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Hypothalamic neuronal responses to iontophoretic application of morphine in rats
HYPOTHALAMIC
NEURONAL
RESPONSES
TO IONTOPHORETIC
APPLICATION
OF MORPHINE
IN RATS
M.T. Lin, W.N. Uang and H.K. Chan Department National
of Physiology
Defense
Medical
Republic
(Accepted
and Biophysics,
Center,
Taipei,
Taiwan,
of China.
28 Febmmtg
J9b?)
Summary. Effects of thermal stimulation of the scrotum and of iontophoretic application of morphine on the activity of neurones in the preoptic anterior hypothalamic area were observed in 30 urethaneanaesthetised rats. The proportions of cold-responsive, warm-responsive and thermally unresponsive units were 20.7, 28.3 and 51%, respectively, of the total number of neurones tested. Iontophoretic application of morphine to neurones in the preoptic anterior hypothalamic area in rats resulted in excitation of the majority of cold-responsive cells and inhibition of the majority of warm-responsive cells tested. However, most of the thermally unresponsive cells were unaffected by application of morphine. These results provide a neuronal basis for the hypothesis that morphine, when administered directly into the hypothalamus, facilitates heat production and inhibits heat loss, which leads to hyperthermia.
It has been documented repeatedly that, in the rat, systemic or intrahypothalamic administration of a small dose of morphine or beta-endorphin causes hyperthermia (Hermann, 1942; Cox, Ary, Chesarek and Lomax, 1976; Martin and Bacino, 19'18;Lin, 1982). The hyperthermia in response to application of morphine or beta-endorphin is due to an increase in metabolic heat production and a decrease in heat loss (e.g. cutaneous vasoconstriction) in rats (Lin, 1982). However, relatively little information is available about the effect of direct application of morphine on unit activity within the preoptic anterior hypothalamic area. It was therefore of interest to observe (a) how thermal stimulation of the scrotum would affect the activity of neurones in the preoptic anterior hypothalamic area, (b) how direct application of morphine would affect neuronal activity in the hypothalamus, and (c) whether any changes in neuronal activity could be related to the action of morphine.
METHODS
Adult male Sprague-Dawley rats, weighing between 250 and 300 g, were used. Each animal was anaesthetised with urethane (1.25 g/kg, i.p.). The rectal temperature was maintained between 36.9 -37.4'C using a water-perfused pad under the animal. All the fur of the scrotum was removed with clippers. The animals were mounted stereotaxically with the heads fixed according to the coordinates of Kijnig and Klipper (1963). A piece of bone was removed from the right half of the skull and the underlying dura was removed. Recording of single unit discharges were made from the right half of the preoptic anterior hypothalamic area at stereotaxic coordinates of A:6.5-7.2; L:O.2-1.2; and H: -0.8 to -1.4 mm (Lin, 1982; Lin, Wu, Chandra and Tsay, 1982). The tips of the three-barreled micropipettes were broken back to a diameter of 4.2?1 pm. The central barrel was filled with 4M N&l, saturated with fast green recording. One of the side barrels was filled with 2M dye, and was used for extracellular NaCl and was used to balance the currents passed through the other barrels. The remaining side barrel was filled with 0.05M morphine sulphate, pH 4.4f0.3 (Merck, Sharp and Dohme, West Point, PA, USA). The impedance, measured at 1,000 Hz by an impedance module, ranged from 3 to 7 megohms for the recording barrel, from 6 to 10 megohms for the balance barrel and from 8 to 12 megohms for the drug-containing barrel. The drugs was retained in or ejected from the micropipette by an electrophoretic unit. The retaining current was 7.5 nA and the ejection current varied from 5 to 100 nA. After the micropipette had been lowered to the desired location in the hypothalamus, a hydraulic microdrive was used to slowly advance the micropipette. The single unit activity was processed using a standard cathode follower 591
592
Preliminary
Notes
and amplification circuitry for extracellular spike potentials (Lin and Simon, 1982). Impulses were counted at 1 sec. intervals by a WPI Scope Raster(Slipper Model 140 and displayed on a Grass Polygraph. The rectal and scrotal temperatures were displayed on the same polygraph record. The method used for thermal stimulation of the scrotum was similar to that described by Hellon and Misra (1973). The skin temperature was measured by a thermocouple which was cemented to the surface of the thermode which was in contact with the skin. Thermal responsiveness was judged by observation of changes in the neuronal discharge rate in response to warming and cooling of the scrotum, and the neurones encountered in this study were classified as thermally unresponsive, warm-responsive or coldresponsive. The warm-responsive units were excited by an increase in scrotal temperature. the cold-responsive units were excited by a decrease in scrotal temperature. Units that were not affected by changes in scrotal temperature were regarded as thermally unresponsive. A change of 25% or more in the spontaneous firing rate in response to application of morphine was the criterion used to define whether a neurone was excited or inhlbited. A lack of response to the test substance was considered valid only if adjacent neurones were affected by the same substance. Statistical significance of the tabulated data was determined using ax 2 test and a 2 x 3 contingency table. Differences were considered statistically significant at p < 0.05. At the end of each experiment, the vertical location of the micropipette was recorded and 25 PA of negative current was passed through the micropipette for 10 min. to deposit fast green dye at the site (Hosford and Haigler, 1980). The locations of the fast green dye spots were used to verify the locations of the recording sites.
RESULTS
Fiftythree single neurones in the preoptic anterior hypothalamic area were examined in 30 rats under urethane anaesthesia. Each unit was subjected to scrotal warming or cooling and to the administration of morphine. Table 1 shows the responses of these hypothalamic neurones, classified by thermal responsiveness to microiontophoretic application of morphine. Of 11 cold-responsive units recorded in the preoptic anterior hypothalamic area, 8 were excited by application of morphine. A typical excitatory response to morphine of a cold-responsive unit, recorded in the preoptic anterior hypothalamic region is illustrated in Figure 1. A microiontophoretic application of morphine (35-65 nA) for about 0.5 min. produced a dose-dependent increase (above control level) in the spontaneous firing rate of this unit. Positive current of the same magnitude (65 "A), applied through the NaClunits behaved in a different containing barrel, was without effect. Another 2 cold-responsive way; these neurones decreased their firing rates with application of morphine. The remainder (1 unit) of the total population of cold-responsive neurones showed no response to iontounits phoretic application of morphine (5-100 nA). On the other hand, of 15 warm-responsive recorded in the preoptic anterior hypothalamic area, 8 were depressed by application of morphine. A typical inhibitory response of a warm-responsive neurone is illustrated in Figure 2. A microiontophoretic application of morphine (lo-50 "A) for about 0.5 min. caused a dose-dependent decrease in the spontaneous discharge rate of this neurone. In 4 out of 15 warm-responsive neurones, the firing rates were unaffected by application of morphine. The remainder (3) increased their firing rates in response to application of morphine. However, the majority (18 out of 27) of the total population of thermally unresponsive units, recorded in the preoptic anterior hypothalamic area, showed no response to iontophoretic application of morphine (Table 1).
DISCUSSION
In the present study, when the 53 units recorded in the region of the preoptic anterior hypothalamus were classified by their thermal responsiveness, in response to warm-responsive and changes in scrotal temperature, the proportions of cold-responsive, thermally unresponsive neurones were 20.7, 28.3 and 519, respectively, of the total neurones tested. This distribution in not greatly different from data reported previously for the hypothalamic region in rats (Nakayama, Tshikawa and Tsurutani, 1979). The results also demonstrate that thermally responsive units in the preoptic anterior hypothalamic region were selectively affected by application of morphine. As indicated in Table 1, most of the warm-responsive (73.3%) and cold-responsive (91%) neurones were affected by application of morphine, while only 33.3% of the thermally unresponsive neurones were affected by morphine. The differences between the responses to morphine of the warm-responsive and cold-responsive neurones, and thermally unresponsive neurones are significant (p i 0.05). In addition, there is a significant difference (p c 0.05) between the responses to application of morphine between warm-responsive and cold-responsive neurones. As indicated in Table 1, most of the cold-responsive units (72.7%) were excited by application of morphine, while most of the warm-responsive neurones (53.3%) were inhibited by application of morphine. The excitatory responses of the cold-responsive neurones and the inhibitory responses of warm-responsive
Preliminary
Table --'
1
Effects
of morphine
warm-responsive --
Unit type
on 53 hypothalamic
or thermally _.~~
Notes
593
classified units ~-
as cold-responsive,
unresponsive.
Responses
No. of units tested
Excitation
to morphine
Inhibition
None
Cold-responsive
11
8 (72.7%)
2 (18.3%)
Warm-responsive
15
3 (20%)
8 (53.3%)
4 (26.7%)
Thermally
27
3 (11.1%)
6 (22.2%)
18 (66.7%)
unresponsive
14
53
Total
1 (9%)
23
16
The difference between responses to morphine of either cold-responsive or warm-responsive neurones and thermally unresponsive neurones is significant (&? c 0.05, using a x2 test and between responses a 2 x 3 contingency table). In addition there is a significant difference to morphine for warm-responsive and cold-responsive neurones (p i 0.05, using a x2 test and a 2 x 3 contingency table).
45 SCROTAL
35
TEMPERATURE
t’c 1
25 15
I
morrrhinc
Saline
63nA
Figure _____-
35 iiA
I mOrDhine
65’nA
unit in the preoptic anterior hypothalamic area 2. Excitation of a cold-responsive produced by iontophoretic application of morphine (35-65 nA). Positive current (65 nA), applied through the NaCl barrel, was without effect. The firing rate of the neurone increased with a decrease in scrotal temperature.
45
SCROTAL TEMF’ERATUREPC)
35
25 I5
FIRING
I min
Fi&re _-"-2.
RATE
Solinc
50 nA
(impulses/sact
morphine 50 nA
tsWphlne 10 nA
morphine 30 nA
Inhibition of a warm-responsive unit in the preoptie anterior hypothalamic area produced by iontophoretic application of morphine (IO-50 nA). Positive current (50 nA), applied through the NaCl barrel, was without effect. The firing rate of the neurone increased with increase in scrotal temperature.
Preliminary
594
Notes
"eurones to application of morphine were similar to the thermoregulatory responses provoked by intrahypothalamic administration of morphine (Lin, 1982). The responses of these presumed thermoregulatory "eurones to application of morphine are compatible with, and may therefore be involved in, inducing the hyperthermic effects (including both augmented heat production and depressed heat lass) which are characteristic of administration of morphine. Therefore, the present results provide a neuronal basis for the hypothesis that morphine facilitates heat production and inhibits heat loss in the region of the preoptic anterior hypothalamus. However, an abstract published by Baldino, Beckman and Adler (1979) has presented different results from those described above. These investigators reported that iontophoretic application of morphine to neurones in the preoptic anterior hypothalamic area in rats resulted in excitation of the majority of warm-responsive cells and inhibition of the majority of cold-responsive cells. There was no difference in the anaesthetic (urethane) used I" the two studies. However, Baldino ct al., determined thermal responsiveness by observation of changes in neuronal discharge rates in response to hypothalamic, rather than scrotal skin, temperature changes. Thus, it is possible that the difference between the results in the two studies might be due to the different populations or categories of hypothalamic neurones tested. Acknowledgements.
The work was supported by grants from the Alexander vo" Humboldt Stiftung, Godesberg, Bonn, FRG and the National Science Council of the Republic of China.
REFERENCES
Baldino, F. Jr., Beckman, A.L. and Adler, M.W. (1979). Actions morphine on rat hypothalamic temperature-sensitive neurons.
of iontophoretically applied Soc.Neuro~ci.Ab::tr.5:548.
Cox, B., Ary, M., Chesarek, W. and Lomax, P. (1976). Morphine hyperthermia action on the central thermostats. ?~zir.J.i%nmnac., 36:33-39.
in the i-at: a"
Hello", R.F. and Misra, N.K. (1973). Neurons in the ventrobasal complex of the rat thalamus responding to scrotal ski" temperature changes. rJ.F’h~~io7., 232:389-399. Hermann, T/wr.
,
J.B. (1942). The pyretic 76:309-315.
action on rats of small doses of morphine.
d.I~~2armn.:.zrp.
different effects on Hosford, D. and Haigler, H.J. (1980). Morphine and met-enkephalin: spontaneous and evoked neuronal firing in the mesencephalic reticular formation of the rat. J. %cmac. eq. T&i?. , 213 _. :355-363. Kb;nig, J.F.R. and Kllppel, R.A. (1963). The Rat Brain: a Stereotaxic Atlas of the Forebrain Baltimore, MD: Williams & Wilkins. and Lower Parts of the Brain Stem Lin, M.T. (1982). An adrenergic link in the hypothalamic pathways which mediate morphineand beta-endorphin-Induced hyperthermia in the rat. flcuri?r;?arma~'., 21:613-617. AMP link in Ll", M.T., Wu, J.J., Chandra, A. and Tsay, B.L. (1982). A "orepinephrine-cyclic the hypothalamic pathways which mediate fever induced by endotoxin and prostaglandin E-2 in the rat. ~i.;s13r~,fac.c;1.~jlily’. , 222:251-25'7. Lin, M.T. and Simon, E thalamus - responses
(1982). Properties of high Q1,, units in the conscious duck's to changes of core temperature. ,/.Fh+oiol., 322:127-137.
Martin, G.E. and Baclno, C.B. (1978). Action of intrahypothalamically on the body temperature of the rat. Soc.We~rorc?:.Ab.~tr., 4:411.
injected
hypo-
beta-endorphin
Nakayama, T., Ishikawa, Y. and Tsurutani, 1‘. (1979). Projection of scrotal thermal to the preoptic and hypothalamic neurons in rats. r?f?tineP:i Arch., 380:59-64.
afferents
NEURONAL
RESPONSES
TO IONTOPHORETIC
APPLICATION
OF MORPHINE
IN RATS
M.T. Lin, W.N. Uang and H.K. Chan Department National
of Physiology
Defense
Medical
Republic
(Accepted
and Biophysics,
Center,
Taipei,
Taiwan,
of China.
28 Febmmtg
J9b?)
Summary. Effects of thermal stimulation of the scrotum and of iontophoretic application of morphine on the activity of neurones in the preoptic anterior hypothalamic area were observed in 30 urethaneanaesthetised rats. The proportions of cold-responsive, warm-responsive and thermally unresponsive units were 20.7, 28.3 and 51%, respectively, of the total number of neurones tested. Iontophoretic application of morphine to neurones in the preoptic anterior hypothalamic area in rats resulted in excitation of the majority of cold-responsive cells and inhibition of the majority of warm-responsive cells tested. However, most of the thermally unresponsive cells were unaffected by application of morphine. These results provide a neuronal basis for the hypothesis that morphine, when administered directly into the hypothalamus, facilitates heat production and inhibits heat loss, which leads to hyperthermia.
It has been documented repeatedly that, in the rat, systemic or intrahypothalamic administration of a small dose of morphine or beta-endorphin causes hyperthermia (Hermann, 1942; Cox, Ary, Chesarek and Lomax, 1976; Martin and Bacino, 19'18;Lin, 1982). The hyperthermia in response to application of morphine or beta-endorphin is due to an increase in metabolic heat production and a decrease in heat loss (e.g. cutaneous vasoconstriction) in rats (Lin, 1982). However, relatively little information is available about the effect of direct application of morphine on unit activity within the preoptic anterior hypothalamic area. It was therefore of interest to observe (a) how thermal stimulation of the scrotum would affect the activity of neurones in the preoptic anterior hypothalamic area, (b) how direct application of morphine would affect neuronal activity in the hypothalamus, and (c) whether any changes in neuronal activity could be related to the action of morphine.
METHODS
Adult male Sprague-Dawley rats, weighing between 250 and 300 g, were used. Each animal was anaesthetised with urethane (1.25 g/kg, i.p.). The rectal temperature was maintained between 36.9 -37.4'C using a water-perfused pad under the animal. All the fur of the scrotum was removed with clippers. The animals were mounted stereotaxically with the heads fixed according to the coordinates of Kijnig and Klipper (1963). A piece of bone was removed from the right half of the skull and the underlying dura was removed. Recording of single unit discharges were made from the right half of the preoptic anterior hypothalamic area at stereotaxic coordinates of A:6.5-7.2; L:O.2-1.2; and H: -0.8 to -1.4 mm (Lin, 1982; Lin, Wu, Chandra and Tsay, 1982). The tips of the three-barreled micropipettes were broken back to a diameter of 4.2?1 pm. The central barrel was filled with 4M N&l, saturated with fast green recording. One of the side barrels was filled with 2M dye, and was used for extracellular NaCl and was used to balance the currents passed through the other barrels. The remaining side barrel was filled with 0.05M morphine sulphate, pH 4.4f0.3 (Merck, Sharp and Dohme, West Point, PA, USA). The impedance, measured at 1,000 Hz by an impedance module, ranged from 3 to 7 megohms for the recording barrel, from 6 to 10 megohms for the balance barrel and from 8 to 12 megohms for the drug-containing barrel. The drugs was retained in or ejected from the micropipette by an electrophoretic unit. The retaining current was 7.5 nA and the ejection current varied from 5 to 100 nA. After the micropipette had been lowered to the desired location in the hypothalamus, a hydraulic microdrive was used to slowly advance the micropipette. The single unit activity was processed using a standard cathode follower 591
592
Preliminary
Notes
and amplification circuitry for extracellular spike potentials (Lin and Simon, 1982). Impulses were counted at 1 sec. intervals by a WPI Scope Raster(Slipper Model 140 and displayed on a Grass Polygraph. The rectal and scrotal temperatures were displayed on the same polygraph record. The method used for thermal stimulation of the scrotum was similar to that described by Hellon and Misra (1973). The skin temperature was measured by a thermocouple which was cemented to the surface of the thermode which was in contact with the skin. Thermal responsiveness was judged by observation of changes in the neuronal discharge rate in response to warming and cooling of the scrotum, and the neurones encountered in this study were classified as thermally unresponsive, warm-responsive or coldresponsive. The warm-responsive units were excited by an increase in scrotal temperature. the cold-responsive units were excited by a decrease in scrotal temperature. Units that were not affected by changes in scrotal temperature were regarded as thermally unresponsive. A change of 25% or more in the spontaneous firing rate in response to application of morphine was the criterion used to define whether a neurone was excited or inhlbited. A lack of response to the test substance was considered valid only if adjacent neurones were affected by the same substance. Statistical significance of the tabulated data was determined using ax 2 test and a 2 x 3 contingency table. Differences were considered statistically significant at p < 0.05. At the end of each experiment, the vertical location of the micropipette was recorded and 25 PA of negative current was passed through the micropipette for 10 min. to deposit fast green dye at the site (Hosford and Haigler, 1980). The locations of the fast green dye spots were used to verify the locations of the recording sites.
RESULTS
Fiftythree single neurones in the preoptic anterior hypothalamic area were examined in 30 rats under urethane anaesthesia. Each unit was subjected to scrotal warming or cooling and to the administration of morphine. Table 1 shows the responses of these hypothalamic neurones, classified by thermal responsiveness to microiontophoretic application of morphine. Of 11 cold-responsive units recorded in the preoptic anterior hypothalamic area, 8 were excited by application of morphine. A typical excitatory response to morphine of a cold-responsive unit, recorded in the preoptic anterior hypothalamic region is illustrated in Figure 1. A microiontophoretic application of morphine (35-65 nA) for about 0.5 min. produced a dose-dependent increase (above control level) in the spontaneous firing rate of this unit. Positive current of the same magnitude (65 "A), applied through the NaClunits behaved in a different containing barrel, was without effect. Another 2 cold-responsive way; these neurones decreased their firing rates with application of morphine. The remainder (1 unit) of the total population of cold-responsive neurones showed no response to iontounits phoretic application of morphine (5-100 nA). On the other hand, of 15 warm-responsive recorded in the preoptic anterior hypothalamic area, 8 were depressed by application of morphine. A typical inhibitory response of a warm-responsive neurone is illustrated in Figure 2. A microiontophoretic application of morphine (lo-50 "A) for about 0.5 min. caused a dose-dependent decrease in the spontaneous discharge rate of this neurone. In 4 out of 15 warm-responsive neurones, the firing rates were unaffected by application of morphine. The remainder (3) increased their firing rates in response to application of morphine. However, the majority (18 out of 27) of the total population of thermally unresponsive units, recorded in the preoptic anterior hypothalamic area, showed no response to iontophoretic application of morphine (Table 1).
DISCUSSION
In the present study, when the 53 units recorded in the region of the preoptic anterior hypothalamus were classified by their thermal responsiveness, in response to warm-responsive and changes in scrotal temperature, the proportions of cold-responsive, thermally unresponsive neurones were 20.7, 28.3 and 519, respectively, of the total neurones tested. This distribution in not greatly different from data reported previously for the hypothalamic region in rats (Nakayama, Tshikawa and Tsurutani, 1979). The results also demonstrate that thermally responsive units in the preoptic anterior hypothalamic region were selectively affected by application of morphine. As indicated in Table 1, most of the warm-responsive (73.3%) and cold-responsive (91%) neurones were affected by application of morphine, while only 33.3% of the thermally unresponsive neurones were affected by morphine. The differences between the responses to morphine of the warm-responsive and cold-responsive neurones, and thermally unresponsive neurones are significant (p i 0.05). In addition, there is a significant difference (p c 0.05) between the responses to application of morphine between warm-responsive and cold-responsive neurones. As indicated in Table 1, most of the cold-responsive units (72.7%) were excited by application of morphine, while most of the warm-responsive neurones (53.3%) were inhibited by application of morphine. The excitatory responses of the cold-responsive neurones and the inhibitory responses of warm-responsive
Preliminary
Table --'
1
Effects
of morphine
warm-responsive --
Unit type
on 53 hypothalamic
or thermally _.~~
Notes
593
classified units ~-
as cold-responsive,
unresponsive.
Responses
No. of units tested
Excitation
to morphine
Inhibition
None
Cold-responsive
11
8 (72.7%)
2 (18.3%)
Warm-responsive
15
3 (20%)
8 (53.3%)
4 (26.7%)
Thermally
27
3 (11.1%)
6 (22.2%)
18 (66.7%)
unresponsive
14
53
Total
1 (9%)
23
16
The difference between responses to morphine of either cold-responsive or warm-responsive neurones and thermally unresponsive neurones is significant (&? c 0.05, using a x2 test and between responses a 2 x 3 contingency table). In addition there is a significant difference to morphine for warm-responsive and cold-responsive neurones (p i 0.05, using a x2 test and a 2 x 3 contingency table).
45 SCROTAL
35
TEMPERATURE
t’c 1
25 15
I
morrrhinc
Saline
63nA
Figure _____-
35 iiA
I mOrDhine
65’nA
unit in the preoptic anterior hypothalamic area 2. Excitation of a cold-responsive produced by iontophoretic application of morphine (35-65 nA). Positive current (65 nA), applied through the NaCl barrel, was without effect. The firing rate of the neurone increased with a decrease in scrotal temperature.
45
SCROTAL TEMF’ERATUREPC)
35
25 I5
FIRING
I min
Fi&re _-"-2.
RATE
Solinc
50 nA
(impulses/sact
morphine 50 nA
tsWphlne 10 nA
morphine 30 nA
Inhibition of a warm-responsive unit in the preoptie anterior hypothalamic area produced by iontophoretic application of morphine (IO-50 nA). Positive current (50 nA), applied through the NaCl barrel, was without effect. The firing rate of the neurone increased with increase in scrotal temperature.
Preliminary
594
Notes
"eurones to application of morphine were similar to the thermoregulatory responses provoked by intrahypothalamic administration of morphine (Lin, 1982). The responses of these presumed thermoregulatory "eurones to application of morphine are compatible with, and may therefore be involved in, inducing the hyperthermic effects (including both augmented heat production and depressed heat lass) which are characteristic of administration of morphine. Therefore, the present results provide a neuronal basis for the hypothesis that morphine facilitates heat production and inhibits heat loss in the region of the preoptic anterior hypothalamus. However, an abstract published by Baldino, Beckman and Adler (1979) has presented different results from those described above. These investigators reported that iontophoretic application of morphine to neurones in the preoptic anterior hypothalamic area in rats resulted in excitation of the majority of warm-responsive cells and inhibition of the majority of cold-responsive cells. There was no difference in the anaesthetic (urethane) used I" the two studies. However, Baldino ct al., determined thermal responsiveness by observation of changes in neuronal discharge rates in response to hypothalamic, rather than scrotal skin, temperature changes. Thus, it is possible that the difference between the results in the two studies might be due to the different populations or categories of hypothalamic neurones tested. Acknowledgements.
The work was supported by grants from the Alexander vo" Humboldt Stiftung, Godesberg, Bonn, FRG and the National Science Council of the Republic of China.
REFERENCES
Baldino, F. Jr., Beckman, A.L. and Adler, M.W. (1979). Actions morphine on rat hypothalamic temperature-sensitive neurons.
of iontophoretically applied Soc.Neuro~ci.Ab::tr.5:548.
Cox, B., Ary, M., Chesarek, W. and Lomax, P. (1976). Morphine hyperthermia action on the central thermostats. ?~zir.J.i%nmnac., 36:33-39.
in the i-at: a"
Hello", R.F. and Misra, N.K. (1973). Neurons in the ventrobasal complex of the rat thalamus responding to scrotal ski" temperature changes. rJ.F’h~~io7., 232:389-399. Hermann, T/wr.
,
J.B. (1942). The pyretic 76:309-315.
action on rats of small doses of morphine.
d.I~~2armn.:.zrp.
different effects on Hosford, D. and Haigler, H.J. (1980). Morphine and met-enkephalin: spontaneous and evoked neuronal firing in the mesencephalic reticular formation of the rat. J. %cmac. eq. T&i?. , 213 _. :355-363. Kb;nig, J.F.R. and Kllppel, R.A. (1963). The Rat Brain: a Stereotaxic Atlas of the Forebrain Baltimore, MD: Williams & Wilkins. and Lower Parts of the Brain Stem Lin, M.T. (1982). An adrenergic link in the hypothalamic pathways which mediate morphineand beta-endorphin-Induced hyperthermia in the rat. flcuri?r;?arma~'., 21:613-617. AMP link in Ll", M.T., Wu, J.J., Chandra, A. and Tsay, B.L. (1982). A "orepinephrine-cyclic the hypothalamic pathways which mediate fever induced by endotoxin and prostaglandin E-2 in the rat. ~i.;s13r~,fac.c;1.~jlily’. , 222:251-25'7. Lin, M.T. and Simon, E thalamus - responses
(1982). Properties of high Q1,, units in the conscious duck's to changes of core temperature. ,/.Fh+oiol., 322:127-137.
Martin, G.E. and Baclno, C.B. (1978). Action of intrahypothalamically on the body temperature of the rat. Soc.We~rorc?:.Ab.~tr., 4:411.
injected
hypo-
beta-endorphin
Nakayama, T., Ishikawa, Y. and Tsurutani, 1‘. (1979). Projection of scrotal thermal to the preoptic and hypothalamic neurons in rats. r?f?tineP:i Arch., 380:59-64.
afferents