative seasonal differences in reaction to naloxone in ground squirrels. Animals showed reduced responsiveness to opiates during hibernation phase. On the other hand, Kulpa et aL (1986) found that naloxone administration did not alter weight gain nor onset of hibernation and Beckman et al. (1986) observed that decreased specific opioid binding in the hippocampus and cortex occurred during hibernation. This might be due to increased level of enkephalins, reported in ground squirrels (Kramarova et al., 1983). Although neuropeptides induce specific changes in body temperature control in normotherms, it still remains in question whether their effect is of physiological significance for hibernators. Hibernators show typical changes in body temperature during a hibernation cycle. Prior to hibernation they control body temperature precisely at a level similar to other homeotherms of similar body weight. When, as a result of action of shorter photoperiods and cold, gonadal involution occurs (Jansk~, 1986a, b) animals suddenly decrease their threshold body temperature to enter hypothermia. After several hours or days the 7.5 .c

c~ zs E 40

.

J 24

I 12

.

.

.

.

--_

I 24

--

z

_

1 12 h

Fig. 7. Changes in metabolic rate and body temperature during one hibernation bout of a golden hamster (Jansk~, 1986a). TB 15/3-4~J

337

threshold body temperature is enhanced to the normal level spontaneously and animals become normothermic again (Fig. 7). Thus, if neuropeptides are to be involved in body temperature control during hibernation, production of neuropeptides or properties of their receptors has to change accordingly. Substantial evidence has been accumulated that neuropeptides are involved not only in thermoregulation, but also in the control of food intake reproduction, sleep and perception in pain. Since anorexia and gonadal involution are the necessary prerequisites for hibernation (Jansk~, 1986a, b), particular attention will be payed to the problem whether or not neuropeptides influence feeding behaviour and gonadal activity of hibernators. Effect on f o o d intake

Recent data strongly suggest that peptide hormones, which are located in the gastrointestinal tract and secreted in response to a meal may be involved in regulation of meal size and meal cessation, i.e. satiety. Since the original work detailing the reduction of eating in rats after administration of cholecystokinin (CCK) (Gibbs et al., 1973a, b) many other putative satiety hormones have been identified. These hormones include, in addition to CCK, somatostatin (Letter et al., 1981), pancreatic polypeptide (Malaisse-Lagae et al., 1977), glucagon (Martin and Novin, 1977) and bombesin (Gibbs et al., 1979). All have been reported to reduce meal size following their peripheral administration before the meal or soon after meal onset. In contrast to meal intake, the water intake is not inhibited by these peptides (CCK--Gibbs et aL, 1973a, bombesin---Gibbs et al., 1979; somatostatin-Letter et al., 1981). More recently it was observed that non-opioid peptides are also effective in inhibiting food intake when administered centrally (Table 4). On the other hand, opioid peptides and pancreatic polypeptides (neuropeptide Y and human pancreatic polypeptide) increase food intake and water intake after central administration (Table 5). Growth hormone-releasing factor (GRF) and calmodulin also stimulate food intake, as found recently (Vaccarino et al., 1985; Myers et al., 1983). Both groups of hormones, e.g. appetite stimulating and appetite inhibiting, act antagonistically at the same sites in the hypothalamus (paraventricular nucleus, ventromedial hypothalamus) (Morlay et al., 1985) (Fig. 8). Some feeding inhibitors also act in the lateral hypothalamus (bombesin, TRH, CCK-8). On the basis of all these data it is presumed that a delicate balance in production of these peptides and their cooperation with aminergic pathways (noradrenergic and serotonergic) in the brain is, eventually, responsible for the control of food intake (Morley and Levine, 1985; Hoebel, 1984) and consequently, for regulating the body weight. Depletion of serotonin in the brain induces hyperphagia and obesity. Activation of serotonergic pathways evokes anorexia (Breisch et al., 1976). It is difficult, however, to specify circumstances under which neuropeptides modulate eating behaviour of hibernators and the extent of their effect in comparison with other humeral factors involved.

L. JANSK~"

338

Table 4. Peptides that decrease feeding after central administration Peptide TRH (pGlu-His-ProNH2)

Somatostatin CRF

Bombesin

Neurotensin

A C T H (1 24) Calcitonin

Calcitonin generelated peptide Anorexigenic peptide Cholecystokinin

Insulin Insulin growth factor Glucagon Caerulein

Route of administration

Dose

Species

References

ICV ICV ICV VMH/LH ICV ICV ICV 1CV PVN ICV ICV ICV LH (bilateral) ICV ICV PVN ICV ICV ICV PVN ICV or VMH 1CV ICV ICV PVN

600 pmol 100,000 pmol 110,369 pmol 8000 pmol 3000 pmol 9768 pmol 150 pmol 214 pmol 107 pmol 62 pmol 62 pmol 154 pmol 3 pmol 0.5- I #g 0.1 M/,u g/kg 1494 pmol 1973 pmol 5997 pmol 10-20 # g 2.5-10 ,ug 4 l~g 12 pmol 0.1 pmol 30 pmol 4 pmol

rat rat rat rat rat rat rat rat rat rat rat rat rat rat baboon rat rat rat rat rat rat rat rat rat rat

Vijayan and McCann (1977) Morley and Levine ( t 980) Lin et al. (1983) Suzuki et al. (1982) Vijayan and McCann (1977) Aponte et al. (1984) Britton et al. (1982) Morley and Levine (1982) Krahn et al. (1984b) Morley and Levine (1981 a) Kulkosky et al. (1982) Avery and Calisher (1982) Stuckey and Gibbs (1982) de Caro el al. (1984) Figlewicz et al. (1986) Hoebel et al. (1980) kuttinger et al. ( 1981 } Levine et al. (1983) Hawkins (1986) Stanley et al. (1983) Vergoni et aL (1986) Freed et al. (1979) Levine and Morley ( 1981a) Twery et al. (1982) DeBeaurepaire and Feed (1983)

ICV ICV ICV (CCK-33) ICV PVN 1CV ICV LH (bilateral) PVN 4th ventricle ICV SCN ICV VMH ICV ICV ICV VMH

263 pmol 0.25-1.25 ,ug 0.10 IDU 875 pmol 131 pmol 218 pmol 800 pmol 80 pmol 28 pmol 87 pmol 0.1-10 nmol 0.8 pmol/h 50-100 ng

rat rat rat rat rat rat rat rat rat rat rat rat golden hamster

Krahn et aL (1984a) Myers et al. (1983) Maddison (1977) Nemeroff et al. (1978) McCaleb and Myers (1980) Levine and Morley (1981bl Telegdy et aL (1984) Willis et al. (1984) Faris et aL (1984) Ritter and Landenheim (1984) Schick et al. (1986) Mori et al. (1986) Miceli and Malsbury (1983) Hatfield et al. (1974) Brief and Davis (I 984) Tannenbaum et al. 0983) lnokuchi et al. (1984) Stern et al. (1976)

5 mU/day 106 Equlnsulin 1 pmol t8 pmol

rat rat rat rat

ICV--intraventricular. VMH--ventromedial hypothalamus. LH--lateral hypothalamus. PVN--paraventricular nucleus. SCN--suprachiasmatic nucleus. Table 5. Peptides that increase food intake after central administration Peptide Growth hormonereleasing factor fl-Endorphin Dynorphin Dynorphin A enkephalinamine D-Ala-2-met-5 H u m a n pancreatic po[ypeptide Neuropeptide Y

Calmodulin

Route of administration

Dose

Species

References

1CV VMH ICV

0.2-20 pmol 1.46 nmol 1 or l0 ,ug

rat rat rat

Vaccarino et al. (1985) Grandison and Guidotti (1977l Morley and Levine ( 1981 b)

PVN ICV

2-8 ,ug 10-20 nmol

rat rabbit

McLean and Hoebel (1983) Gosnell and Lipton (1986)

rat rat rat rat rat cat cat

Clark et al. (1984) Clark et aL (1984) Stanley and Leibowitz (1985) Stanley et al. (1985) Stanley et al. (1986) Lee and Myers (1984) Myers et al. (1983)

ICV ICV PVN PVN, LMH, LH PVN ICV 1CV

2 or 10 ,ug 2 or 10,ug 24-2351 pmol 78 pmol 235 pmol 2.5-10 ,ug 1.25 10 ng

Obligatory hibernators (ground squirrels, dormice, marmots) show marked seasonal changes in food intake. They exhibit a long period of hyperphagia prior to entering hibernation and become anorexic during hibernation season. This is reflected in

changes of their body weight (Fig. 9). Suggestions have been made that changes in feeding behaviour of hibernators can be induced by neuropeptides. Changes in concentration of bombesin, cholecystokinin, neurotensin and somatostatin in the brain at

Neuropeptides and the central regulation of body temperature during fever and hibernation

339

FEEDING INHIBITORS PARAVENTRICULAR NUCLEUS

FEEDING STIMULATORS PARAVENTRICULAR

NUCLEUS

Leibowitz ond Hot, 1962 Goenell et01.,1984 Goenell et o1., 1 9 8 4

B-ENDORPHIN OYNORPHIN NPY

McColeb ond Myero, 1 9 8 0

NEUROTENSlN CCK-8

Hoebel et~o/.,1982 F0ris e~oL, 1983

CALCITONIN

DeOeourepore ond Fceed, 1983

CRF

Krohn e t ol., 1984

VENTROMEOIAL HYPOTHALAMUS

PERIFORNICAL AREA O-ALA-2-MET-ENK

CCK-8

Stonl(

CAERULEIN

Stern ond Poge, 1977

TRH

Suzuki ecol., 1 9 8 3

VENTROMEDIAL HYPOTHALAMUS #-ENDORPHIN

Grondison ond G u i d o t t i , 1 9 7 7

LATERAL

D-ALA-D-LEU-ENK

Teppermon 0nd Hirst, 1983

BOMBESIN

HYPOTHALAMUS Stuckey end G i b b s , 1 9 8 2

NPY

Goenell etol.,198A

TRH

Suzuki e t 0/., 1 9 0 3

CCK-S

Willis et o/., 1 9 8 4

Fig. 8. Hypothalamic sites activating or inhibiting food intake during neuropeptide action (Morley et al., 1985). different seasons of the year coincide with seasonal changes in body mass (Muchlinski et al., 1983). While neurotensin levels seem to increase with the increase in body mass, concentrations of other peptides fall. In addition, there appears to be a correlation between the effect of peptides on control of food intake and on control of body temperature in normotherms. Opioid peptides, which increase food intake induce hyperthermia, while non-opioid peptides, which inhibit appetite, induce hypothermia. This correlation is not valid for all peptides, however. 300

200 o

/

HIBERNATION

=.

Effect on gonadal activity

100 I

A

m

E

I

I

I

I

I

I

i

I

I

I

I

I

I

I

I

I

II~

I

3

2

,\ l

I

v

o

6

4 oJ

2

V.

Under certain circumstances met-enkephalins, TRH and somatostatin may inhibit food intake and yet exhibit a hyperthermic effect. On the other hand, there is an obvious discrepancy between the observed effect of opioid substances on body temperature and food intake at one hand and hibernation on the other hand. Opioid substances usually induce hyperthermia and stimulation of food intake and, therefore, can hardly induce hypothermia and anorexia, which typically occur during hibernation. More data are needed to elucidate this problem.

Vl. VII. VIII. I X . X . X l . X l l . monfh

I.

II.

III.

IV.

Fig. 9. Scheme of seasonal changes in body weight, testes mass and testosterone production in obligatory hibernators (Jansk~, 1986a).

Hibernating animals also exhibit marked seasonal changes in gonadal activity and testosterone production (Fig. 9) Our data clearly show that hibernation can only occur in individuals with involuted gonads. Administration of testosterone prevents hibernation (Jansk~ et al., 1984; Jansk~, 1986a, b). Evidently, the absence of gonadal steroids is a necessary prerequisite for hypothalamic neurones to regulate body temperature differently than in normotherms. Gonadal activity of small mammals is regulated by changes in production of melatonin from the pineal. Melatonin acts on the preoptic, supraoptic and retrochiasmatic areas of the hypothalamus (Glass and Lynch, 1981) by lowering the production of luteinizing hormone releasing hormone (LHRH). Our data show an exclusive appearance of melatonin receptors in median eminence (VanG~ek and Jansk~, 1989) of golden hamsters. Due to lowered production of LHRH the production of gonadotropins from the pituitary decreases (Turek et al., 1979), which in turn, inhibits gonadal activity. Melatonin may also induce changes in the sensitivity of the hypothalamicpituitary axis to the negative effect of gonadal steroids (Sisk and Turek, 1982) and decrease sensitivity of gonadrotropin producing cells to LHRH (Martin et al., 1982). There is strong evidence that the secretion of gonadotropins and prolactin is modulated by opioid peptides originating in the brain. In the rat, opioid peptides lower the production of gonadotropins (Meites et al., 1979). On the other hand, prolaction levels increase after administration of endorphins

340

L. JANSK~'

(Rivier et al., 1977) and lowered production of LH and FSH induced by exposure to a short photoperiod can be prevented by the injections of an opioid antagonist-naloxone (Chen et al., 1984). Opiates also lower sensitivity of the hypothalamic-pituitary axis to testosterone feedback (Cicero et al., 1979) and may stimulate release of melatonin from the pineal (Nir, 1984). Neuropeptides may influence gonadal activity by modulating activity of aminergic pathways. According to some reports activation of serotonergic pathways lowers production of gonadotropins (Schneider and McCann, 1970). Dopamine was found to be identical with prolactin inhibitory factor (Brown et al., 1976). A clear correlation between changes in gonadal activity and production of neuropeptides in hibernators has not been established, however.

WARM

COLD

J, ÷ 'P ' ~

÷ *

~ excl~tory action~ • "prlmaryJpyrogen}

WARM

"

"

~

~"

~

~/ H E A T l O S S

go,o WARM

4- *

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-

~

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Neuropeptides, acting on structures within the central nervous system influence body temperature. Non-opioid peptides, when injected intracerebroventricularly or intrahypothalamically, induce hypothermia usually, while opioid peptides are mostly hyperthermic. Some peptides may induce both hyperor hypothermia, depending on experimental conditions and on species used. Neuropeptides exert their effect only when injected into specific brain areas. Bombesin is effective in the anterior hypothalamus, but not in the posterior hypothalamus, arginine vasopressin acts in septal areas. Hypo- or hyperthermic effects of neuropeptides may be either due to changes in threshold body temperatures for induction of thermoregulatory effectors or due to changes in hypothalamic thermosensitivity. Neurotensin and some other substances (dopamine, prostaglandins) induce a shift of the temperature threshold for induction of thermoregulatory effectors (cold thermogenesis, peripheral vasomotor tone, panting) upwards, without changing the hypothalamic thermosensitivity. Other peptides, namely ACTH and substances released during the late phase of the fever, induce dissociation of thresholds for cold and warm defence. Bombesin, shifts the temperature thresholds downwards and lowers hypothalamic thermosensitivity. At the cellular level the opioid peptides act differently than the non-opioid peptides. The opioid peptides mostly inhibit spontaneous neuronal firing, while the non-opioid peptides usually stimulate it. Neuropeptides exert their influence on all neurones in the hypothalamus, independently of their temperature characteristics. Neuropeptides also influence the thermosensitivity of individual neurones. Neuropeptide may play a role in regulation body temperature under stressful conditions and during fever or hibernation, in particular. Some neuropeptides, namely AVP, ~-MSH and ACTH, act as natural antipyretic substances by lowering the threshold for cold thermogenesis. On the basis of the available evidence it is tempting to speculate about sites of neuropeptide action within neural pathways participating in regulation of thermal homeostasis during fever.

HEAT PRODUCTION

f f inhibitory ~lction ~ o f • " s e c o n d o r y " egenk~

COLD CONCLUSIONS

H E A T LOSS

-----~

| • ~prlm•ry ~ pyro~lenJ

-

~

-

•

H E A T LOSS

•

HEAT PRODUCTION

"

fsupo,-Imposml Ktion~ ~|

• " ....

dary- ~len~

Fig. 10. Scheme of possible action of pyrogenic agents during the early (A) and the late phase of endotoxin fever (B or C) on neural pathways participating in body temperature control. An additional excitatory input at cold sensors or at a synapse from the cold sensor to the heat production pathway before the point of origin of crossing inhibition upon the drive to the heat loss pathway, could be expected to cause an elevation of the threshold temperatures for both heat production and heat loss effector mechanisms, as it occurs in the first phase of the endotoxin induced fever [Fig. 10(A)]. In the second phase of the fever the downward shift of the threshold for cold thermogenesis could be either due to cessation of the action of the primary pyrogen and its replacement with another one acting elsewhere on the neural pathways or due a second factor acting additionally to the primary pyrogen. If this is replacement, then it seems necessary to hypothesize the imposition of another inhibitory influence on the heat loss pathway to keep the threshold temperature for heat loss mechanisms elevated and an inhibitory influence on the heat production effector pathway to bring the heat production threshold temperature to below that in the apyretic state [Fig. 10(B)]. If there is addition of action of a second pyrogenic factor, with the continued action of the first one, then it is necessary to hypothesize the addition of an inhibitory influence on the heat production effector pathway behind the point of origin of crossing inhibition, since the continuing action of the primary pyrogen would sustain the inhibitory influence on the heat loss pathway and the added inhibition of the heat production pathway could over-ride the continuing excitatory influence of the primary pyrogen. [Fig. 10(C)]. An important aspect of this concept is the possible generality of the crossing neural inhibition within the central nervous system. Such crossing inhibition must induce massive interactions between neural pathways by which means the integrative role of the central nervous system is achieved. The massive interaction between pathways carries the inevitable consequence

Neuropeptides and the central regulation of body temperature during fever and hibernation that any action effects m a n y other concurrent actions, while it is being affected by m a n y other concurrent actions. It is known that neither fever nor hibernation are isolated phenomena, but involve the integrated modifications to many aspects of the physiology of the organism. Thus it is not surprising that the experimental modulation of synaptic events in the thermoregulatory "centre" exerts influences on many other functions, to a greater or lesser degree. Similarly, afebrile thermoregulation is effected by, and effects other homeostatic functions. At the same time, however, since it is highly likely that the same transmitter and modulator substances are employed in the central neurology of m a n y bodily functions, concurrent consequence of centrally-injected substances could be due, in part at least, to multiple sites of action of these substances. In addition to thermoregulation, neuropeptides also modulate food intake, reproduction and many other functions, which are substantially changed during hibernation. Appetite stimulating and appetite inhibiting neuropeptides act antagonistically at the paraventricular and the ventromedial hypothalamus. There appears to be a correlation between the effect of peptides on control of food intake and on control of body temperature. Opioid peptides, which increase food intake, induce hyperthermia, while nonopioid peptides, which are appetite inhibiting, induce hypothermia. This correlation is not valid for all peptides, however. The exact role of neuropeptides in the regulation of body temperature, food intake and gonadal activity of hibernators remains unclear. Neither is there enough evidence to specify conditions under which neuropeptides come into play in normotherms. Nevertheless, central administration of neuropeptides represents a useful method for tracing neural pathways participating in regulation of different physiological functions. REFERENCES

Adler M. W. (1980) Opioid peptides. Life Sci. 26, 497-510. Aponte G., Leung P., Gross D. and Yamada T. (1984) Effects of somatostatin on food intake in rats. Life Sci. 35, 741-746. Avery D. D. and Calisher S. B. (1982) The effects of injections of bombesin into the cerebral ventricles on food intake and body temperature in food-deprived rats. Neuropharmacology 21, 1059-1063. Baldino F. Jr and Wolfson B. (1985) Postsynaptic action of neurotensin on POAH neurons in vitro. Brain Res. 325, 161-170. Baldino F., Beckman A. L. and Adler M. W. (1980) Actions of iontophoretically applied morphine on hypothalamic thermosensitive units. Brain Res. 196, 199-208. Beckman A. L. and Eisenman J. S. (1970) Microelectrophoresis of biogenic amines on hypothalamic thermosensitive cells. Science 170, 334-336. Beckman A. L. and Llados-Eckman C. (1985) Antagonism of brain opioid peptide action reduces hibernation bout duration. Brain Res. 328, 201-205. Beckman A. L., Dean R. R. and Wamsley J. K. (1986) Hippocampal and cortical opioid receptor binding: changes related to the hibernation state. Brain Res. 386, 223-231.

341

Beckman A. L., Llados-Eckman C., Stanton T. L. and Adler M. W. (1981) Physical dependence on morphine fails to develop during the hibernating state. Science 212, 1527-1529. Bernardini G. L., Lipton J. M. and Clark W. G. (1983) Intracerebroventricular and scptal injections of arginine vasopressin are not antipyretic in the rabbit. Peptides 4, 195-198. Bissette G., Nemeroff C. B., Loosen P. T., Prange A. J. Jr and Lipton M. A. (1976) Hypothermia and cold intolerance induced by the intracisternal administration of the hypothalamic peptide neurotensin. Nature 262, 607~09. Bjoro T., Torjesen P. A., Ostberg B. C., Sand O., Iversen J.-G., Gautvik K. M. and Haug R. (1987) Bombesin stimulates prolaktin secretion from cultured rat pituitary tumor cells (GH4CI) via activation of phospholipase C. Reg. Peptides 19, 169-182. Bligh J., Cottle W. H. and Maskrey M. (1971) Influence of ambient temperature on the thermoregulatory responses to 5-hydroxytryptamine, noradrenaline and acetylcholine injected into the lateral cerebral ventricles of sheep, goats and rabbits. J. Physiol., Lond. 212, 377-392. Bloom A. S. and Tseng L.-F. (1981) Effects of/~-endorphin on body temperature in mice at different ambient temperatures. Peptides 2, 293-297. Boden P. and Hill R. G. (1988) Effects of cholecystokinin and related peptides on neuronal activity in the ventromedial nucleus of the rat hypothalamus. Br. J. Pharmac. 94, 246--252. Boschi G. and Rips R. (1981) Effects of thyrotropin releasing hormone injections into different loci of rat brain on core temperature. Neurosci. Lett. 23, 93-98. Bo~tlk J., Jansk~, L. and Li~kov:i Z. (1982) The role of adrenal steroids and ACTH in cold thermogenesis. Physiol. Bohemoslov. 31, 256--257. Boulant J. A. and Scott I. M. (1983) Effects of leukocytic pyrogen on hypothalamic neurons in tissue slices. In Environment, Drugs" and Thermoregulation (Edited by Lomax P. and SchSnbaum E.), pp. 125-127. Karger, Basel. Boulant J. A. and Scott I. M. (1986) Comparison of prostaglandin E2 and leukocytic pyrogen on hypothalamic neurons in tissue slices. In Homeostasis and Thermal Stress (Edited by Cooper K. E., Lomax P., SchSnbaum E. and Veale W. L.), pp. 78-80. Karger, Basel, Breisch S. T., Zemlan F. P. and Hoebel B. G. (1976) Hyperphagia and obesity following serotonin depletion by intraventricular p-chlorophenylalanine. Science 192, 382-385. Brief D. J. and Davis J. D. (1984) Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res. Bull. 12, 571-575. Britton D., Koop G., Rivier J. and Vale W. (1982) Intraventricular corticotropin-releasing factor enhances behavioral effects of novelty. Life Sci. 31, 363-367. Broccardo M., Falconieri G., Erspamer V., Melchiorri P., Negri L. and de Castilogne, R. (1975) Relative potency of bombesin-like peptide. Br. J~ Pharmac. 55, 221-227. Brown G., Seeman P. and Lee T. (1976) Dopamine/ neuroleptic receptors in basal hypothalamus and pituitary. Endocrinology 99, 1407-1410. Brown K. D., Blakeley D. M., Hamon M. H., Laurie M. St and Corps A. N. (1987) Protein kinase C-mediated negative-feedback inhibition of unstimulated and bombesinstimulated polyphosphoinositide hydrolysis in swissmouse 3T3 cells. Biochem. J. 245, 631-639. Brown M., Ling N. and Rivier J. (1981) Somatostatin-28, somatostatin-14 and somatostatin analogs: effects on thermoregulation. Brain Res. 214, 127-135. Brown M., Rivier J. and Vale W. (1977) Actions of bombesin, thyrotropin releasing factor, prostaglandin E 2 and naloxone on thermoregulation in the rat. Life Sci. 20, 1681-1688.

342

L. JANSKq

Bunney B. S., Grace A. A., Hommer D. W. and Skirboll (1982) Effect of cholecystokinin of the activity of midbrain dopaminergic neurons. In Regulatory Peptides: From Molecular Biology to Function (Edited by Costa E. and Trabucchi M.), pp. 429-436. Raven Press, New York. Cabanac M., Stolwijk J. A. J. and Hardy J. D. (1968) Effect of temperature and pyrogens on single-unit activity in the rabbit's brainstem. J. appl. Physiol. 24, 645~i51. Carino M. A., Smith J. R., Weick B. G. and Horita A. (1976) Effects of thyrothropin-reteasing hormone (TRH) micro-injected into various brain areas of conscious and pentobarbital-pretreated rabbits. Life Sci. 16, 1692. Chandra A., Chou H. C., Chang C. and Lin M. T. (1981) Effects of intraventricular administration of neurotensin and somatostatin on thermoregulation in the rat. Neuropharmacology 20, 715 718. Chen H. J., Targovik J., McMillan L. and Randall S. (1984) Age difference in endogenous opiate modulation of short photoperiod-induced testicular regression in golden hamsters. J. Endocr. 101, 1-6. Cicero T. J., Schainker B. A. and Meyer E. R. (1979) Endogenous opioids participate in the regulation of the hypothalamic-pituitary-luteinizing hormone axis and testosterone's negative feedback control of luteinizing hormone. Endocrinology 104, 1286--1291. Clark J. J.. Kalra P. S., Crowley W. G. and Kalra S. P. (1984) Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115, 427 -429. Clark W. G. (1977) Emetic and hyperthermic effects of centrally injected methionine-enkephalin in cats. Proc. soc. exp. Biol. Med. 154, 540-542. Clark W. G. and Bernardini G. L. (1981) /~-Endorphininduced hyperthermia in the cat. Peptides 2, 371-373. Clark W. G., Bernardini G. L. and Ponder S. W. (1982) Extreme hyperthermia induced in cats by the enkephalin analog FK33-824. Pharmac. Biochem. Behav. 16, 989 993. Cohn M. J., Cohn M. and Taube D. (1980) Thyrotropin releasing hormone induced hyperthermia in the rat inhibited by lysine acetylsalicylate and indomethacin. In Thermoregulatory Mechanisms and Their Therapeutic Implications (Edited by Cox B., Lomax P., Milton A. S. and Schrnbaum), pp. 198-201. Karger, Basel. Cooper K. E., Maylor A. M. and Veale W. L. (1987) Evidence supporting a role for endogenous vasopressin in fever suppression in the rat. J. Physiol., Lond. 387, 163-172. Cooper K. E., Kasting N. W., Lederis K. and Veale W. L. (1979) Evidence supporting a role for endogenous vasopressin in natural suppression of fever in the sheep. J. Physiol.. Lond. 295, 33-45. Dawe A. R. and Spurrier W. A. (1969) Hibernation induced in ground squirrels by blood transfusion. Science 163, 298 299. Debeaurepaire R. and Freed W. J. (1983) Anorectic effect of calcitonin: localization to the paraventricular nucleus of the hypothalamus. Soc. Neurosci. Abstr. 9, 188. De Caro G., Massi M., Micossi L. G. and Perfumi M. (1984) Drinking and feeding inhibition by ICV pulse injection or infusion of bombesin, ranatensin and litorin to rats. Peptides 5, 607~513. Dodd J. and Kelly J. S. (1981) The actions of cholecystokinin and related peptides on pyramidal activity neurones of the mammalian hippocampus. Brain Res. 205, 337-350. Ehymayed H. M. and Jansk~, L. (1990) The mode of AVP antipyretic action. Physiol. Bohemoslov. In press. Eisenman J. S. (1968) Pyrogen induced changes in the thermosensitivity of septal and preoptic neurons. Am. J. Physiol. 216, 330 334. Erne D. and Schwyer R. (1987) Membrane structure of bombesin studied by infrared spectroscopy. Prediction

of membrane interactions of gastrin-releasing peptide, neuromedin B, and neuromedin C. Biochemistry 26, 631645319. Fargeas M. J., Fioramonti J. and Bueno L. (1985) Central actions of calcitonin on body temperature and intestinal motility in rats: evidence for different mediations. Reg. Pept. 11, 95-103. Faris P. L., Scallet A. C., Olney J. W., Della-fera M. A. and Baile C. A. (1984) Behavioral and immunohistochemical analysis of cholecystokinin in the hypothalamic paraventricular nucleus. Soc. Neurosci. Abstr. 10, 652. Ferri S., Arrigo Reina R., Santagostino A., Scoto G. M. and Spadaro C. (1978) Effects of met-enkephalin on body temperature of normal and morphine-tolerant rats. Psychopharmacology 58, 227-281. Figlewicz D. P., Sipols A., Porte D. Jr and Woods S. C. (1986) Intraventricular bombesin can decrease single meal size in the baboon. Brain Res. Bull. 17, 535 537. Ford D. M. (1974) A selective action of prostaglandin E~ on hypothalamic neurons in the cat which respond to brain cooling. J. Physiol., Lond. 242, 142-143. Francesconi R. and Mager M. (1981) Thermoregulatory effect of centrally administered bombesin, bradykinin, and methionine-enkephalin. Brain Res. Bull. 7, 63~8. Freed W. J., Perlow M. J. and Wyatt R. D. (1979) Calcitonin: inhibitory effect on eating in rats. Science 206, 850-852. Gibbs J., Young R. C. and Smith G. P. (1973a) Cholecystokinin decreases food intake in rats. J. comp. Physiol. Psychol. 84, 488-495. Gibbs J., Young R. C. and Smith G. P. (1973b) Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245, 323-325. Gibbs J., Fauser D. J., Rowe E. A., Rolls B. J., Rolls E. T. and Madison S. P. (1979) Bombesin suppresses feeding in rats. Nature 282, 208-210. Glass J. D. and Lynch G. R. (1981) Melatonin: identification of sites of antigonadal action in mouse brain. Science 214, 821-823. Glyn J. R. and Lipton J. M. (1981) Hypothermic and antipyretic effects of centrally administered ACTH (1-24) and ~-melanotropin. Peptides 2, 177 187. Glyn-Ballinger J. R., Bernardini G. L. and Lipton J. M. (1983) ~-MSH injected into the septal region reduces fever in rabbits. Peptides 4, 199-203. Gordon C. J. and Heath J. E. (1980) Effects of prostaglandin E on the activity of thermosensitive and insensitive single units in the preoptic/anterior hypothalamus of unanesthetized rabbits. Brain Res. 183, 113-12l. Gordon C. J. and Heath J. E. (1981) Effect of monoamines on firing rate and thermal sensitivity of neurons in the preoptic area of awake rabbits. Exp. Neurol. 72, 352 365. Gosnell B. A. and Lipton J. M. (1986) Opioid peptide effects on feedings in rabbits. Peptides 7, 745-747. Grandison L. and Guidotti (1977) Stimulation of food intake by muscimol and beta endorphin. Neuropharmacology 16, 533-536. Hashimoto M., Nagai M. and Iriki M. (1985) Comparison of the action of prostaglandin with endotoxin on thermoregulatory responses thresholds. Pflfigers Archs 405, 1-4. Hatfield J. S., Millard J. and Smith C. J. V. (1974) Short-term influence of intra-ventromedial hypothalamic administration of insulin on feeding in normal and diabetic rats. Pharmac. Biochem. Behav. 2, 223 226. Hawkins M. F. (1986) Aphagia in the rat following microinjection of neurotensin into the ventral tegmental area. Life Sci. 38, 2383-2388. Hench P. S., Kendal E. C., Slocumb C. H. and Policy H. F. (1949) The effect of a hormone of the adrenal cortex (17-hydroxy-1 l-dehydrocorticosterone: compound E) and pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc. Staff Meet. Mayo Clin. 24, 181-197.

Neuropeptides and the central regulation of body temperature during fever and hibernation Hoebel B. G. (1984) Neurotransmitters in the control of feeding and its rewards: monoamines, opiates, and brain gut peptides. In Eating and Its Disorders (Edited by Stunkard N. I. and Stellat B.), pp, 15-38. Raven Press, New York. Hoebel B. G., Hernandez L., McLean S. and Stanley B. C. (1980) Catecholamines, enkephalin and neurotensin in feeding and reward. In The Neural Basis of Feeding and Reward (Edited by Hoebel B. G. and Novin D.), pp. 465-478. The Haer Institute, Brunswick, Maine. Hoebel B. G., Hernandez L., McLean S., Stanley B. G., Aulissi E. F., Glimcher P. and Margolin D. (1982) Catecholamines, enkephalin and neurotensin in feeding and reward. In The Neural Basis of Feeding and Reward (Edited by Hoebel B. G. and Novin D.), pp. 465-478. Haer Institute, Brunswick, Maine. Holaday J. W., Loh H. H. and Li C. H. (1978a) Unique behavioral effects of fl-endorphin and their relationship to thermoregulation and hypothalamic function. Life Sci. 22, 1525-1535. Holaday J. W., Tseng L.-F., Loh H. H. and Li C. H. (1978b) Thyrotropin releasing hormone antagonizes fl-endorphin hypothermia and catalepsy. Life Sci. 22, 1537-1543. Hori T. and Nakayama T. (1973) Effects of biogenic amines on central thermoresponsive neurons in the rabbit. J. Physiol., Lond. 232, 71-85. Hori T., Nakashima T., Kiyohoara T. and Shibata M. (1984) Effects of leukocytic pyrogen and sodium salicylate on hypothalamic thermosensitive neurons in vitro. Neurosci. Lett. 49, 313-318. Hori T., Yamasaki M., Kiyohara T. and Shibata M. (1986) Responses of preoptic thermosensitive neurons to poikilothermia-inducing peptides--bombesin and neurotensin. Pfliigers Archs 407, 558-560. Hori T., Shibata M., Nakashima T., Yamasaki M., Asami A., Asami T. and Koga H. (1988) Effects of interleukin-1 and arachidonate on the preoptic and anterior hypothalamic neurons. Brain Res. Bull. 20, 75-82. Horita A. and Carino M. A. (1976) Thyrotropin releasing hormone-induced hyperthermia and arousal in the rabbit. In Drugs, Biogenic Amines and Body Temperature (Edited by Cooper K. E., Lomax P. and Seh6nbaum), pp. 66-74. Karger, Basel. Huang B.-S., Kluger M. J. and Malvin R. L. (1985) Thermal responses to central angiotensin II, SQ 20881, and dopamine infusions in sheep. Am. J. Physiol. 2411, R371-R377. Huidobro-Toro J. P., Anderson H. H. and Way E. L. (1979) Pharmacological characterization of the hyperthermia produced by fl-endorphin in mice. Fed. Proc. 38, 364. Inokuchi A., Oomura Y. and Nishimura H. (1984) Effect of intracerebroventricularly infused glucagon on feeding behavior. Physiol. Behav. 33, 397-400. Inomoto T., Mercer J. B. and Simon E. (1982) Opposing effects of hypothalamic cooling on threshold and sensitivity of metabolic response to body cooling in rabbits. J. Physiol., Lond. 322, 139-150. Iriki M., Hashimoto M. and Riedel W. (1984) Threshold dissociations of thermoregulatory effector responses in febrile rabbits in warm environments. In Thermal Physiology (Edited by Hales J. R. S.), pp. 535-537. Raven Press, New York. Isacke C. M., Meisenhelder J., Brown K. D., Gould K. L., Gould St. J. and Hunter T. (1986) Early phosphorylation events following the treatment of Swiss 3T3 cells with bombesin and the mammalian bombesin-related peptide, gastrin-releasing peptide. EMBO J. 5, 2889-2898. Itoh S. and Hirata R. (1982) Effect of intraventricular administration of vasoaetive intestinal polypeptide on body temperature in the rat. Jap. J. Physiol. 32, 677-681. Jansk~ L. (1986a) Pineal, gonads, and hibernation. In Pineal Research Reviews (Edited by Reiter R. J.), pp. 141-181. Liss, New York.

343

Jansk~, L. (1986b) Gonads and hibernation. In Living in the Cold: Physiological and Biochemical Adaptations (Edited by Heller H. C. et al.), pp. 331-340. Elsevier, New York. Jansk~' L., Haddad G., Kahlerov~. Z. and Nedoma J. (1984a) Effect of external factors on hibernation of golden hamsters. J. comp. Physiol. 154B, 427-433. Jansk# L., Andrews J. F., Simon E., Riedel W. and Simon-Oppermann Ch. (1984b) Role of humoral substances in the control of body temperature during hibernation. In Thermal Physiology (Edited by Hales J. R. S.), pp. 441-446. Raven Press, New York. Jansk# L., Riedel W., Simon E., Simon-Oppermann C. and Vybiral S. (1987) Effect of bombesin on thermoregulation of the rabbit. Pfliigers Archs 409, 318-322. Jansk~ L., Vybiral S., Moravec J., Nachfizel J,, Riedel W., Simon E. and Simon-oppermann C. (1986) Neuropeptides and temperature regulation. J. therm. Biol. I1, 79-83. Jell R. M. and P. Sweatman (1977) Prostaglandin-sensitive neurones in cat hypothalamus: relation to thermoregulation and to biogenic amines. Can. J. Physiol. Pharmac. 55, 560-567. Jolicoeur F. B., St-Pierre S., Aube C., Rivest R. and Gagn6 M. A. (1984) Relationships between structure and duration of neurotensin's central action: emergences of long acting analogs. Neuropeptides 4, 467-476. Kalivas P. W., Hernandez D. E., Bissette G., Mason G. A., Nemeroff C. B. and Prange A. J. Jr (1983) Neurotensin induced hypothermia: neuroanatomical and neurochemical mechanisms. In Environment, Drugs and Thermoregulation (Edited by Lomax P. and Sch6nbaum E.), pp. 108-112. Karger, Basel. Kandasamy S. B. and Williams B. A. (1983) Peptide and non-peptide opioid-induced hyperthermia in rabbits. Brain Res. 265, 63-71. Kass E. H. and Finland M. (1950) Effect of ACTH on induced fever. N. Engl. J. Med. 243, 693-695. Kasting N. W. (1986) Characteristics of body temperature, vasopressin, and oxytoxin responses to endotoxin in the rat. Can. J. Physiol. Pharm. 64, 1575-1578. Kasting N. W. and Wilkinson M. F. (1986) An antagonist to the antipyretic effects of intracerebroventricularly administered vasopressin in the rat. In Homeostasis and Thermal Stress (Edited by Cooper K. E., Lomax P. and Sch6nbaum E.), pp. 137-139. Karger, Basel. Kasting N. W., Cooper K. E. and Veale W. L. (1979) Antipyresis following perfusion of brain sties with vasopressin. Experientia 35, 208-209. Katsuura G. and Itoh S. (1981) Effects of cholecystokinin octapeptide on body temperature in the rat. Jap. J. Physiol. 31, 849-858. Kiohara T., Hori T., Shibata M. and Nakashima T. (1984) Effects of angiotensin II on preoptic thermosensitive neurones in the rat. In Thermal Physiology (Edited by Hales J. R. S.), pp. 141-144. Raven Press, New York. Konecka A. M., Sadowski B., Jaszczak J., Panocko I., Sroczynska I. and Misicka A. (1982) The effect of intracerebroventricular infusion of morphine, methionineenkephalin and D-Ala2-Met-enkephalinamide on body temperature of rabbits. Archs Int. Physiol. Biochim. 911, 1-7. Kovaes G. L. and DeWied D. (1983) Hormonally active vasopressin suppresses endotoxin-induced fever in rats. Lack of effect of oxytocin and a behaviorally active vasopressin fragment. Neuroendocrinology 37, 258-261. Kow L.-M. and Pfaff D. W. (1986a) CCK-8 stimulation of ventromedial hypothalamic neurons in vitro: a feelingrelevant event? Peptides 7, 473-479. Kow L.-M. and Pfaff D. W. (1986b) Vasopressin excites ventro-medial hypothalamic glucose-responsive neurons in vitro. Physiol. Behav. 37, 153-158. Krahn D. D., Gosnell B. A., Levine A. S. and Morley J. E. (1984a) Effects of calcitonin gene-related peptide on food intake. Peptides 5, 861-864.

344

L. JANSKY

Krahn D. D., Gosnell B. A., Levine A. S. and Morley J. E. (1984b) Localization of the effects of corticotropin releasing factor on feeding. Soc. Neurosci. Abstr. 10, 302. Kramarova L. I., Kolaeva S. H., Yukhananov R. Y. and Rozhanets V. V. (1984) Content of DSIP, enkephalins and ACTH in some tissues of active and hibernating ground squirrels (Citellus suslicus). Comp. Biochem. Physiol. 74C, 31-33. Kromer W. (1980) Naltrexone influence on hibernation. Experientia 36, 581-582. Kruk Z. L. and Brittain R. T. (1972) Changes in body core and skin temperature following intracerebroventricular injection of substances in the conscious rat: interpretation of data. J. Pharrn. Pharmac. 24, 835-837. Kulkosky P. J., Gibbs J. and Smith G. P. (1982) Behavioral effects of bombesin administration in rats. Physiol. Behav. 2,8, 502-512. Kulpa C. M., Mammajiwalla S. N., Christman L. M., Beebe J. A. and Hall K. D. (1986) Persistence of weight gain and hibernation onset in juvenile thirteen-lined ground squirrels (Spermophilus tridecemlineatus) in spite of long-term administration of naloxone. Comp. Biochem. Physiol. g5C, 363-367. Lahti H., Koskinen M., Py6rnil/i A. and Hissa R. (1983) Hyperthermia after intrahypothalamic injections of thyrotropin releasing hormone (TRH) in the pigeon. Experimentia 39, 1338-1340. Lee T. F. and Myers R. D. (1983) Analysis of the thermolytic action of ICV neurotensin in the rat at different ambient temperatures. Brain Res. Bull. 10, 661~65. Lee T. F. and Myers R. D. (1984) Calmodulin-induced feeding in the satiated cat: Evidence for involvement of calcium and norepinephrine in the brain. Brain Res. Bull. 12, 71 76. Lee T. F., Mora F. and Myers R. D. (1985) Effect of intracerebroventricular vasopressin on body temperature and endotoxin fever of macaque monkey. Am. J. Physiol. 248, R674-R678. Levine A. S. and Morley J. E. (1981a) Reduction of feeding in rats by calcitonin. Brain Res. 222, 187-191. Levine A. S. and Morley J. E. (1981b) Cholecystokinin octapeptide suppresses stress-induced eating by inducing hyperglycemia. Reg. Pept. 2, 353-357. Levine A. S., Kneip J., Grace M. and Morley J. E. (1983) Effect of centrally administered neurotensin on multiple feeding paradigms. Pharmac. Biochem. Behav. 18, 19-23. Lin M. T. (1980) Effects of angiotensin II on metabolic, respiratory and vasomotor activities as well as body temperatures in the rabbit. J. Neural Trans. 49, 197-209. Lin K. S. and Lin M. T. (1986) Effect of bombesin on thermoregulatory responses and hypothalamic neuronal activites in the rat. Am. J. Physiol. 251, R303-R309. Lin M. T., Chandra A. and Jou J. J. (1980) Angiotensin II inhibits both heat production and heat loss mechanisms in rat. Can. J. Physiol. Pharmac. 58, 909-914. Lin M. T., Chu P. C. and Leu S. Y. (1983) Effects of TSH, TRH LH and LHRH on thermoregulation and food and water intake in the rat. Neuroendocrinology 37, 206-211. Lin M. T., Uang W. N. and Ho L. T. (1990) Hypothalamic somatostatin may mediate endotoxin-induced fever in the rat. Naunyn-Schmiedeberg's Archs Pharmac. In press. Lipton J. M. and Glyn J. R. (1980) Central administration of peptides alters thermoregulation in the rabbit. Peptides 1, 15-18. Lipton J. M. and Murphy M. T. (1983) Aging enhances the antipyretic effect of ct-MSH and the hyperthermic effect of central fl-endorphin. In Environment, Drugs and Thermoregulation (Edited by Lomax P. and Sch6nbaum E.), pp. 104-I07. Karger, Basel. Lipton J. M., Glyn J. R. and Zimmer J. A. (1981) ACTH and ct-melanotropin in central temperature control. Fed. Proc. 40, 2760-2764.

Lipton J. M., Glyn-Ballinger J. R., Murphy M. T., Zimmer J. A., Bernardini G. and Samson W. K. (1984) The central neuropeptides ACTH and ~-MSH in fever control. J. therm. Biol. 9, 139-143. Liu H. J. and Lin M. T. (1985) Cholecystokinin-induced hypothermia: possible involvement of serotonergic mechanisms in the rat hypothalamus. Pharmacology 31, 108-114. Loosen P. T., Nemeroff C. B., Bissette G., Burnett G. B., Prange A. J., Jr and Lipton M. A. (1978) Neurotensininduced hypothermia in the rat: structure-activity studies. Neuropharmacology 17, 109-113. Lotter E. C., Krinsky R., McKay J. M., Treneer C. M., Porte D. Jr and Woods S. C. (1981) Somatostatin decreases food intake of rats and babboons. J. comp. Physiol. Psychol. 95, 278-287. Luttinger D., King R. A., Shippard D., Strup J., Nemeroff C. B. and Prange A. J. Jr (1981) The effect of neurotensin on food consumption in the rat. Eur. J. Pharmac. 81, 699-703. Maddison S. (1977) Intraperitoneal and intracranial cholecystokinin depress operant responding for food. Ph.vsiol. Behav. 19, 819-824. Malaisse-Lagae F., Carpentier J. L., Patel Y. C., Malaisse W. J. and Orci L. (1977) Pancreatic polypeptide: a possible role in the regulation of food intake in the mouse. Hypothesis. Experientia 33, 915-918. Malkinson T. J., Bridges T. E., Lederis K. and Veale W. L. (1987) Perfusion of the septum of the rabbit with vasopressin antiserum enhances endotoxin fever. Peptides 8, 385-389. Margules D. U, Goldman B. and Finck A. (1977) Hibernation: an opioid-dependent state? Brain Res. Bull. 4, 721-724. Martin G. E. and Bacino C. B. (1979) Action of intracerebrally injected fl-endorphin on the rat's core temperature. Eur. J. Pharmac. 59, 227-236. Martin J. E., McKeel D W. Jr and Sattler C. (1982) Melatonin directly inhibits rat gonadotroph cells. Endocrinology 110, 1079-1084. Martin J. R. and Novin D. (1977) Decreased feeding in rats following hepatic-portal infusion of glucagon. Physiol. Behav. 19, 461-466. McCaleb M. L. and Myers R. D. (1980) Cholecystokinin acts on the hypothalamic "noradrenergic system" involved in feeding. Peptides I, 47-49. McLean S. and Hoebel B. G. (1983) Feeding induced by opiates injected into the paraventricular hypothalamus. Peptides 4, 287-292. Mason G. A., Nemeroff C. B., Luttinger D., Hatley O. L. and Prange A. J. Jr (1980) Neurotensin and bombesin: differential effects on body temperature of mice after intracisternal administration. Reg. Pept. I, 53~0. Mason G. A., Hernandez D. E., Nemeroff C. B., Adcock J. W., Hatley O. L. and Prange A. J. Jr (1982) Interaction of neurotensin with prostaglandin E 2 and prostaglandin synthesis inhibitors: effects on colonic temperature in mice. Reg. Pept. 4, 285 292. Meites J., Bruni J. F., Van Vugh D. A. and Smith A. F. (1979) Relation of endogenous opioid peptides and morphine to neuroendocrine functions. Life Sci. 24, 1325-1336. Mendoza St. S., Schneider J. A., Lopez-Rivas A., SinnettSmith J. W. and Rozengurt E. M. (1986) Early events elicited by bombesin and structurally related peptides in quiescent swiss 3T3 cells--I. Changes in Na + and Ca 2+ fluxes, Na+/K + pump activity, and intracellular pH. J. Cell Biol. 102, 2223-2233. Metcalf G. (1974) TRH: a possible mediator of thermoregulation. Nature 252, 310-311. Metcalf G. and Myers R. D. (1975) Investigations concerning TRH-induced hypotherrnia in cats. Br. J. Pharmac. 55, 273P-274P.

Neuropeptides and the central regulation of body temperature during fever and hibernation Metcalf G., Dettmar P. W. and Watson T. (1980) The role of neuropeptides in thermoregulation. In Thermoregulatory Mechanisms and Their Therapeutic Implications (Edited by Cox B., Lomax P., Milton A. S. and Sch6nbaum E.), pp. 175-179. Karger, Basel. Miceli M. O. and Malsbuty C. W. (1983) Feeding and drinking responses in the golden hamster following treatment with cholecystokinin and angiotensin II. Peptides 4, 103-106. Miller R. (1984) How do opiates act? Trends Neurosci. 184-185. Moody T. W., Murphy A., Mahmoud S. and Fiskum G. (1987) Bobesin-like peptides elevate cytosolic calcium in small lung cancer cells. Biochem. biophys. Res. Commun. 147, 189-195. Mori T., Nagai K., Nakagawa H. and Yanaihara N. (1986) Intracranial infusion of CCK-8 derivates suppresses food intake in rats. Am. J. Physiol. 251, RT18-R723. Morimoto A., Murakami N. and Watanabe T. (1988) Effect of prostaglandin E2 on thermoresponsive neurones in the preoptic and ventromedial hypothalamic regions of rats. J. Physiol., Lond. 405, 713-725. Morley J. E. and Levine A. S. (1980) Thyrotropin releasing (TRH) suppresses stress induced eating. Life Sci. 27, 269-274. Morley J. E. and Levine A. S. (1981a) Bombesin inhibits stress-induced eating. Pharm. Biochem. Behav. 14, 149-151. Morley J. E. and Levine A. S. (1981b) Dynorphin-(1-13) induces spontaneous feeding in rats. Life Sci. 29, 1901-1903. Morley J. E. and Levine A. S. (1982) Corticotropin releasing factor grooming and ingestive behaviors. Life Sci. 31, 1459-1464. Morley J. E. and Levine A. S. (1985) The pharmacology of eating behavior. A. Rev. Pharmac. Toxic. 25, 127-146. Morley J. E., Levine A. S. and Lindblad S. (1981) Intraventricular cholecystokinin-octapeptide produces hypothermia in rats. Fur. J. Pharmac. 74, 249-251. Morley J. E., Levine A. S., Gosnell B. A. and Krahn D. D. (1985) Peptides as central regulators of feeding. Brain Res. Bull. 14, 511-519. Morley J. E., Levine A. S., Oken M. M., Grace M. and Kneip J. (1982) Neuropeptides and thermoregulation: the interactions of bombesin, neurotensin, TRH, somatostatin, naloxone and prostaglandins. Peptides 3, 1-6. Muchlinski A. E., Ho F. J., Chew P. and Yamada T. (1983) The concentrations of four neuropeptides in various brain areas of summer active and hibernating Spermophilus lateralis. Comp. Biochem. Physiol. 74C, 185-189. Muir J. G. and Murray A. W. (1987) Bombesin and phorbol ester stimulate phospharidylcholin hydrolysis by phospholipase C: evidence for a role of protein kinase C. J. Cell Physiol. 130, 382-391. Murakami N. (1973) Effects of iontophoretic application of 5-hydroxytryptamin, noradrenaline and acetylcholine upon hypothalamic temperature-sensitive neurons in rats. Jap. J. Physiol. 23, 435-446. Murphy M. T. and Lipton J. M. (1982) Peripheral administration of c¢-MSH reduces fever in older and younger rabbits. Peptides 3, 775-779. Myers R. D., Hepler J. R. and Holahan W. (1983) Action of anorexigenic peptide injected into the brain: dissociation of effect on body weight and feeding in the rat. Peptides 4, 85-88. Myers R. D., Lee T. F. and King S. E. (1983) Calmodulin infused intracerebroventricularly enhances food intake in the cat. Brain Res. 266, 178-181. Myers R. D., Oeltgen P. R. and Spurrier W. A. (1981) Hibernation "trigger" injected in brain induces hypothermia and hypophagia in the monkey. Brain Res. Bull. 7, 691-695. Nakashima T., Hori T., Kiyohara T. and Shibata (1985) Effects of endotoxin and sodium salicylate on the preoptic

345

thermosensitive neurons in tissue slices. Brain Res. Bull. 15, 459-463. Nakayama T. and Hori T. (1973) Effects of anesthetic and pyrogen on thermally sensitive neurons in the brainstem. J. appl. Physiol. 34, 351-355. Nayar R., Sirett N. E. and Hubbard J. I. (1987) Neuron responses to substance P and enkephalin in rat dorso lateral septum in vitro. Brain Res. Bull. 19, 507-509. Naylor A. M., Cooper K. E. and Veale W. L. (1987) Vasopressin and fever: evidence supporting the existence of an endogenous antipyretic system in the brain. Can. J. Physiol. Pharmac. 65, 1333-1338. Naylor A. M., Ruwe W. D. and Veale W. L. (1986a) Antipyretic action of centrally administered arginine vasopressin but not oxytocin in the cat. Brain Res. 385, 156-160. Naylor A. M., Ruwe W. D. and Veale W. L. (1986b) Thermoregulatory actions of centrally-administered vasopressin in the rat. Neuropharmacology 25, 787-794. Naylor A. M., Ruwe W. D., Kohut A. F. and Veale W. L. (1985) Perfusion of vasopressin within the ventral septum of the rabbit suppresses endotoxin fever. Brain Res. Bull. 15, 209-213. Nemeroff C. B., Bissette G., Manberg P. J., Osbahr A. J., III, Brecse G. R. and Prange A. J. Jr (1980a) Neurotensininduced hypothermia: evidence for an interaction with dopaminergic systems and the hypothalamic-pituitarythyroid axis. Brain Res. 195, 69-84. Nemeroff C. B., Osbahr J. A., Bissette G., Jahnke G., Lipton M. A. and Prange A. J. (1978) Cholecystokinin inhibits tail-pinch induced eating in rats. Science 200, 793-794. Nemeroff C. B., Bissette G., Manberg P. J., Moore S. I., Ervin G. N., Osbahr A. J. and Prange A. J. (1980b) Hypothermic response to neurotensin in vertebrates. In Thermoregulatory Mechanisms and Their Therapeutic Implications (Edited by Cox B., Lomax P., Milton A. S. and Schtnbaum E.), pp. 180-185. Karger, Basel. Nicoll R. A. (1978) The action of thyrotropin-releasing hormone, substance P and related peptides on frog spinal motoneurons. J. Pharmac. exp. Ther. 207, 817-824. Nicoll R. A. (1983) Response of central neurons to opiates and opioid peptides. In Regulatory Peptides: From Molecular Biology to Function (Edited by Costa E. and Trabucci M.), pp. 337-345. Raven Press, New York. Nir I. (1984) Can enkephaline be playing a role in pineal functions? EPSG Newslett. Suppl. 5, 38. Normanton J. R. and Gent J. P. (1983) Comparison of the effect of two "sleep" peptides, delta sleep inducing peptide and arginine-vasotocin, on single neurons in the rat and rabbit brain stem. Neuroscience 8, 107-114. North R. A. (1979) Opiates, opioid peptides and single neurones. Life Sci. 24, 1527-1546. North R. A. (1986) Electrophysiological effects of neuropeptides. In Neuropeptides and Psychiatric Disease (Edited by Martin J. B. and Barchas J. D.), pp. 71-77. Raven Press, New York. North R. A. and Williams J, T. (1985) On the potassium conductance increased by opioids in rat locus coeruleus neurones. J. Physiol., Lond. 364, 265-280. Oeltgen P. R. and Spurrier W. A. (1981) Characterization of a hibernation induction trigger. In Survival in the Cold. Hibernation and Other Adaptations (Edited by Musacchia X. J. and Jansk~ L.), pp. 139-157. Elsevier, New York. Oeltgen P. R., Spurrier W. A. and Bergmann L. C. (1979) Hemoglobin alterations of the 13-lined ground squirrel in various activity states. Comp. Biochem. Physiol. 64B, 207-211. Oeltgen P. R., Blouin R. A., Spurrier W. A. and Myers R. D. (1985) Hibernation "trigger" alters renal function in the primate. Physiol. Behav. 34, 79-81. Oeltgen P. R., Spurrier W. A., Bergmann L. C. and Jones S. B. (1978) Isolation of a hibernation inducing trigger(s)

346

L. JANSKT

from the plasma of hibernating woodchucks. Prep. Biochem. 8, 171 188. Oeltgen P. R., Walsh J. W., Hamann S. R., Randall D. C., Spurrier W. A. and Myers R. D. (19821 Hibernation "trigger": opioid-like inhibitory action on brain function of the monkey. Pharmac. Biochem. Behav. 17, 1271 1274. Okuno A., Yamamoto M. and Itoh S. (1965) Lowering the body temperature induced by vasopressin. Jap. J. Physiol. 15, 378 387. Ono T., Morimoto A., Watanabe T., Murakami N. (1987) Effect of endogenous pyrogen and prostaglandin E, on hypothalamic neurons in guinea pigs brain slices. J. appl. Physiol. 63, 175 180. Orloff M. S., Reeve J. R., Miller Ben-Avram Ch., Shively J. E. and Walsh J. H. (19841 Isolation and sequence analysis of human bombesin-like peptides. Peptides 5, 865-870. Ozawa S. (19851 TRH-induced membrane hyperpolarization in rat clonal anterior pituitary cells. Ant. J. Physiol. 248, E64-E69. Pan J.-T., Kow L.-M. and Pfaff D. W. (1986) Single-unit activity of hypothalamic arcuate neurons in brain tissue slices. Neuroendocrinology 43, 189 196. Pepper C. M. and Hendersen G. (19801 Opiates and opioid peptides hyperpolarize locus coeruleus neurons in vitro. Science 209, 397 396. Phillis J. W. and Kirkpatrick J. R. (1979) Actions of various gastrointestinal peptides on the isolated amphibian spinal cord. Can. J. Physiol. Pharmac. 57, 887 889. Pierau Fr.-K., Schmid H. and Jansk~, L. (I 989) Recruitment of warm sensitive hypothalamic neurones by peptides and changes of extracellular calcium. In Living in the Cold I1 (Edited by Malan A. and Canguilhem B.), pp. 255. 263. INSERM, Libbey Eurotext, Pittman Q. J., Tach6 Y. and Brown M. R. (1980) Bombesin acts in preoptic area to produce hypothermia in rats~ Lift, Sci. 26, 725-730. Prasad C., Matsui T., Williams J. and Peterkofsky A. (19781 Thermoregulation in rats: opposing effects of thyrotropin releasing hormone and its metabolite histidyl-proline, diketopiperazine. Biochem. biophys. Res. Commun. 85, 1582- 1587. Rasler F. E. (1983) Bombesin produces hypothermia in hypophysectomized rats. Life Sci. 32, 2503-2507. Rezvani A. H., Gordon C. J. and Heath J. E. (1982) Action of preoptic injections of ,g-endorphin on temperature regulation in rabbits. Am. J. Physiol. 243, RI04--RII1. Richards D. B. and Lipton J. M. (1984) Antipyretic doses of ~-MSH do not alter afebrile body temperature in the cold. J. therm. Biol. 9, 299 301. RiedeI W., Kozawa E. and Iriki M. (19821 Renal and cutaneous vasomotor and respiratory rate adjustments to peripheral cold and warm stimuli and to bacterial endotoxin in conscious rabbits. J. Autonom. Nerv. Syst. 5, 177--194. Ritter R. C. and Landenheim E. E. (19841 Fourth ventricle infusion of cholecystokinin suppresses feeding in rats. Soc. Neurosci. Abstr. 10, 652. Rivier C., Vale W., Ling N., Brown M. and Guillemin (1977) Stimulation in ritro of the secretion of prolactin and growth hormone by/~-endorphin. Endocrinology 100, 238 242. Rivier J. E. and Brown M. R. (19781 Bombesin, bombesin analogues and related peptides: effects on thermoregulation. Biochemistry 17, 1766 1771. Sakata Y. (1979) Effect of pyrogen on the medullary temperature-responsive neurone of rabbits. Jap. J. Physiol. 29, 585-596. Sakurada T., Sakurada S., Watanabe S., Matsumura H., Kisara K., Akutsu Y., Sasaki Y. and Suzuki K. (19831 Actions of intracerebroventricular administration of kyotorphin and analog on thermoregulation in the mouse. Peptides 4, 859 863.

Salzman S. K. and Beckman (19811 Effects o~ thyrotropm releasing hormone on hypothalamic thermosensitive neurons of the rat. Brain Res. Bull. 7, 325 332. Satinoff E. (1978) Neural organization and evolution of thermal regulation in mammals. Science 20h 16 22. Schick R. R., Yaksh T. [,. and Go V. L. W. (1986) lntracerebroventricular injections of cholecystokinin ocstapeptide suppress feeding in rats- pharmacological characterization of this action. Reg. Pept. 14, 277 291. Schmid H., Jansk) L. and Pierau F.-K. (1987a1 The effect of neuropeptides on temperature-sensitive and thermosensitive neurones in hypothalamic slices of the rat. Pfliigers Archs Suppl. 1 408, R53. Schmid H., Jansk} L. and Pierau F.-K. (1987b) The effect of bombesin and substance P on temperature-sensitive and temperature-insensitive neurones in hypothalamic slices of the rat. Neuroscience 22, $834. Schneider H. P. and McCann S. M. (19701 Mono- and indolamines and control of Lft secretion. Endocrinology 86, 1127 1133. Schoener E. P. and Wang S. C. (1975) Leukocytic pyrogen and sodium acetylsalicylate on hypothalamic neurons of the cat. Am. J. Physiol. 229, 185 190. Schoener E. P. and Wang S. C. (1976) Effects ol locally administered prostaglandin E, on anterior hypothalamic neurons. Brain Res. 117, 157 162. Scott I. M. and Boulant J. A. (19841 Dopamine effects on thermosensitive neurons in hypolhalamic tissue slices. Brain Res. 306, 157 163. Sharpe L. C., Garnett J E. and Olsen N. S. (19781 Thermoregulatory changes to cholinomimetics and angiotensin It, but not to the monoamines microinjected into the brain stem of rabbit. Neuropharmacology 18, 117 125. Shian L. R. and Lin M. T. (1985) Effects of cholecystokinin octapeptide on thermoregulatory responses and hypothalamic neuronal activity in the rat. Naunyn-Schmiedeber~'s Archs Pharmac. 328, 363 367. Shido O. and Nagasaka T. (1985a) Effects of intraventricular neurotensin on blood pressure and heat balance in rats. Jap. J. Physiol. 35, 311-320. Shido O. and Nagasaka T. (1985b) Effects of intraventricular angiotensin II on heat balance at various ambient temperatures in rats. ,lap. J. Physiol. 35, 163 167. Shido O., Kifune A. and Nagasaka T. ~19841 Baroreflexive suppression of heat production and fall in body temperature following peripheral administration of vasopressin in rats. Jap. ,1. Physiol. 34, 397~.06. Shih S. T. and Lipton .1. M. (19851 Intravenous :~-MSH reduces fever in the squirrel monkey. Peptides 6, 685 687. Simon E. (19741 Temperature regulation: the spinal cord as a site of extrahypothalamic thermoregulatory functions. Rev. Physiol. Biochem. Pharmac. 71, 1 76. Simon E. (1987) Paradigms and concepts in thermal regulation of homeotherms. News Physiol. Sci. 2, 89.-93. Simon E., Pierau F . - K and Taylor D. C. M. (19861 Central and peripheral thermal control of effectors in homeothermic temperature regulation. Physiol. Rev. 66, 235 300. Sisk C. L. and Turek F. W. (19821 Daily melatonin injections mimic the short-day-induced increase in negative feedback effects of testosterone on gonadotropin secretion in hamsters. Biol. Reprod. 27, 602 608. Spurrier W. A. and Dawe A. R. (1973) Several blood and circulatory changes in the hibernation of the t3-1ined squirrel. Comp. Biochem. Physiol. 44A, 267 282. Stanley B. G. and Leibowitz S. F. (1985) Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc. natn. Acad. Sci. U.S.A. 82, 3940~3943. Stanley B. G., Chin A. S, and Leibowitz S. F. (19851 Feeding and drinking elicited by central injection of neuropeptide Y: Evidence for a hypothalamic site(s) of action. Brain Res. Bull. 14, 521-524.

Neuropeptides and the central regulation of body temperature during fever and hibernation Stanley B. G., Hoebel B. G. and Leibowitz S. F. (1983) Neurotensin: effects of hypothalamic and intravenous injections on eating and drinking in rats. Peptides 4, 493-500. Stanley B. G., Kyrkouli S. E., Lampert S. and Leibowitz S. F. (1986) Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7, 1189-1192. Stanton T. L., Sartin N. F. and Beckman A. L. (1985) Changes in body temperature and metabolic rate following microinjection of Met-enkephalinamide in the preoptic/ anterior hypothalamus of rats. Reg. Pept. 12, 333-343. Stanzione P. and Zieglgiinsberger W. (1983) Action of neurotensin on spinal cord neurons in the rat. Brain Res. 268, 111-118. Stern J. J., Cudillo C. A. and Kruper J. (1976) Ventromedial hypothalamus and short term feeding suppression by caerulein in male rats. J. comp. Physiol. PsychoL 90, 484-490. Stitt J. T. (1980) CNS control of body temperature. In Contribution to Thermal Physiology (Edited by Szel~nyi Z. and Sz~kely M.), pp. 13-20. Pergamon Press, Akademiai Kiado, Budapest. Stitt J. T. and Hardy J. D. (1975) Microelectrophoresis of PGEt into single units in the rabbit hypothalamus. Am. J. Physiol. 229, 240-245. Stitt J. T., Hardy J. D. and Stolwijk J. A. J. (1974) PGE I fever: its effect on thermoregulation at different low ambient temperatures. Am. J. Physiol. 227, 622-629. Stuckey J. A. and Gibbs S. (1982) Lateral hypothalamic injection of bombesin decreases food intake in rats. Brain Res. Bull. 8, 617-621. Suzuki T., Kohmo H., Sakurada T., Tadano T. and Kisara K. (1982) Intracranial injection of thyrotropin releasing hormone suppresses starvation induced feeding and drinking in rats. Pharmac. Biochem. Behav. 17, 249-253. Swope SH. L. and Schonbrunn A. (1988a) Mechanism of bombesin-stimulated insulin secretion in a pancreatic beta cell line. Biochem. J. Swope SH. L. and Schonbrunn A. (1988b) Desensitization to bombesin is a complex process involving receptor down-modulation and decreased accumulation of intra~ellular second messengers. Biochem. J. Ta'che Y., Pittman Q. J. and Brown M. R. (1980) Bombesininduced poikilotermia in rats. Brain Res. 188, 525-530. Tannenbaum G. S., Guyda H. J. and Posner B. I. (1983) Insulin-like growth factors: a role in growth hormone negative feedback and body weight regulation. Science 220, 777-779. Telegdy G., Kader T., Kovacs K. and Penke B. (1984) The inhibition of tail-pinch-induced food intake by cholecystokinin octapeptides and their fragments. Life Sci. 35, 163-170. Teppermann F. S. and Hirst M. (1983) Effect of intrahypothalamic injection of t~-Ala2, o-Leu s enkephalin on feeding and temperature in the rat. Eur. J. Pharmac. 96, 243-249. Thornhill J. A. and Saunders W. S. (1984) Thermoregulatory (core, surface and metabolic) responses of unrestrained rats to repeated POAH injections of fl-endorphin or adrenocorticotropin. Peptides 5, 713-719. Thornhill J. A. and Wilfong A. (1982) Lateral cerebral ventricle and preoptic-anterior hypothalamic area infusion and perfusion of fl-endorphin and ACTH to unrestrained rats: Core and surface temperature responses. Can. J. Physiol. Pharmac. 60, 1267-1274. Tseng L. F., Oswald P. J., Loh H. H. and Li C. H. (1979) Behavioral activities of opioid peptides and morphine sulfates in golden hamsters and rats. Psychopharmacology 64, 215-218. Turek F. (1977) The interaction of the photoperiod and testosterone in regulating serum gonadotropin levels in castrated male hamsters. Endocrinology 101, 1210-1215.

347

Twery M. J., Obie J. F. and Cooper C. W. (1982) Ability of calcitonin to alter food and water consumption in the rat. Peptides 3, 749-755. Vaccarino F. J., Bloom F. E., Rivier J., Vale W. and Koob G. F. (1985) Stimulation of food intake in rats by centrally administered hypothalamic growth hormonereleasing factor. Nature 314, 167-168. Van6tSek J. and Jansk~ L. (1989) Short days induce changes in specific melatonin binding in hamster median eminence and anterior pituitary. Brain Res. 477, 387-390. Vergoni A. V., Poggioli R. and Bartolini A. (1986) Corticotropin inhibits food intake in rats. Neuropeptides 7, 153-158. Vijayan E. and McCann S. M. (1977) Suppression of feeding and drinking activity in rats following intraventricular injections of thyrotropin releasing hormone (TRH). Endocrinology 100, 1727-1730. Vybiral S. and Jansk~, L. (1989) The role of dopaminergic pathways in thermoregulation of the rabbit. Neuropharmacology 28, 15-20. Vybiral S., (~ern~, L. and Jansk~' L. (1988) Mode of ACTH antipyretic action. Brain Res. Bull. 21, 557-562. Vybiral S., Nach~.zel J. and Jansk~ L. (1986) Hyperthermic effect of neurotensin in the rabbit. Pfliigers Archs 406, 312-314. Vybiral S., Sz6kely M., Jansk~ L. and (~ern~' L. (1987) Thermoregulation of the rabbit during the late phase of endotoxin fever. Pfliigers Archa 410, 220-222. Wang L. C. H., Lee T. F. and Jourdan M. L. (1987) Seasonal difference in thermoregulatory responses to opiates in a mammalian hibernator. Pharmac. Biochem. Behav. 26, 565-571. Watanabe T., Morimoto A. and Murakami N. (1987) Effect of endogenous pyrogen and postaglandin E 2 on hypothalamic neurons in rat brain slices. Can. J. Physiol. Pharmac. 65, 1382-1388. Wertz A. A. and Macdonald R. L. (1983) Opioids selective for mu and delta opiate receptors reduce calciumdependent action potential duration by increasing potassium conductance. Neurosci. Lett. 42, 173-178. Wertz M. A. and Macdonald R. L. (1984) Dynorphin reduces calcium-dependent action potential duration by decreasing voltage-dependent calcium conductance. Neurosci. Lett. 46, 185-190. Westendorf J. M. and Schonbrunn A. (1983) Characterization of bombesin receptors in a rat pituitary cell line. J. biol. Chem. 258, 7527-7535. Wilkinson M. F. and Kasting N. W. (1987) The antipyretic effects of centrally administered vasopressin at different ambient temperature. Brain Res. 415, 275-280. Willis A. L., Hansky J. and Smith A. C. (1984) The role of some central catecholamine systems in cholecystokinininduced satiety. Peptides 5, 41--46. Wit A. and Wang S. C. (1968) Temperature sensitive neurons in preoptic/anterior hypothalamic region: actions of pyrogen and acetylsalicylate. Am. J. Physiol. 215,

1160-1169. Wunder B. A., Hawkins M. F., Avery D. D. and Swan H. (1980) The effects of bombesin injected into the anterior and posterior hypothalamus on body temperature and oxygen consumption. Neuropharmacology 19, 1095-1097. Yehuda S, and Carasso R. L. (1983) Changes in circadian rhythms of thermoregulation and motor activity in rats as a function of aging: effects of d-amphetamine and alphaMSH. Peptides 4, 865-869. Zetler G. (1982) Caerulein and cholecystokinin octapeptide (CCK-8): sedative and anticonvulsive effects in mice unaffected by the benzodiazepine antagonist Ro 15-1788. Neurosci. Left. 28, 287-290. Zimmer J. A. and Lipton J. M. (1981) Central and peripheral injections of ACTH (1-24) reduce fever in adrenalectomized rabbits. Peptides 2, 413-417.