- Email: [email protected]
Further investigations on the antipropulsive effect of centrally administered histamine and its relation with morphine
European Journal of Pharmacology, 210 (1992) 259-264 © 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
259
EJP 52237
Further investigations on the antipropulsive effect of centrally administered histamine and its relation with morphine G a b r i e l a Patrini, P a o l a Massi, T i z i a n a R u b i n o , L a u r a D o n i n , E n z o G o r i a n d D a n i e l a P a r o l a r o Institute of Pharmacology, Faculty of Sciences, University of Milan, Milan, Italy Received 27 May 1991,revised MS received 13 September 1991, accepted 29 October 1991
The effect of intracerebroventricularly (i.c.v.) administered histamine (100 p~g/rat) on intestinal myoelectrical activity was investigated in the jejunum of fasted rats. Histamine caused the disappearance of phase III and a partial reduction of phase II of migrating myoelectric complexes. This effect was antagonized by i.c.v, pretreatment with mepyramine (10 p.g/rat), an H~ receptor antagonist. Lesions of central noradrenergic neurons by i.c.v, injection of the neurotoxin 6-hydroxydopamine strongly reduced both the inhibition of intestinal propulsion and the migrating myoelectric complexes profile induced by i.c.v, histamine, whereas pretreatment with p-chlorophenylalanine, a selective depictor of serotonin stores, had no effect. It thus appears that aminergic pathways are involved in the visceral effects of central histamine. Mepyramine (200/xg/rat i.c.v.) partially reduced the slowing of intestinal transit induced by high doses of morphine. Pretreatment with compound 48/80 (10/xg/rat i.c.v.), a mast cell degranulator, but not with a-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, reduced the antipropulsive action of i.c.v, morphine to the same extent as mepyramine, suggesting that histamine released from cerebral mast cells by high doses of morphine could contribute to the intestinal inhibition by morphine. Histamine; Morphine; Intestinal motility
1. Introduction
In recent years evidence has emerged that histamine acts as a neurotransmitter in the mammalian brain. Its role in neuroregulation was elucidated by identification of the histaminergic neuron system (Hough, 1988) and the characterization of specific pre- and postsynaptic receptor subtypes (Schwartz et al., 1986; Watanabe et al., 1990). There is also considerable evidence that histamine and its receptors are involved in the central regulation of some vegetative activities such as hypothermia (Brezenoff and Lomax, 1970; Brimblecombe and Calcutt, 1974; Costentin et al., 1973), cardiovascular regulation (Klein and Gertner, 1983; Poulakos and Gertner, 1986; Poulakos and Gertner, 1989), water intake (Kraly and Miller, 1982; Kraly, 1985) and antidiuretic hormone release (Bennett and Pert, 1974). Our recent studies have shown that cerebral histamine H t receptors appear to be involved in the inhibition of intestinal transit and analgesia induced by intracerebroventricular (i.c.v.) histamine (Parolaro et
al., 1989). These receptors become desensitized after repeated i.c.v, injections of histamine, resulting in strong tachyphylaxis to both effects (Parolaro et al., 1989). Thus the central histaminergic system could be involved in the modulation of gastrointestinal motility. To characterize the antipropulsive effect of centrally administered histamine further, we monitored intestinal myoelectrical activity in conscious rats and attempted to identify the neuronal pathway involved in this effect. Finally, in the light of reports that the amine might be involved in the analgesia, tolerance and physical dependence induced by central morphine (Hough, 1988), the second aim of the present study was to investigate the influence of central histamine pools (neurons and mast cells) on the inhibition of gastrointestinal motility evoked by centrally administered morphine.
2. Materials and methods 2.1. Animals
Correspondence to: D. Parolaro, Institute of Pharmacology,Faculty of Sciences, Universityof Milan, Via Vanvitelli 32/A, 20129 Milan, Italy. Tel. 39.27.385 568, fax 39.27.000 2270.
Female Sprague-Dawley rats were used, weighing either 180-200 or 280-300 g depending on the experiments, fed on a pellet diet with water ad libitum.
260 Environmental conditions were standardized (22 + 2°C, 60% humidity and 12 h artificial lighting per day). Before treatment the animals were randomizied according to a complete block design and fasted for 15-18 h.
2. 2. Drugs The following drugs were used: histamine (HA, Sigma Chemical Co., St. Louis, MO), mepyramine maleate (MEP, Sigma Chemical Co.), DL-p-chlorophenylalanine (p-CPA, Sigma Chemical Co.), 6-hydroxydopamine hydrobromide (6-OHDA, Sigma Chemical Co.), compound 48/80 (Sigma Chemical Co.), afluoromethylhistidine monohydrochloride hemihydrate (a-FMH, kindly supplied by Merck Sharp & Dohme Research Laboratories, Rahway, NJ, U.S.A.), morphine hydrochloride (M, S.I.F.A.C., Milan, Italy). All the drugs were dissolved in saline except for 6-OHDA, which was dissolved in saline with 0.1% ascorbic acid.
2.3. I.c.v. microinjection The rats were anesthetized with tribromoethanol (200 mg/kg i.p.) and prepared for i.c.v, microinjections according to Altaffer's procedure (Altaffer et al., 1970). Briefly, anesthetized rats were fixed in a stereotaxic apparatus and the right lateral ventricle was located using a stereotaxic atlas (Paxinos and Watson, 1982). A permanent polyethylene cannula (Ulrich and Co., type PE 10) was implanted to penetrate the ventricle 4.5 mm from the top of the skull, and was fixed to the skull with dental cement (Hottinger Baldwin Messtechnik, type X 60). After the operation the animals were placed in individual cages and allowed to recover for five days. Drug solutions in a constant volume of 5 /~1 were injected in conscious rats by inserting a Hamilton microsyringe into the cut cannula tip. Control rats were injected i.c.v, with 5 /zl of saline. At the end of each experiment rats were killed by decapitation and 5 tzl Evans blue dye (0.5%) was microinjected through the cannula and after 5 min the brains were removed and placed in 10% formalin. The brains were frozen 24 h later, cut to a thickness of 80 /zm, and examined microscopically to verify cannula placements.
2.4. 6-OHDA and p-CPA injection To lesion noradrenaline pathways, 6-OHDA (200 # g / r a t ) in 0.1% ascorbic acid was injected i.c.v, on two consecutive days; six days after the microinjection of vehicle or toxin, the rats were given HA (100 tzg/rat) i.c.v. Noradrenaline was assayed in the hypothalamus, midbrain and spinal cord by high-pressure liquid chro-
matography (HPLC) with electrochemical detection according to Keller et al. (1976). To induce serotonin (5-HT) depletion, one group of rats received 100 mg/kg of p-CPA methyl ester i.p. for three days; 24 h after the third injection the rats received HA (100 /~g/rat) i.c.v. 5-HT was assayed in the midbrain and in the spinal cord according to the method of Lackovic et al. (1981).
2.5. Intestinal transit Intestinal transit was assessed in fasted rats on the basis of the progression of a charcoal meal through the small intestine (Parolaro et al., 1977). The animals were killed by cervical dislocation 20 min after the charcoal meal. The whole gastrointestinal tract was quickly and carefully removed and the small intestine was gently stretched to its full length. The distance the meal had traveled from the pylorus to the cecum was measured and expressed as the percentage inhibition in relation to control transit (Tc) as follows: (Tc Tt)/T ~ • 100 where T t is the transit in treated animals. A preliminary statistical covariance test showed that the total intestinal length was independent of an animal's weight and not significantly different from one rat to another.
2.6. Motility Motility was recorded as myoelectric activity in conscious adult female rats weighing 280-300 g . Anesthetized rats were prepared chronically with pairs of insulated Ni/Cr electrodes (100 tzm in diameter) implanted along the jejunum (40-45 cm from the pylorus). The free ends of the electrodes were carried s.c. to the back of the neck, exteriorized on the top of the skull and connected to the socket (Souriau, Boulogne, France). Solder connections to the socket were encapsulated in dental acrylic cement (Hottinger Baldwin Messtechnik, type X 60). The animals were also fitted with cannulas for i.c.v, microinjections. Measurements of intestinal myoelectric activity began 7-10 days after the operation, when the animals had completely recovered. Each animal was housed in a wire-bottomed cage and was fasted 18 h before recording. Water was allowed ad libitum. Bipolar recordings were made from conscious, unrestrained animals by connecting the electrode socket with a direct writing polygraph (Battaglia-Rangoni, Bologna, Italy), at a time constant of 0.1 s. Myoelectrical activity was separated into slow waves and spikes by using low band-pass and high band-pass filters, respectively. Spike electrical activity and slow waves were summed every 20 s by an integrator circuit connected to a potentiometric recorder. The integrated records of electrical activity are expressed in
261 mml 5ahnr
+ HA
[;~ p-CPA ÷ scllne p--CPA + 14k 100
z
O "20"
......
E
]
m
5o
I Z
i HISTAMINE (100 p g / R A T / l e V I
ae SLOW Ir u.| ru ..,luk, ill I I i . _all. . . . ... J k ~ l i - I L , WAVI~SU
tllbb, II . . . . . .
I
Fig. 2. Effect of p-CPA pretreatment (100 mg/kg i.p. for three days) on the intestinal inhibition induced by i.c.v, histamine (HA, 100 /~g/rat).
20'
mepyramine (MEP, 30 rain before) fully prevented the effect of H A (fig. 1).
.....
4 ' 20" HISTAMINE ( 10OMg/RAT/leVI
MEPYRAMINE
120/a:j/RAT/ICV
)
Fig. 1. Effect of histamine (100 #g/rat i.c.v.) and its antagonism by mepyramine (10 ~g/rat i.c.v. 30 min before) on the myoelectrical activityof the jejunum in fasted rats (integrated records).
/ z C / m i n as a motility index. This integrated record gave a clear picture of the pattern of intestinal activity.
2. 7. Statistical analysis The data reported are means + S.E. Results were analyzed statistically with a one-way analysis of variance and compared by using Tukey's procedure (Steel and Torrie, 1960).
3. Results
3,1. Myoelectrical activity Jejunal myoelectrical activity before and after i.c.v. H A is shown in fig. 1. A typical recording from small intestine after an 18-h fast comprises a basal rhythm (slow waves) and spiking activity organized in migrating myoelectric complexes (MMC) at regular intervals of 17 + 1.43 min. I.c.v. microinjection of 100 ~ g / r a t of H A (a dose causing about 90% inhibition of intestinal transit in the charcoal meal test) caused the disappearance of phase III and a partial reduction of phase II of the MMC. The mean duration of the loss of phase III activity was 71.5 + 10.3 min (n = 6). At the end of this period the MMC were restored. The basal rhythm was unaffected by H A (fig. 1). As previously seen in transit experiments (Parolaro et al., 1989), pretreatment with
3.2. 5-HT depletion The role of the serotoninergic system in the gastrointestinal inhibition evoked by i.c.v. H A was investigated after selective depletion of 5-HT by p-CPA pretreatment. This procedure had no effect on the antipropulsive effect of i.c.v. HA, with intestinal inhibition being the same in pretreated rats as in rats injected with H A alone (fig. 2). 5-HT levels were lowered by p-CPA, by 50% in the midbrain (control value 1200 + 47 n g / g wet weight of tissue) and by 75% in the spinal cord (control value 565 + 40 n g / g wet weight of tissue).
3.3. Noradrenaline (NA) depletion I.c.v. 6 - O H D A caused a substantial depletion of noradrenaline in the midbrain (82%, control value 360 + 70 n g / g wet weight of tissue), hypothalamus (86%, control value 660 __ 120 n g / g wet weight of tissue) and spinal cord (83%, control value 266 _+ 16 n g / g wet weigh of tissue). In these 6-OHDA-pretreated rats the antipropulsive effect of H A was significantly reduced from 85 to 10% (F(3,9)= 50.97, P <
100
IMm saline + HA [ 2 ~ 6-OHDA + saline 6-OHDA + HA
Z
o T Z
so
te
Fig. 3. Effect of 6-OHDA pretreatment (200 /.tg/rat i.c.v, for two days) on the intestinal inhibition induced by i.c.v, histamine (HA, 100 /zg/rat). ** P < 0.001 vs. saline+HA.
262
1O0
I---I a-FMH + =;aline i l l 4 8 / 8 0 + saline tN~'R saline + M t-TU] a-FMH + IA 82Z1 4 8 / 8 0 + M
z o I---
......
20--
(
6-OHDA
T
50
Z
HISTAMINE
( 200 p , , g / R A T / ICV/X 2 |
(100/~/RAT/ICV)
Fig. 4. Effect of 6 - O H D A pretreatment (200 / z g / r a t i.c.v, for two days) on the reduction of the histamine spike potential in the jejunum of fasted rats (integrated records).
0.001) (fig. 3). The importance of the noradrenergic system in mediating the antitransit effect of central HA was confirmed by electromyographic experiments (fig. 4). Six days after 6-OHDA pretreatment HA no longer abolished spiking activity, the MMC remaining at the same frequency as before treatment (21 + 0.7 vs. basal frequency 18.3 __+0.3).
Fig. 6. Effect of pretreatment with a - F M H (200 / x g / r a t i.c.v. 3 h before) and compound 4 8 / 8 0 ( 1 0 / z g / r a t i.c,v. 24 h before) on the intestinal inhibition evoked by morphine (M, 3 6 / ~ g / r a t i.c.v.).
evoked by i.c.v.M. However, i.c.v, pretreatment with compound 48/80 (24 h before), a mast cell degranulatar, caused a partial reduction (about 25%) of the intestinal inhibition induced by M (fig. 6).
4. Discussion
3.4. Role of the histaminergic system in morphine-induced intestinal inhibition Figure 5 shows the dose-related inhibition of gastrointestinal transit after i.c.v. M in rats. When M was preceded by i.c.v. MEP, the effect of M on intestinal transit was only partially reduced (about 30%) and only at high doses of M (from 18 to 72 /~g/rat); at lower doses intestinal inhibition was the same after M alone and after pretreatment with MEP (fig. 5). Thus to clarify the role of the endogenous HA system in the intestinal inhibition induced by M, we used a-FMH and compound 48/80 to deplete neuronal and mast cell HA pools, respectively. Figure 6 shows the effect of ot-FMH, a specific and irreversible inhibitor of histidine decarboxylase, on the antipropulsive effects of centrally administered M. ot-FMH per se did not affect intestinal transit or reduce the intestinal inhibition 0"="~0 saline + M
e~l 100 z 0
75
If °
IdEP + M
.-----O
O
I
1
i----
m Z 50 1/2 Z
~
25
~/RAT/~CV
Fig. 5. Effect of pretreatment with mepyramine(MEP, 200 /zg/rat i.c.v.) on the dose-response curve for the inhibition of intestinal propulsion inducedby i.c.v,morphine(M).
The present findings provide extra information on the antipropulsive effect of central HA and the role of the histaminergic system in the opioid inhibition of gastrointestinal motility. Firstly, we have clarified the action of central HA on intestinal motility, showing that the antipropulsive effect of centrally administered HA could be related to the amine's ability to modify the regular appearance of MMC in the jejunum of fasted rats. In fact, i.c.v. HA in fasted rats caused a motor change characterized by the disappearance of phase III (regular spiking activity) and a partial reduction of phase II (irregular spiking activity) of the MMC. The various phases of the MMC and the movement of intraluminal contents are known to be related. Studies by Ruckebusch and Fioramonti (1975) have shown that the intraluminal contents are moved during phase II activity and that material already present in the bowel is mainly propelled during the transition from phase II to phase III activity. Thus the effect of central HA on myoelectric activity may be related to the block of gastrointestinal transit already observed in the charcoal meal test (Parolaro et al., 1989). Our data are not entirely consistent with those of Fargeas et al. (1989), who reported that i.c.v. HA had no effect on the electromyographic profile of the jejunum. However, Fargeas used a dose of HA about 20 times lower than ours (5 /xg/rat) and they did not assess whether this dose actually affected gastrointestinal propulsion. Our previous work has shown that HA blocks gastrointestinal transit in a dose range from 20 to 100/zg/rat. Thus the dose of 5 / x g / r a t may well be too low to affect both the electromyographic profile and gastrointestinal propulsion. In addition, the obser-
263
vation that pretreatment with MEP antagonized these effects of HA confirms that the amine's central action in the gut is mediated by the activation of cerebral H1 receptors. The present results also suggest that activation of noradrenaline pathways in the central nervous system mediates the changes in gastrointestinal motility that follow i.c.v. HA. In fact, after i.c.v, injection of the neurotoxin 6-OHDA, which damages cerebral noradrenaline-containing neurons, HA did not alter either the electromyographic recording or gastrointestinal transit. These results are in agreement with previous findings that cerebral catecholamine pathways may contribute to other central effects of HA, e.g. the antidiuretic (Leibowitz, 1973; Bhargava et al., 1973) and hypertensive actions (Finch and Hicks, 1976). Thus our data seem to indicate that the gastrointestinal motor changes induced by i.c.v. HA result from activation of catecholaminergic pathways. Donoso and Barontini (1986) demonstrated that i.c.v, administered HA promoted the release of adrenaline and noradrenaline in conscious rats, as shown by an increase in plasma concentrations of these catecholamines. These authors suggested that catecholamine might be released through a close association of HA with a hypothalamic catecholaminergic mechanism. Interaction may take place in the paraventricular and supraoptic nuclei where an ascending adrenergic circuit integrates autonomic regulation, or, alternatively, in the caudal hypothalamic area where adrenergic structures have an important role in the regulation of pressor responses to HA. Such responses always occur with gastroiintestinal actions, as demonstrated by the strong increase in blood pressure induced by i.c.v, administered amine (data not shown). Therefore this increase in catecholamines could enhance local intestinal adrenergic mechanisms, thereby reducing gut motility. The second part of this study focussed on the role of endogenous HA in mediating the intestinal inhibition induced by i.c.v.M. Pretreatment with i.c.v. MEP only partially reduced the block of gastrointestinal transit evoked by high doses of M and had no effect on the inhibition induced by low doses of M. This suggests that cerebral histamine might participate in the intestinal inhibition induced by M. This would agree with several studies supporting the idea that other actions of opiates may be mediated by HA such as analgesia (Hough, 1988), catalepsy (Malec and Langwinski, 1983) and hyperactivity (Mickley, 1986). HA turnover in the brain is modified by several drugs including opiates. M (Nishibori et al., 1985), DAGO, a specific /x agonist (Itoh et al., 1988), and [D-Ala 2, D-LeuS]enkephalin, a non-specific ~ agonist, but not ethylketazocine, a K agonist (Itoh et al., 1987), act on brain opiate receptors in mice to stimulate the activity of HA-releasing neurons.
Although the M-induced changes in brain HA turnover are likely to represent modulation of neuronal HA, brain mast cells should not be overlooked as a potential site of opiate action. The appreciable contribution of these cells to brain HA levels and the welldocumented ability of opiates to release HA from mast cells (Ellis et al., 1970; Rosow et al., 1982; Theoharides, 1990) suggest that opiates could release HA from these cells in the brain. To test this we used the inhibitor of histidine decarboxylase, a-FMH, and the mast cell degranulator, compound 48/80. a-FMH did not affect the M-induced inhibition of gastrointestinal motility, and 48/80 reduced the effect of M by about 30%. This reduction is the same as that seen with the H~ antagonist (fig. 6) at high doses of M, suggesting that M at these doses could release HA from a mast cell store. This would explain why MEP did not antagonize low doses of M and suggests that HA does not play a fundamental role in the gastrointestinal inhibition induced by central M. However, the amount of HA released from mast cells by high doses of M enhances the opioid effect on gut. In conclusion, this study shows that the antipropulsive effect of central HA depends on the amine's ability to modify the electromyographic motor profile of the jejunum in fasted rats and that activation of the catecholaminergic system is fundamental to this effect. Neuronal HA is not involved in the antitransit effect of M, which appears to be unrelated to the cerebral levels of the amine; only when high doses of opioid are used is HA released from mast cells, and this could contribute to the effect of M on the gut.
Acknowledgements This work was supported by a grant from the Italian Ministero della Pubblica Istruzione. Judy D. Baggot helped prepare the manuscript.
References Altaffer, F.B., V. De Balbian, S. Hall, C.J. Long and A. D'Encarnacao, 1970, A simple and inexpensive cannula tecnique for chemical stimulation of the brain, Physiol. Behav. 5, 119. Bennett, C.T. and A. Pert, 1974, Antidiuresis produced by injections of histamine into the cat supraoptic nucleus, Brain Res. 78, 156. Bhargava, K.P., V.K. Kulshrestha, G. Santhakumari and Y.P. Srivastava, 1973, Mechanism of histamine-induced antidiuretic response, Br. J. Pharmacol. 47, 700. Brezenoff, H.E. and P. Lomax, 1970, Temperature changes following microinjection of histamine into the thermoregulatory centers of the rat, Experientia (Basel) 26, 51. Brimblecombe, R.W. and C.R. Calcutt, 1974, The involvement of H 1 and H 2 histamine receptors in the hypothermic response to intracerebroventricularly injected histamine and related drugs, J. Pharmacol. (Paris) 5, 11.
264 Costentin, J., P. Boulu and J.C. Schwartz, 1973, Pharmacological studies on the role of histamine in thermoregulation, Agents Actions 3, 177. Donoso, A.O. and M. Barontini, 1986, Increase in plasma catecholamines by intraventricular injection of histamine in conscious rats, Naunyn-Schmiedeb. Arch. Pharmacol. 334, 188. Ellis, III, H.V., A.R. Jhonson and N.C. Moran, 1970, Selective release of histamine from rat mast cells by several drugs, J. Pharmacol. Exp. Ther. 175, 627. Fargeas, M.J., J. Fioramonti and L. Bueno, 1989, Involvement of different receptors in the central and peripheral effects of histamine on intestinal motility in the rat, J. Pharm. Pharmacol. 41, 534. Finch, L. and P.E. Hicks, 1976, The cardiovascular effects of intracerebroventricularly administered histamine in the anesthetized rats, Naunyn-Schmiedeb. Arch. Pharmacol. 293, 151. Hough, L.B., 1988, Cellular localization and possible functions for brain histamine: recent progress, Prog. Neurobiol. 30, 469. Itoh, Y., R. Oishi, M. Nishibori and K. Saeki, 1987, Involvement of opioid receptors in phencyclidine-induced enhancement of brain histamine turnover in mice, Naunyn-Schmiedeb. Arch. Pharmacol. 335, 285. Itoh, Y., R. Oishi, M. Nishibori and K. Saeki, 1988, Involvement of mu receptors in the opioid-induced increase in the turnover of mouse brain histamine, J. Pharmacol. Exp. Ther. 234, 1021. Keller, R., A. Oke, I. Mefford and N. Adams, 1976, Liquid chromatographic analysis of catecholamines routine assay for regional brain mapping, Life Sci. 19, 995. Klein, M.C. and S.B. Gertner, 1983, Studies of the mechanism of the cardiovascular action of central injections of histamine, Neuropharmacology 22, 1109. Kraly, F,S., 1985, Histamine: a role in normal drinking, Appetite 6, 153. Kraly, F.S. and L.A. Miller, 1982, Histamine-elicited drinking is dependent upon gastric vagal afferents and peripheral angiotensin II in the rat, Physiol. Behav. 28, 841. Lackovic, Z., M. Parenti and N.H. Neff, 1981, Simultaneous determination of femtomole quantities of 5-hydroxytryptophan, serotonin and 5-hydroxyindolacetic acid in brain using HPLC with electrochemical detection, Eur. J. Pharmacol. 69, 347. Leibowitz, S.F., 1973, Histamine: modifications of behavioral and physiological components of body fluid homeostasis in: Histamine Receptors, ed. T.O. Yelling (SP Medical and Scientific Books: New York).
Malec, D. and R. Langwinski, 1983, Is the brain histamine involved in cataleptogenic action of analgesics and haloperidol?, Life Sci. 33, 623. Mickley, G.A., 1986, Histamine H 2 receptors mediate morphine-induced locomotor hyperactivity of the C57BL/6J mouse, Behav. Neurosci. 100, 79. Nishibori, M., R. Oishi, Y. Itoh and K. Saeki, 1985, Morphine-induced changes in histamine dynamics in mouse brain, J. Neurochem. 45, 719. Parolaro, D., M. Sala and E. Gori, 1977, Effect of intracerebroventricular administration of morphine upon intestinal motility in rat and its antagonism with naloxone, Eur. J. Pharmacol. 46, 329. Parolaro, D., G. Patrini, P. Massi, P. Mainardi, G. Giagnoni, M. Sala and E. Gori, 1989, Histamine as a central modulator of rat intestinal transit, J. Pharmacol. Exp. Ther. 249, 324. Paxinos, G. and C. Watson, 1982, The Rat Brain in Stereotaxic Coordinates (Academic Inch., New York). Poulakos, J.J. and S.B. Gertner, 1986, Studies on the desensitization of the central cardiovascular responses of histamine, J. Pharmacol. Exp. Ther. 239, 730. Poulakos, J.J. and S.B. Gertner, 1989, Studies on the cardiovascular actions of central histamine H 1 and H 2 receptors, J. Pharmacol. Exp. Ther. 250, 500. Rosow, C.E., J. Moss, D.M. Philbin and J.J. Savarese, 1982, Histamine release during morphine and fentanyl anesthesia, Anesthesiology 56, 93. Ruckebush, M. and J. Fioramonti, 1975, Electrical spiking activity and propulsion in small intestine in fed and fasted rats, Gastroenterology 68, 1500. Schwartz, J.C., M. Garbarg and H. Pollard, 1986, Histaminergic transmission in the brain, in: Handbook of Physiology. The Nervous System. Intrinsic Regulatory Systems of the Brain, Sect. 1, Vol. IV, Ch. 5, ed. F.E. Bloom (American Physiological Society, Bethesda, MD) p. 257. Steel, F.G. and J.H. Torrie, 1960, Principles and Procedures of Statistics (McGraw-Hill, New York). Theoharides, T.C., 1990, Mast cells: the immune gate to the brain, Life Sci. 47, 607. Watanabe, T., A. Yamatodani, K. Maeyama and H. Wada, 1990, Pharmacology of a-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, Trends Pharmacol. Sci. 11, 363.
259
EJP 52237
Further investigations on the antipropulsive effect of centrally administered histamine and its relation with morphine G a b r i e l a Patrini, P a o l a Massi, T i z i a n a R u b i n o , L a u r a D o n i n , E n z o G o r i a n d D a n i e l a P a r o l a r o Institute of Pharmacology, Faculty of Sciences, University of Milan, Milan, Italy Received 27 May 1991,revised MS received 13 September 1991, accepted 29 October 1991
The effect of intracerebroventricularly (i.c.v.) administered histamine (100 p~g/rat) on intestinal myoelectrical activity was investigated in the jejunum of fasted rats. Histamine caused the disappearance of phase III and a partial reduction of phase II of migrating myoelectric complexes. This effect was antagonized by i.c.v, pretreatment with mepyramine (10 p.g/rat), an H~ receptor antagonist. Lesions of central noradrenergic neurons by i.c.v, injection of the neurotoxin 6-hydroxydopamine strongly reduced both the inhibition of intestinal propulsion and the migrating myoelectric complexes profile induced by i.c.v, histamine, whereas pretreatment with p-chlorophenylalanine, a selective depictor of serotonin stores, had no effect. It thus appears that aminergic pathways are involved in the visceral effects of central histamine. Mepyramine (200/xg/rat i.c.v.) partially reduced the slowing of intestinal transit induced by high doses of morphine. Pretreatment with compound 48/80 (10/xg/rat i.c.v.), a mast cell degranulator, but not with a-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, reduced the antipropulsive action of i.c.v, morphine to the same extent as mepyramine, suggesting that histamine released from cerebral mast cells by high doses of morphine could contribute to the intestinal inhibition by morphine. Histamine; Morphine; Intestinal motility
1. Introduction
In recent years evidence has emerged that histamine acts as a neurotransmitter in the mammalian brain. Its role in neuroregulation was elucidated by identification of the histaminergic neuron system (Hough, 1988) and the characterization of specific pre- and postsynaptic receptor subtypes (Schwartz et al., 1986; Watanabe et al., 1990). There is also considerable evidence that histamine and its receptors are involved in the central regulation of some vegetative activities such as hypothermia (Brezenoff and Lomax, 1970; Brimblecombe and Calcutt, 1974; Costentin et al., 1973), cardiovascular regulation (Klein and Gertner, 1983; Poulakos and Gertner, 1986; Poulakos and Gertner, 1989), water intake (Kraly and Miller, 1982; Kraly, 1985) and antidiuretic hormone release (Bennett and Pert, 1974). Our recent studies have shown that cerebral histamine H t receptors appear to be involved in the inhibition of intestinal transit and analgesia induced by intracerebroventricular (i.c.v.) histamine (Parolaro et
al., 1989). These receptors become desensitized after repeated i.c.v, injections of histamine, resulting in strong tachyphylaxis to both effects (Parolaro et al., 1989). Thus the central histaminergic system could be involved in the modulation of gastrointestinal motility. To characterize the antipropulsive effect of centrally administered histamine further, we monitored intestinal myoelectrical activity in conscious rats and attempted to identify the neuronal pathway involved in this effect. Finally, in the light of reports that the amine might be involved in the analgesia, tolerance and physical dependence induced by central morphine (Hough, 1988), the second aim of the present study was to investigate the influence of central histamine pools (neurons and mast cells) on the inhibition of gastrointestinal motility evoked by centrally administered morphine.
2. Materials and methods 2.1. Animals
Correspondence to: D. Parolaro, Institute of Pharmacology,Faculty of Sciences, Universityof Milan, Via Vanvitelli 32/A, 20129 Milan, Italy. Tel. 39.27.385 568, fax 39.27.000 2270.
Female Sprague-Dawley rats were used, weighing either 180-200 or 280-300 g depending on the experiments, fed on a pellet diet with water ad libitum.
260 Environmental conditions were standardized (22 + 2°C, 60% humidity and 12 h artificial lighting per day). Before treatment the animals were randomizied according to a complete block design and fasted for 15-18 h.
2. 2. Drugs The following drugs were used: histamine (HA, Sigma Chemical Co., St. Louis, MO), mepyramine maleate (MEP, Sigma Chemical Co.), DL-p-chlorophenylalanine (p-CPA, Sigma Chemical Co.), 6-hydroxydopamine hydrobromide (6-OHDA, Sigma Chemical Co.), compound 48/80 (Sigma Chemical Co.), afluoromethylhistidine monohydrochloride hemihydrate (a-FMH, kindly supplied by Merck Sharp & Dohme Research Laboratories, Rahway, NJ, U.S.A.), morphine hydrochloride (M, S.I.F.A.C., Milan, Italy). All the drugs were dissolved in saline except for 6-OHDA, which was dissolved in saline with 0.1% ascorbic acid.
2.3. I.c.v. microinjection The rats were anesthetized with tribromoethanol (200 mg/kg i.p.) and prepared for i.c.v, microinjections according to Altaffer's procedure (Altaffer et al., 1970). Briefly, anesthetized rats were fixed in a stereotaxic apparatus and the right lateral ventricle was located using a stereotaxic atlas (Paxinos and Watson, 1982). A permanent polyethylene cannula (Ulrich and Co., type PE 10) was implanted to penetrate the ventricle 4.5 mm from the top of the skull, and was fixed to the skull with dental cement (Hottinger Baldwin Messtechnik, type X 60). After the operation the animals were placed in individual cages and allowed to recover for five days. Drug solutions in a constant volume of 5 /~1 were injected in conscious rats by inserting a Hamilton microsyringe into the cut cannula tip. Control rats were injected i.c.v, with 5 /zl of saline. At the end of each experiment rats were killed by decapitation and 5 tzl Evans blue dye (0.5%) was microinjected through the cannula and after 5 min the brains were removed and placed in 10% formalin. The brains were frozen 24 h later, cut to a thickness of 80 /zm, and examined microscopically to verify cannula placements.
2.4. 6-OHDA and p-CPA injection To lesion noradrenaline pathways, 6-OHDA (200 # g / r a t ) in 0.1% ascorbic acid was injected i.c.v, on two consecutive days; six days after the microinjection of vehicle or toxin, the rats were given HA (100 tzg/rat) i.c.v. Noradrenaline was assayed in the hypothalamus, midbrain and spinal cord by high-pressure liquid chro-
matography (HPLC) with electrochemical detection according to Keller et al. (1976). To induce serotonin (5-HT) depletion, one group of rats received 100 mg/kg of p-CPA methyl ester i.p. for three days; 24 h after the third injection the rats received HA (100 /~g/rat) i.c.v. 5-HT was assayed in the midbrain and in the spinal cord according to the method of Lackovic et al. (1981).
2.5. Intestinal transit Intestinal transit was assessed in fasted rats on the basis of the progression of a charcoal meal through the small intestine (Parolaro et al., 1977). The animals were killed by cervical dislocation 20 min after the charcoal meal. The whole gastrointestinal tract was quickly and carefully removed and the small intestine was gently stretched to its full length. The distance the meal had traveled from the pylorus to the cecum was measured and expressed as the percentage inhibition in relation to control transit (Tc) as follows: (Tc Tt)/T ~ • 100 where T t is the transit in treated animals. A preliminary statistical covariance test showed that the total intestinal length was independent of an animal's weight and not significantly different from one rat to another.
2.6. Motility Motility was recorded as myoelectric activity in conscious adult female rats weighing 280-300 g . Anesthetized rats were prepared chronically with pairs of insulated Ni/Cr electrodes (100 tzm in diameter) implanted along the jejunum (40-45 cm from the pylorus). The free ends of the electrodes were carried s.c. to the back of the neck, exteriorized on the top of the skull and connected to the socket (Souriau, Boulogne, France). Solder connections to the socket were encapsulated in dental acrylic cement (Hottinger Baldwin Messtechnik, type X 60). The animals were also fitted with cannulas for i.c.v, microinjections. Measurements of intestinal myoelectric activity began 7-10 days after the operation, when the animals had completely recovered. Each animal was housed in a wire-bottomed cage and was fasted 18 h before recording. Water was allowed ad libitum. Bipolar recordings were made from conscious, unrestrained animals by connecting the electrode socket with a direct writing polygraph (Battaglia-Rangoni, Bologna, Italy), at a time constant of 0.1 s. Myoelectrical activity was separated into slow waves and spikes by using low band-pass and high band-pass filters, respectively. Spike electrical activity and slow waves were summed every 20 s by an integrator circuit connected to a potentiometric recorder. The integrated records of electrical activity are expressed in
261 mml 5ahnr
+ HA
[;~ p-CPA ÷ scllne p--CPA + 14k 100
z
O "20"
......
E
]
m
5o
I Z
i HISTAMINE (100 p g / R A T / l e V I
ae SLOW Ir u.| ru ..,luk, ill I I i . _all. . . . ... J k ~ l i - I L , WAVI~SU
tllbb, II . . . . . .
I
Fig. 2. Effect of p-CPA pretreatment (100 mg/kg i.p. for three days) on the intestinal inhibition induced by i.c.v, histamine (HA, 100 /~g/rat).
20'
mepyramine (MEP, 30 rain before) fully prevented the effect of H A (fig. 1).
.....
4 ' 20" HISTAMINE ( 10OMg/RAT/leVI
MEPYRAMINE
120/a:j/RAT/ICV
)
Fig. 1. Effect of histamine (100 #g/rat i.c.v.) and its antagonism by mepyramine (10 ~g/rat i.c.v. 30 min before) on the myoelectrical activityof the jejunum in fasted rats (integrated records).
/ z C / m i n as a motility index. This integrated record gave a clear picture of the pattern of intestinal activity.
2. 7. Statistical analysis The data reported are means + S.E. Results were analyzed statistically with a one-way analysis of variance and compared by using Tukey's procedure (Steel and Torrie, 1960).
3. Results
3,1. Myoelectrical activity Jejunal myoelectrical activity before and after i.c.v. H A is shown in fig. 1. A typical recording from small intestine after an 18-h fast comprises a basal rhythm (slow waves) and spiking activity organized in migrating myoelectric complexes (MMC) at regular intervals of 17 + 1.43 min. I.c.v. microinjection of 100 ~ g / r a t of H A (a dose causing about 90% inhibition of intestinal transit in the charcoal meal test) caused the disappearance of phase III and a partial reduction of phase II of the MMC. The mean duration of the loss of phase III activity was 71.5 + 10.3 min (n = 6). At the end of this period the MMC were restored. The basal rhythm was unaffected by H A (fig. 1). As previously seen in transit experiments (Parolaro et al., 1989), pretreatment with
3.2. 5-HT depletion The role of the serotoninergic system in the gastrointestinal inhibition evoked by i.c.v. H A was investigated after selective depletion of 5-HT by p-CPA pretreatment. This procedure had no effect on the antipropulsive effect of i.c.v. HA, with intestinal inhibition being the same in pretreated rats as in rats injected with H A alone (fig. 2). 5-HT levels were lowered by p-CPA, by 50% in the midbrain (control value 1200 + 47 n g / g wet weight of tissue) and by 75% in the spinal cord (control value 565 + 40 n g / g wet weight of tissue).
3.3. Noradrenaline (NA) depletion I.c.v. 6 - O H D A caused a substantial depletion of noradrenaline in the midbrain (82%, control value 360 + 70 n g / g wet weight of tissue), hypothalamus (86%, control value 660 __ 120 n g / g wet weight of tissue) and spinal cord (83%, control value 266 _+ 16 n g / g wet weigh of tissue). In these 6-OHDA-pretreated rats the antipropulsive effect of H A was significantly reduced from 85 to 10% (F(3,9)= 50.97, P <
100
IMm saline + HA [ 2 ~ 6-OHDA + saline 6-OHDA + HA
Z
o T Z
so
te
Fig. 3. Effect of 6-OHDA pretreatment (200 /.tg/rat i.c.v, for two days) on the intestinal inhibition induced by i.c.v, histamine (HA, 100 /zg/rat). ** P < 0.001 vs. saline+HA.
262
1O0
I---I a-FMH + =;aline i l l 4 8 / 8 0 + saline tN~'R saline + M t-TU] a-FMH + IA 82Z1 4 8 / 8 0 + M
z o I---
......
20--
(
6-OHDA
T
50
Z
HISTAMINE
( 200 p , , g / R A T / ICV/X 2 |
(100/~/RAT/ICV)
Fig. 4. Effect of 6 - O H D A pretreatment (200 / z g / r a t i.c.v, for two days) on the reduction of the histamine spike potential in the jejunum of fasted rats (integrated records).
0.001) (fig. 3). The importance of the noradrenergic system in mediating the antitransit effect of central HA was confirmed by electromyographic experiments (fig. 4). Six days after 6-OHDA pretreatment HA no longer abolished spiking activity, the MMC remaining at the same frequency as before treatment (21 + 0.7 vs. basal frequency 18.3 __+0.3).
Fig. 6. Effect of pretreatment with a - F M H (200 / x g / r a t i.c.v. 3 h before) and compound 4 8 / 8 0 ( 1 0 / z g / r a t i.c,v. 24 h before) on the intestinal inhibition evoked by morphine (M, 3 6 / ~ g / r a t i.c.v.).
evoked by i.c.v.M. However, i.c.v, pretreatment with compound 48/80 (24 h before), a mast cell degranulatar, caused a partial reduction (about 25%) of the intestinal inhibition induced by M (fig. 6).
4. Discussion
3.4. Role of the histaminergic system in morphine-induced intestinal inhibition Figure 5 shows the dose-related inhibition of gastrointestinal transit after i.c.v. M in rats. When M was preceded by i.c.v. MEP, the effect of M on intestinal transit was only partially reduced (about 30%) and only at high doses of M (from 18 to 72 /~g/rat); at lower doses intestinal inhibition was the same after M alone and after pretreatment with MEP (fig. 5). Thus to clarify the role of the endogenous HA system in the intestinal inhibition induced by M, we used a-FMH and compound 48/80 to deplete neuronal and mast cell HA pools, respectively. Figure 6 shows the effect of ot-FMH, a specific and irreversible inhibitor of histidine decarboxylase, on the antipropulsive effects of centrally administered M. ot-FMH per se did not affect intestinal transit or reduce the intestinal inhibition 0"="~0 saline + M
e~l 100 z 0
75
If °
IdEP + M
.-----O
O
I
1
i----
m Z 50 1/2 Z
~
25
~/RAT/~CV
Fig. 5. Effect of pretreatment with mepyramine(MEP, 200 /zg/rat i.c.v.) on the dose-response curve for the inhibition of intestinal propulsion inducedby i.c.v,morphine(M).
The present findings provide extra information on the antipropulsive effect of central HA and the role of the histaminergic system in the opioid inhibition of gastrointestinal motility. Firstly, we have clarified the action of central HA on intestinal motility, showing that the antipropulsive effect of centrally administered HA could be related to the amine's ability to modify the regular appearance of MMC in the jejunum of fasted rats. In fact, i.c.v. HA in fasted rats caused a motor change characterized by the disappearance of phase III (regular spiking activity) and a partial reduction of phase II (irregular spiking activity) of the MMC. The various phases of the MMC and the movement of intraluminal contents are known to be related. Studies by Ruckebusch and Fioramonti (1975) have shown that the intraluminal contents are moved during phase II activity and that material already present in the bowel is mainly propelled during the transition from phase II to phase III activity. Thus the effect of central HA on myoelectric activity may be related to the block of gastrointestinal transit already observed in the charcoal meal test (Parolaro et al., 1989). Our data are not entirely consistent with those of Fargeas et al. (1989), who reported that i.c.v. HA had no effect on the electromyographic profile of the jejunum. However, Fargeas used a dose of HA about 20 times lower than ours (5 /xg/rat) and they did not assess whether this dose actually affected gastrointestinal propulsion. Our previous work has shown that HA blocks gastrointestinal transit in a dose range from 20 to 100/zg/rat. Thus the dose of 5 / x g / r a t may well be too low to affect both the electromyographic profile and gastrointestinal propulsion. In addition, the obser-
263
vation that pretreatment with MEP antagonized these effects of HA confirms that the amine's central action in the gut is mediated by the activation of cerebral H1 receptors. The present results also suggest that activation of noradrenaline pathways in the central nervous system mediates the changes in gastrointestinal motility that follow i.c.v. HA. In fact, after i.c.v, injection of the neurotoxin 6-OHDA, which damages cerebral noradrenaline-containing neurons, HA did not alter either the electromyographic recording or gastrointestinal transit. These results are in agreement with previous findings that cerebral catecholamine pathways may contribute to other central effects of HA, e.g. the antidiuretic (Leibowitz, 1973; Bhargava et al., 1973) and hypertensive actions (Finch and Hicks, 1976). Thus our data seem to indicate that the gastrointestinal motor changes induced by i.c.v. HA result from activation of catecholaminergic pathways. Donoso and Barontini (1986) demonstrated that i.c.v, administered HA promoted the release of adrenaline and noradrenaline in conscious rats, as shown by an increase in plasma concentrations of these catecholamines. These authors suggested that catecholamine might be released through a close association of HA with a hypothalamic catecholaminergic mechanism. Interaction may take place in the paraventricular and supraoptic nuclei where an ascending adrenergic circuit integrates autonomic regulation, or, alternatively, in the caudal hypothalamic area where adrenergic structures have an important role in the regulation of pressor responses to HA. Such responses always occur with gastroiintestinal actions, as demonstrated by the strong increase in blood pressure induced by i.c.v, administered amine (data not shown). Therefore this increase in catecholamines could enhance local intestinal adrenergic mechanisms, thereby reducing gut motility. The second part of this study focussed on the role of endogenous HA in mediating the intestinal inhibition induced by i.c.v.M. Pretreatment with i.c.v. MEP only partially reduced the block of gastrointestinal transit evoked by high doses of M and had no effect on the inhibition induced by low doses of M. This suggests that cerebral histamine might participate in the intestinal inhibition induced by M. This would agree with several studies supporting the idea that other actions of opiates may be mediated by HA such as analgesia (Hough, 1988), catalepsy (Malec and Langwinski, 1983) and hyperactivity (Mickley, 1986). HA turnover in the brain is modified by several drugs including opiates. M (Nishibori et al., 1985), DAGO, a specific /x agonist (Itoh et al., 1988), and [D-Ala 2, D-LeuS]enkephalin, a non-specific ~ agonist, but not ethylketazocine, a K agonist (Itoh et al., 1987), act on brain opiate receptors in mice to stimulate the activity of HA-releasing neurons.
Although the M-induced changes in brain HA turnover are likely to represent modulation of neuronal HA, brain mast cells should not be overlooked as a potential site of opiate action. The appreciable contribution of these cells to brain HA levels and the welldocumented ability of opiates to release HA from mast cells (Ellis et al., 1970; Rosow et al., 1982; Theoharides, 1990) suggest that opiates could release HA from these cells in the brain. To test this we used the inhibitor of histidine decarboxylase, a-FMH, and the mast cell degranulator, compound 48/80. a-FMH did not affect the M-induced inhibition of gastrointestinal motility, and 48/80 reduced the effect of M by about 30%. This reduction is the same as that seen with the H~ antagonist (fig. 6) at high doses of M, suggesting that M at these doses could release HA from a mast cell store. This would explain why MEP did not antagonize low doses of M and suggests that HA does not play a fundamental role in the gastrointestinal inhibition induced by central M. However, the amount of HA released from mast cells by high doses of M enhances the opioid effect on gut. In conclusion, this study shows that the antipropulsive effect of central HA depends on the amine's ability to modify the electromyographic motor profile of the jejunum in fasted rats and that activation of the catecholaminergic system is fundamental to this effect. Neuronal HA is not involved in the antitransit effect of M, which appears to be unrelated to the cerebral levels of the amine; only when high doses of opioid are used is HA released from mast cells, and this could contribute to the effect of M on the gut.
Acknowledgements This work was supported by a grant from the Italian Ministero della Pubblica Istruzione. Judy D. Baggot helped prepare the manuscript.
References Altaffer, F.B., V. De Balbian, S. Hall, C.J. Long and A. D'Encarnacao, 1970, A simple and inexpensive cannula tecnique for chemical stimulation of the brain, Physiol. Behav. 5, 119. Bennett, C.T. and A. Pert, 1974, Antidiuresis produced by injections of histamine into the cat supraoptic nucleus, Brain Res. 78, 156. Bhargava, K.P., V.K. Kulshrestha, G. Santhakumari and Y.P. Srivastava, 1973, Mechanism of histamine-induced antidiuretic response, Br. J. Pharmacol. 47, 700. Brezenoff, H.E. and P. Lomax, 1970, Temperature changes following microinjection of histamine into the thermoregulatory centers of the rat, Experientia (Basel) 26, 51. Brimblecombe, R.W. and C.R. Calcutt, 1974, The involvement of H 1 and H 2 histamine receptors in the hypothermic response to intracerebroventricularly injected histamine and related drugs, J. Pharmacol. (Paris) 5, 11.
264 Costentin, J., P. Boulu and J.C. Schwartz, 1973, Pharmacological studies on the role of histamine in thermoregulation, Agents Actions 3, 177. Donoso, A.O. and M. Barontini, 1986, Increase in plasma catecholamines by intraventricular injection of histamine in conscious rats, Naunyn-Schmiedeb. Arch. Pharmacol. 334, 188. Ellis, III, H.V., A.R. Jhonson and N.C. Moran, 1970, Selective release of histamine from rat mast cells by several drugs, J. Pharmacol. Exp. Ther. 175, 627. Fargeas, M.J., J. Fioramonti and L. Bueno, 1989, Involvement of different receptors in the central and peripheral effects of histamine on intestinal motility in the rat, J. Pharm. Pharmacol. 41, 534. Finch, L. and P.E. Hicks, 1976, The cardiovascular effects of intracerebroventricularly administered histamine in the anesthetized rats, Naunyn-Schmiedeb. Arch. Pharmacol. 293, 151. Hough, L.B., 1988, Cellular localization and possible functions for brain histamine: recent progress, Prog. Neurobiol. 30, 469. Itoh, Y., R. Oishi, M. Nishibori and K. Saeki, 1987, Involvement of opioid receptors in phencyclidine-induced enhancement of brain histamine turnover in mice, Naunyn-Schmiedeb. Arch. Pharmacol. 335, 285. Itoh, Y., R. Oishi, M. Nishibori and K. Saeki, 1988, Involvement of mu receptors in the opioid-induced increase in the turnover of mouse brain histamine, J. Pharmacol. Exp. Ther. 234, 1021. Keller, R., A. Oke, I. Mefford and N. Adams, 1976, Liquid chromatographic analysis of catecholamines routine assay for regional brain mapping, Life Sci. 19, 995. Klein, M.C. and S.B. Gertner, 1983, Studies of the mechanism of the cardiovascular action of central injections of histamine, Neuropharmacology 22, 1109. Kraly, F,S., 1985, Histamine: a role in normal drinking, Appetite 6, 153. Kraly, F.S. and L.A. Miller, 1982, Histamine-elicited drinking is dependent upon gastric vagal afferents and peripheral angiotensin II in the rat, Physiol. Behav. 28, 841. Lackovic, Z., M. Parenti and N.H. Neff, 1981, Simultaneous determination of femtomole quantities of 5-hydroxytryptophan, serotonin and 5-hydroxyindolacetic acid in brain using HPLC with electrochemical detection, Eur. J. Pharmacol. 69, 347. Leibowitz, S.F., 1973, Histamine: modifications of behavioral and physiological components of body fluid homeostasis in: Histamine Receptors, ed. T.O. Yelling (SP Medical and Scientific Books: New York).
Malec, D. and R. Langwinski, 1983, Is the brain histamine involved in cataleptogenic action of analgesics and haloperidol?, Life Sci. 33, 623. Mickley, G.A., 1986, Histamine H 2 receptors mediate morphine-induced locomotor hyperactivity of the C57BL/6J mouse, Behav. Neurosci. 100, 79. Nishibori, M., R. Oishi, Y. Itoh and K. Saeki, 1985, Morphine-induced changes in histamine dynamics in mouse brain, J. Neurochem. 45, 719. Parolaro, D., M. Sala and E. Gori, 1977, Effect of intracerebroventricular administration of morphine upon intestinal motility in rat and its antagonism with naloxone, Eur. J. Pharmacol. 46, 329. Parolaro, D., G. Patrini, P. Massi, P. Mainardi, G. Giagnoni, M. Sala and E. Gori, 1989, Histamine as a central modulator of rat intestinal transit, J. Pharmacol. Exp. Ther. 249, 324. Paxinos, G. and C. Watson, 1982, The Rat Brain in Stereotaxic Coordinates (Academic Inch., New York). Poulakos, J.J. and S.B. Gertner, 1986, Studies on the desensitization of the central cardiovascular responses of histamine, J. Pharmacol. Exp. Ther. 239, 730. Poulakos, J.J. and S.B. Gertner, 1989, Studies on the cardiovascular actions of central histamine H 1 and H 2 receptors, J. Pharmacol. Exp. Ther. 250, 500. Rosow, C.E., J. Moss, D.M. Philbin and J.J. Savarese, 1982, Histamine release during morphine and fentanyl anesthesia, Anesthesiology 56, 93. Ruckebush, M. and J. Fioramonti, 1975, Electrical spiking activity and propulsion in small intestine in fed and fasted rats, Gastroenterology 68, 1500. Schwartz, J.C., M. Garbarg and H. Pollard, 1986, Histaminergic transmission in the brain, in: Handbook of Physiology. The Nervous System. Intrinsic Regulatory Systems of the Brain, Sect. 1, Vol. IV, Ch. 5, ed. F.E. Bloom (American Physiological Society, Bethesda, MD) p. 257. Steel, F.G. and J.H. Torrie, 1960, Principles and Procedures of Statistics (McGraw-Hill, New York). Theoharides, T.C., 1990, Mast cells: the immune gate to the brain, Life Sci. 47, 607. Watanabe, T., A. Yamatodani, K. Maeyama and H. Wada, 1990, Pharmacology of a-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, Trends Pharmacol. Sci. 11, 363.