J. Phyaiol. (1979), 295, pp. 179-189 With 5 text-figures Printed in Great Britain

179

METABOLIC, RESPIRATORY, VASOMOTOR AND BODY TEMPERATURE RESPONSES TO BETA-ENDORPHIN AND MORPHINE IN RABBITS BY M. T. LIN AND C. Y. SU From the Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, Republic of China, and the Department of Pharmacology, Taipei Medical College, Taipei, Taiwan, Republic of China

(Received 25 January 1979) SUMMARY

1. The effects of beta-endorphin and morphine on thermoregulatory responses of unanaesthetized rabbits to different ambient temperatures (Ta) of 2, 22 and 32 0C were assessed. 2. Intraventricular administration of either beta-endorphin or morphine produced dose-dependent hypothermia at 2 and 22 0C Ta. At 2 0C Ta the hypothermia was brought about solely by a decrease in metabolic heat production. At 22 0C Ta the hypothermia was due to a decrease in metabolism and an increase in peripheral blood flow. However, at 32 'C T,, there were no changes in rectal temperature in response to either beta-endorphin or morphine application. 3. Hypothermic effects of the administration of beta-endorphin or morphine were greatly antagonized by pretreatment of animals with either an opiate antagonist naloxone or a serotonin depletor 5,6-dihydroxytryptamine. 4. These findings indicate that the hypothermic responses to beta-endorphin or morphine in rabbits may be mediated through central serotonergic mechanisms. The hypothermia was due to a decrease in heat production and/or an increase in heat loss. INTRODUCTION

There is ample evidence that morphine interferes with body temperature regulation. The effects of morphine on thermoregulation vary not only among species but also within species. For example, systemic administration of morphine was reported to produce hypothermia in rabbits (Girndt & Lipshitz, 1931), chimpanzees (Spragg, 1940), monkeys (Eddy & Reid, 1934), Birds (Zeihuisen, 1895) and mice (Estler, 1962), but hyperthermia in cats, goats, cattle and horses (Damman, 1878; Stewart & Rogoff, 1922; Kreuger, Eddy & Sumwalt, 1943). A biphasic change in body temperature followed the systemic administration of morphine to guinea-pigs and rats (Glaubach & Pick, 1930; Winter & Flataker, 1953). Moreover, Banerjee, Burks, Feldberg & Goodrich (1968) found that morphine administered intraventricularly to rabbits produced hyperthermia which contrasts with the hypothermic effect on this species of systemically administered morphine (Dhawan, 1960; Jacob & Lafille, 1964). Recently, endogenous peptides with opiate activity (beta-endorphins) have been isolated and identified in brain and pituitary tissues (Li & Chung, 1976; Tseng, Tseng, 0022-3751/79/5300-0977 $01.50

c

1979 The Physiological Society

180

1M. T. LIN AND C. Y. SU

Loh & Li, 1977; Segal, Browne, Bloom, Ling & Guillemin, 1977). Beta-endorphin not only binds to brain opiate receptors but also has some morphine-like actions such as analgesia, catatonia (Tseng et al. 1977; Motomatsu, Lis, Seidah & Chretien, 1977; Grevert & Goldstein, 1978). It is not known whether beta-endorphin shares with morphine the same effects on body temperature. In the present study, therefore, the effects of beta-endorphin and morphine on metabolic, respiratory, vasomotor and body temperature responses of rabbits to different ambient temperatures were assessed. METHODS

Experiments were performed on male New Zealand rabbits, initially weighing between 3-0 and 3-5 kg. All experiments were conducted on conscious animals which were trained to sit quietly under minimal restraint in rabbit stocks. Between experiments the animals were individually caged in an ambient temperature of 22 1-0 "C and were maintained on standard Purina Laboratory Chow, with tap water available ad libitum. Surgical techniques. A ventricular cannula was implanted into each animal under general anaesthesia (sodium pentobarbitone 30 mg/kg, i.v.). Standard aseptic techniques were employed. The stereotaxic atlas and co-ordinates of Sawyer, Everett & Green (1954) were used. The cannula was located in the third cerebral ventricle; the stereotaxic co-ordinates were: A, + 1.0 mm; L, 0*0 mm; and H, + 0-5 mm. The animal was placed in the stereotaxic apparatus and the frontal and parietal bones were exposed by a mid line incision on the scalp. After the appropriately located craniotomy hole had been trephined, two self-tapping screws were inserted into the parietal or frontal bones and the cannula was inserted to the desired depth through the craniotomy hole. The correct positioning of the cannula was indicated by the successful aspiration of cerebrospinal fluid during the operation. The cannula was anchored with dental acrylic cement to the calvarium surface, which had been scraped clean of periosteum. The reflected muscles and skin were replaced around the acrylic mound containing the cannula and screws and were sutured with chromic gut (000). A period of 2 weeks was permitted to allow the animals to recover before they were used. Measurement of thermoregulatory parameters. Metabolic rate (M) was calculated from the animal's oxygen consumption and was calculated in Watts assuming an R.Q. = 0-83 so that 11 oxygen consumed per hour was equivalent to a heat production of 5-6 W (Lin, Pang, Chern & Chia, 1978). Respiratory evaporative heat loss (Ere,) was calculated by measuring the increase in water vapour content in the helmet effluent air over that of the ambient air. Two pairs of wet and dry bulb thermocouples were used. The first pair, placed in the environmental chamber, gave a measure of the water content of the inspired air, while the second pair, located downstream from the Plexiglass helmet, continuously monitored the water content of the air containing the expired air of the animals. Substraction of the first value from the second provided the respiratory water loss, since the airflow through thehelmet was measured. The amount of water evaporated by the rabbit was calculated by the equation: water loss (water content of circuit air water content of ambient air) x airflow. Respiratory evaporative heat loss expressed as W was calculated from evaporative water loss assuming the latent heat of the evaporization of water to be 0-7 W.hr/g (Lin, 1978a). Estimated ear skin blood flow (EBF) was used as a sensitive index of ear vasomotor activity ini terms of ml./min. Actually, the value so estimated is the minimal flow required to maintain the heat balance of the ears and was calculated from the equation: EBF A, h, +c (T, -T) / (T - Te), where A, ear surface area; the ear skin surface was calculated by the equation: Ae(M112) =0-0084 x body wt. (kg) (Gonzalez, Kluger & Hardy, 1971),hr+c = combined coefficient of radiant and convective heat transfer of the ear; hr+c was given the value 9-0 W/M2 IC (Gonzalez et al. 1971), s = the specific heat of blood was taken as 1-09 W. hr/L 'C (Gonzalez et al. 1971). Rectal (Tr) and ear skin (Te) temperatures were measured using copper-constantan thermocouples. Rectal temperature was measured with a copper-constantan thermocouple enclosed in PE 200 tubing, sealed at one end, inserted 100 mm into the rectum. +

=

-

=

s x

x

x

BETA-ENDORPHIN AND MORPHINE

181

Drug solutions. All drug solutions were prepared in pyrogen-free glassware which was baked at 180 0C for 5 hr before use. Freshly prepared drug solutions were used for all injections. Drugs administered intraventricularly included beta-endorphin (Hormone Research Laboratory, University of California, San Franscisco; 10-50 jug, third ventricle); morphine sulphate (Merck & Company Inc., Rahway, N.J.); naloxone hydrochloride (Endo Laboratories Inc., Garden City, N.Y.); and 5,6-dihydroxytryptamine (5,6-DHT; Sigma, 100 #g). A 100 ,A. aliquot containing either beta-endorphin, morphine, naloxone or 5,6-DHT was administered into the third cerebral ventricle. Histological verification. After the completion of the experiments, a 100 /d. aliquot of China ink was injected down the ventricular cannula to measure the spread of the injected solution. It was found that the spread was confined to the whole ventricular system with the highest concentration in the walls of the third ventricle. The head of representative animals was perfused with 0 9 % saline, followed by 10 % (v/v) formalin solution. Later, the fixed brains were cut in 40 jsm sections and stained with thionin so that stereotaxic co-ordinates of ventricular cannulae were verified. All tips of the cannulae were found to be located at the third ventricle. Data collection and analysis. The maximal changes in rectal temperature, metabolic rate, respiratory evaporative heat loss and ear blood flow produced during 60 min period after the injection of drugs were expressed 'as AT,, AM, AEre, and AEBF, respectively. These data were collected at three different ambient temperatures (Ta: 2, 22 and 32 0C). Differences in the mean values of variables between the groups of control and experimental animals were analysed by means of one way analysis of variance.

RESULTS

Effects of intraventricular administration of beta-endorphin on thermoregulatory responses of rabbits to different ambient temperatures. Rabbits with implanted ventricular cannulae were equilibrated in a partitional calorimetry for a period of at least 90 min at the selected ambient temperature. The effects obtained with 20 ,tg betaendorphin injected into the third cerebral ventricle at ambient temperatures of 2, 22 and 32 0C are illustrated by Figs. 1, 2 and 3. In each experiment a control injection of 0.1 ml. 0 9 % NaCl solution did not affect thermoregulatory responses (Table 1). At an ambient temperature of 2 0C (Fig. 1), the hypothermia developed immediately after the injection and rectal temperature fell 2-0 'C (Table 1). The hypothermia was brought about solely by a decrease in metabolic heat production. There were no changes in either peripheral blood flow or respiratory evaporative heat loss. At an ambient temperature of 22 0C (Fig. 2), the hypothermia again developed immediately after the beta endorphin injection and rectal temperature fell again about 1-7 0C (Table 1). The hypothermia was due to a decrease in metabolism and an increase in heat loss. Ear skin blood flow was significantly increased by betaendorphin application. At an ambient temperature of 32 'C (Fig. 3), there were no changes in rectal temperature in response to beta-endorphin application, since neither heat production nor heat loss responses were affected by beta-endorphin at this ambient temperature (Table 1). Fig. 4 summarizes the effects of naloxone and of 5,6-DHT treatment on the betaendorphin-induced hypothermia at an ambient temperature of 22 'C. No statistically significant changes in rectal temperature occurred as a result of control injections of naloxone or 5,6-DHT injection. The hypothermia induced by an intraventricular dose of beta-endorphin was greatly reduced by pretreatment of animals with a intraventricular injection of naloxone or 5,6-DHT.

182

M. T. LIN AND C. Y. SU

+l +l +l +l +l +l

14

00

00

Rooooo

"=

Q

0

-

0~~~~~~~~ d M _ > X~~~~~~-

0 O X

~

+1+1+1+

S1+

C) COO

O O

_41O-V>

~

V

C;^N---0-0 o00

~

C +I +I +I +I +I +I ~~ ~,:4&00

*=c4D

0 l+ l+ l+

0

~0

0

~

c

~

0~

~

~

0

4l+ l+ ~~

e~~~ ~-

02

Q 0

ooO°°°°

._~ ~~o

0

l+

ce
>>>N

-

0

V

°5 4

.

-

M 00

-o

>,>

M~~~

BETA-ENDORPHIN AND MORPHINE

183

Beta-endorphin 20 pg (Ta: 2 °C) 7

1-4

44 114

6

-

1-2

5

-

1-0 _

-

42

40

12

-

10

-

E

0

3¢8-

C

3i6 X6

LU~~~~~~~~~~~~~~~~~~~~~~~~~~~~~4

2

-

0-4

1

-

0-2

EM

-

-

34

-

32

2

30

0

-

4

EBF

0

00 0

20 40

60 80 100 120 140 Time (min) Fig. 1. Thermal responses produced by an intracerebroventricular administration of 20 ,Ug beta-endorphin in an unanaesthetized rabbit at an ambient temperature of 2 'C.

Tr: rectal temperature; M: metabolic rate; EBF: ear blood flow.

Er.: respiratory evaporative

heat loss;

Beta-endorphin 20,gg (T.: 22 'C) 7

-

14

6

-

1-2

5

-

-

6T

10

44

14

42

'12

'40 `10C E

M

~3

-910.6 -36

1

-

8Z E

34

4

32

2

i30

0

kZ6 L&.

0-4 -s

2

'3

0-2 EBF

0 -0.0 0

20 40 60 80 100 120 140 Time (min)

Fig. 2. Thermal responses produced by an intracerebroventricular administration of 20 jtg beta-endorphin in an unanaesthetized rabbit at an ambient temperature of 22 'C. Tr: rectal temperature; M: metabolic rate; Ere,: respiratory evaporative heat loss; EBF: ear blood flow.

Effects of intraventricular administration of morphine on thermoregulatory responses of rabbits to different ambient temperatures. The effects obtained with 100 jug morphine injected into the third cerebral ventricle at ambient temperatures of 2, 22 and 32 0C are summarized in Table 2. In the cold, at a Ta of 2 0C, the hypothermia developed immediately after the injection and rectal temperature fell 1-6 0C (Table 2). The hypothermia was brought about by a decrease in metabolism. At room temperature

M. T. LIN AND C. Y. SU

184

Beta-endorphin 20pg (T. 32 'C) 1-4

7 6

-

1-2

5

10

4

0-8

-

Tr

-

-

04

1

-

0-2

0

L o.o

14

-

42

12

-

40

10

38c

8

Eres

EBF

Z 3 PEO06 -36 -6 2

44

-

WJ

M~~~~~~~~~~~~~~~~~~~~~~~~~~~A 34

4

32

2

J30

0

-

-

_

60 80 100 120 140 Time (min) Fig. 3. Thermal responses produced by an intracerebroventricular administration of 0

20 40

20 jug beta-endorphin in an unanaesthetized rabbit at an ambient temperature of 32 0C. T.: rectal temperature; M: metabolic rate; Eres: respiratory evaporative heat loss; EBF: ear blood flow. -4

T,,: 22 'C 09% saline

-3

-2

-1

5, 6-DHT (100 g) + Naloxone (20 ,ug)

0I 10

30 20 Beta endorphin (jg)

50

Fig. 4. Dose-response relation for beta-endorphin injected into the third cerebral ventricle in three groups of saline-treated, 5,6-DHT-treated and naloxone-treated animals. The points represent the mean reduction in rectal temperature (Tr) and the vertical bars denote + S.E. of mean at an ambient temperature of 22 TC. Each point contains four animals.

(22 0C Ta), the hypothermia again developed immediately after the morphine injection and rectal temperature fell about 1-3 'C. The hypothermia was due to a decrease in metabolism and an increase in heat loss. However, in the heat (32 'C Ta), there were no changes in thermoregulatory responses in response to morphine application. Fig. 5 summarizes the effects of naloxone and of 5,6-DHT treatment on the morphine-induced hypothermia at an ambient temperature of 22 'C. The hypothermia induced by an intraventricular dose of morphine was greatly antagonized by pretreatment of animals with an intraventricular dose of naloxone or 5,6-DHT.

BETA-ENDORPHIN AND MORPHINE

OO O O O O

+1 +1 +1 +1 +1 +1 0

C)

w _ _ --

C

4

te

E

o

-__

_

Oo

lo

XZ

o o o to v-

%4)

o4 o-

4a

+1 +1 +1 +1 +1 +1

w0

6aos W

4a 0

I"

_0;

00

0t

_).-

ow

oas

0

qa

qNa

o

¢ 1+ + Z 5.;X4°°°

1 1+ wo

Q

j

4 I_

-

_

-V

-a)

a),:

*a) * + a

.5 E *

*;

S

o

0~0 o

0

o~ 0

185

M. T. LIN AND C. Y. SU

186 -4

TT: 22'C

-3

0-9% saline -2

5,6-DHT (100 gg)

-1 -

i - t

/ a

0

50

l

100 Morphine

l

150

Naloxone (20 ig)

250

Fig. 5. Dose-response relation for morphine injected into the third cerebral ventricle in three groups of saline-treated, 5,6-DHT-treated and naloxone-treated rabbits. The points represent the mean reduction in rectal temperature (Tr) and the vertical bars denote + S.E. of mean at an ambient temperature of 22 0C. Each point contains four animals.

DISCUSSION

The present results show that intraventricular administration of either betaendorphin or morphine produced dose-dependent hypothermia in rabbits at both 2 and 22 0C Ta. At a Ta of 2 0C, the hypothermia was brought about solely by a decrease in metabolic heat production. There were no changes in either peripheral blood flow or respiratory evaporative heat loss, since both heat loss pathways had already been reduced to minimal levels by the low ambient temperature. The fall in rectal temperature was thus achieved by the only means possible: a reduction in metabolic heat production. At a Ta of 22 0C, the hypothermia was due to a decrease in metabolism and an increase in peripheral blood flow. However, at a Ta of 32 0C, intraventricular injections of beta-endorphin or of morphine produced no changes in rectal temperature. This ineffectiveness of the drugs at a high ambient temperature was because the heat production pathway was already inactive. The data suggest that both beta-endorphin and morphine decrease heat production and/or increase heat loss in rabbits. It has been shown that opioids interact with more than one neurotransmitter. Opioids increased acetylcholine levels in the brain (Harris & Dewey, 1973; Lees, Kosterlitz & Waterfield, 1973). Also, opioids enhanced the release, synthesis and turnover of catecholamines in the C.N.S. (Way & Shen, 1971; Lees et al. 1973; Smith & Sheldon, 1973). Moreover, it was found that chronic treatment with morphine increased the turnover of 5-hydroxytryptamine (5-HT; serotonin) in the brain (Way & Shen, 1971). It is thus possible that neurotransmitters may play a specific roles in opioid-induced hypothermia. According to our recent reports, the elevation of serotonergic receptor activity by means of local injection of the 5-HT precursor 5-hydroxytryptophan (Lin, Pang, Chern & Chia, 1978; Lin, Chow, Chem & Wu, 1978) or of an inhibitor of the uptake pump in serotonergic neurones such as fluoxetine and chlorimipramine (Lin, 1978)

BETA-ENDORPHIN AND MORPHINE 187 results in a fall in the body temperature of rabbits and rats at 2 and 22 0C Ta. Again, the hypothermia was due to a decrease in heat production and/or an increase in heat loss. At high ambient temperature, however, the elevation of serotonergic receptor activity had no effect on thermoregulatory responses. The present results show that hypothermic effects of intracerebroventricular administration of beta-endorphin or morphine was greatly antagonized not only by pretreatment of the rabbits with the opiate antagonist naloxone (Zaks, Jones, Fink & Freedman, 1971) but also with a 5-HT depletor 5,6-dihydroxytryptamine (Lin, 1979; Baumgarten & Schlossberger, 1973). These observations indicate that the hypothermic responses to beta-endorphin or morphine in rabbits may be mediated through central serotonergic mechanisms. This interpretation is supported by the findings of others that morphine hypothermia in rats is mediated through central serotonergic systems. For example, Lotti, Lomax & George (1965) and Feldberg & Lotti (1967) reported that centrally administered morphine and 5-HT both caused hypothermia in rats. Moreover, morphine hypothermia in rats was abolished following 5-HT depletion with p-chlorophenylalanine (an inhibitor of 5-HT synthesis) (Haubrich & Blake, 1971; Oka, Nozaki & Hosoya, 1972). Furthermore, the administration of 5-hydroxytryptophan restored the hypothermic action of morphine in p-chlorophenylalanine treated rats (Oka et al. 1972). On the other hand, the present results are inconsistent with the findings of Banerjee et al. (1968). They reported that intracerebral injections of morphine and 5-HT both caused hyperthermia in rabbits. It is not known whether their effects in response to both morphine and 5-HT were non-specific and due to the liberation of endogenous prostaglandins. A neuronal model was used by Bligh, Cottle & Maskrey (1971) to describe the thermoregulatory effects of intracerebroventricular injections of biogenic amines in the sheep, goat and rabbit. It represents a portion of the neural pathways between warm sensors and heat-loss effectors and between cold sensors and heat-production effectors with crossed inhibitory pathways between them. The effects on injected 5-HT were as if it was simulating the action of an excitatory transmitter substance acting at a synapse on the heat-loss pathway before the origin of an inhibitory influence on the heat-production pathway. The results reported here show that betaendorphin or morphin increases heat loss and/or decreases heat production. Their points of action can thus be readily expressible in terms of the neuronal model of Bligh et al. (1971). The effects of injected beta-endorphin or morphine are at least as if they were exerting an excitatory effect on the pathway between warm sensors and heat loss effectors, before a serotonergic synapse and before the point of origin of a crossing inhibitory influence on the cold sensors to heat production pathway. This work reported here was supported by grants from National Science Council of Republic of China and J. Aron Charitable Foundation (N.Y., U.S.A.). The authors are grateful to Dr C. Y. Chai for his advice and encouragement during experimentation. Also, we would like to thank Dr C. J. Shih for his generous support. The excellent technical assistance of Y. F. Chern and S. I. Chern was much appreciated. We wish to thank Dr C. H. Li (The Hormone Research Laboratory, University of California, San Franscisco) for the supply of beta-endorphin.

188

M. T. LIN AND C. Y. SU REFERENCES

BANERJEE, U., BURKS, T. F., FELDBERG, W. & GOODRICH, C. A. (1968). Temperature effects and catalepsy produced by morphine injected into the cerebral ventricles of rabbits. Br. J. Pharmac. 33, 544-551. BAUMGARTEN, H. G. & SCHLOSSBERGER, H. G. (1973). Effects of 5,6-dihydroxytryptamine on brain monoamine neurons in the rat. In Serotonin and Behavior, ed. BARCHAS, J. & USDIN, E., pp. 209-224. New York: Academic. BLIGH, J., COTTLr, W. H. & 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. 212, 377-392. DAMMAN, X. X. (1878). Uber Glycosurie nach Morphium. Tagber. Leist. Fortochr. ges. Med. 13, 625-626. DHAWAN, B. N. (1960). Blockade of LSD-25 pyrexia by morphine. Archs int. Pharmacodyn. Ther. 127, 307-313. EDDY, N. B. & REID, J. G. (1934). Studies of morphine, codeine and their derivatives. VII. Dihydromorphine (paramorphine), dihydromorphine (Dilaudid) and dihydrocodeinone (Dicodide). J. Pharmac. exp. Ther. 52, 468-493. ESTLER, C. J. (1962). The influence of morphine and levallorphan on mortality, oxygen consumption and rectal temperature and on the creatine-phosphate, ATP-. ADP-, lactic acid, glycogen and coenzyme-A content of the mouse brain. Proc. 1st Int. Pharmacol. Meet. 8, 153156. FELDBERG, W. & LoTTi, V. J. (1967). Temperature responses to monoamines and an inhibitor of MAO injected into the cerebral ventricles of rats. Br. J. Pharmac. 31, 152-161. GIRNDT, 0. & LIPSCHITZ, W. (1931). The effect of morphine upon the body temperature. Experiments on normal rabbits. Arch. exp. Path. Pharmak. 159, 249-258. GLAUBACH, S. & PICK, E. P. (1930). Uber die Beeinflussumg der Temperaturregulierung durch Thyroxin. I. Mitteilung. Arch. exp. Path. Pharmak. 151, 341-370. GONZALEZ, R. R., KLUGER, M. J. & HARDY, J. D. (1971). Partitional calorimetry of the New Zealand white rabbits at temperatures of 5-35 'C. J. apple. Physiol. 31, 728-734. GREVERT, P. & GOLDSTEIN, A. (1978). Endorphin: Naloxone fails alter experimental pain or mood in humans. Science, Wash. 199, 1090-1095. HARRIS, L. S. & DEWEY, W. L. (1973). Role of cholinergic systems in the central action of narcotic agonists and antagonists. In Agonist8 and Antagonists Actions of Narcotic Analgesic Drugs, ed. KOSTERLITZ, H. W., COLLIER, H. 0. J. & VILLARREAL, J. E., pp. 198-206. Baltimore: University Parl Press. HAUBRICH, D. R. & BLAKE, D. E. (1971). Modification of the hypothermic action of morphine after depletion of brain serotonin and catecholamines. Life Sci. Oxford 10, 175-180. JACOB, J. & LAFILLE, C. (1964). Antagonists de l'action hyperthermisante du lysergamide chez le chez le lapin. In Biochemical and Neurophysiological Correlation Centrally Acting Drugs, ed. TRBUCCHI, PAOLETTI & CANAL, pp. 249-261. New York: Macmillan. KREUGER, H., EDDY, N. B. & SUMWALT, D. (1943). The Pharmacology of the opium Alkaloids. Publ. Hlth Rep., Wash. Suppl. 165. LEES, G. M., KOSTERLITZ, H. W. & WATERFIELD, A. A. (1973). Characteristics of morphinesensitive release of neurotransmitter substances. In Agonists and Antagonists Actions of Narcotic Analgesic Drugs, ed. KOSTERLITZ, H. W., COLLIER, H. 0. J. & VILLARREAL, J. E., pp. 142-152. Baltimore: University Park Press. LI, C. H. & CHUNG, D. C. (1976). Isolation and structure of an unitriakontapeptide with opiate activity from pituitary glands. Proc. natn. Acad. Sci. U.S.A. 73, 1145-1148. LIN, M. T. (1978a). Effects of intravenous and intraventricular prostaglandin E1 on thermoregulatory responses in rabbits. J. Pharmac. exp. Ther. 204, 39-45. LIN, M. T. (1978b). Effects of specific inhibitors of 5-hydroxytryptamine uptake on thermoregulation in rats. J. Physiol. 284, 147-154. LIN, M. T. (1979). Effects of hypothalamic injections of 5,6-dihydroxytryptamine on thermoregulation in rats. Experientia 35, 359-361. LIN, M. T., CHOW, C. F., CHERN, Y. F. & Wu, K. M. (1978a). Elevating serotonin levels in brain with 5-hydroxytryptophan produce hypothermia in rats. Pfluigers Arch. 377, 245-249.

BETA-ENDORPHIN AND MORPHINE

189

LIN, M. T., PANG, I. H., CHERN, S. I. & CHIA, W. Y. (1978b). Change in serotonin contents in brain affect metabolic heat production of rabbits in cold. Am. J. Physiol. 235, R41-47. LOTTI, V. J., LOMAX, P. & GEORGE, R. (1965). Temperature responses in the rat following intracerebral microinjection of morphine. J. Pharmac. exp. Ther. 150, 135-139. MOTOMATSU, T., Lis, M., SEIDAH, N. & CHRETIEN, M. (1977). Inhibition by beta-endorphin of dopamine-sensitive adenylate cyclase in rat striatum. Biochem. biophys. res. Commun. 77, 442-447. OKA, T., NOZAKI, M. & HOSOYA, E. (1972). Effects of p-chloropheylalanine and cholinergic antagonist on body temperature changes induced by the administration of morphine to non-tolerant and morphine-tolerant rats. J. Pharmac. exp. Ther. 180, 136-143. SAWYER, C. H., EVERETT, J. W. & GREEN, J. D. (1954). The rabbit diencephalon in stereotaxic coordinates. J. comp. Neurol. 101, 801-824. SEGAL, D. S., BROWNE, R. G., BLOOM, F., LING, N. & GuiTTsMIN, D. (1977). Beta-endorphin: Endogenous opiate or neuroleptic? Science, Wash. 198, 411-414. SMITH, C. B. & SHELDON, M. I. (1973). Effects of narcotic analgesic drugs on brain noradrenergic mechanisms. In Agonist and Antagonists Actions of Narcotic Analgesic Drugs, ed. KOSTERLITZ, H. W., COLLIER, H. 0. J. & VILLARREAL, J. E., pp. 164-175. Baltimore: University Park Press. SPRAGG, S. D. D. (1940). Morphine addiction in chimpanzees. Comp. Psychol. Monogr. 15, 132. STEWART, G. N. & ROGOFF, J. M. (1922). Influence of morphine on normal cats and on cats deprived of the greater part of the adrenals, with special reference to body temperature, pulse, and respiratory rate and blood sugar content. J. Pharmac. exp. Ther. 19, 97-130. TsENG, L. F., LOH, H. H. & Li, C. H. (1977). Human beta-endorphin: development of tolerance and behavioral activity in rats. Biochem. biophys. res. Common. 74, 390-396. WAY, E. L. & SHEN, F. H. (1971). Effects of narcotic analgesic drugs on specific systems: catecholamines and 5-hydroxytryptamine. In Narcotic Drugs: Biochemical Pharmacology, ed. CLOUET, D. H., pp. 229-253. New York- Plenum. WINTER, C. A. & FLATAKER, L. (1953). The relation between skin temperature and the effect of morphine upon the response to thermal stimuli in the albino rat and the dog. J. Pharmac. exp. Ther. 109, 183-188. ZAxs, A., JoNEs, T., FINE, M. & FREEDMAN, A. (1971). Treatment of opiate dependence with dose oral naloxone. J. Am. med. Ass. 215, 2108-2110. ZEIHUISEN, H. (1895). Beitrage zur lehre der Immunitat und Idiosynkrasie. I. Uber den Einfluss der Korpertemperatur auf wirkung einiger Gifte an Tauben. Arch. exp. Path. Pharmak. 35, 181-212.

Metabolic, respiratory, vasomotor and body temperature responses to beta-endorphin and morphine in rabbits.

J. Phyaiol. (1979), 295, pp. 179-189 With 5 text-figures Printed in Great Britain 179 METABOLIC, RESPIRATORY, VASOMOTOR AND BODY TEMPERATURE RESPONS...
1MB Sizes 0 Downloads 0 Views