Dopaminergic mechanisms in withdrawal hypothermia in morphine dependent rats

Life Sciences Vol. 17, pp . 41-42 Printed in the U .S .A .

Perqamon Press

DOPAMINERGIC MECHANISMS IN WITHDRAWAL HYPOTHERMIA IN I7DRPHINE DEPENDENT RATS Barry Coxl, Marylouise Aryl and Peter Lomax Department of Pharmacology, School of Medicine and the Brain Research Institute, University of California, Los Angeles, California 90024 . (Received in final form May 24, 1975) The role of several putative neurotransmitters in the development of tolerance and dependence to the narcotic analgesics has been the subject of a recent review (1), which demonstrated the lack of a consensus on the precise role of the catecholamines in this syndrome . A definitive role for brain dopamine in withdrawal aggression and withdrawal hypothermia has been suggested (2,3,4), although in the case of the hypothermia few details are available . We therefore decided to assess the importance of dopamine in withdrawal using apomorphine and pimozide, drugs claimed to be specific for dopamine receptors . Methods Male Sprague Dawley rats weighing 210-230 g were rendered dependent by subcutaneous implantation of a 75 mg morphine pellet . Withdrawal was induced by injection of naloxone (1 mg/kg i .p .) 72 hr later . Hypothermia was measured in rata placed in restraining cages at an ambient temperature of 18 °C using rectal thermistor probes inserted to a depth of 6 cm . Some rats had been implanted with stainless steel cannula guides into the preoptic/anterior hypothalamic (PO/AH) nuclei 7 days before receiving the morphine pellet . Withdrawal hypothermia was measured in rats receiving either pimozide (0 .5 mg/kg i.p .), apomorphine (1 .25 mg/kg i .p .) or vehicle (1 ml/kg i .p .), the systemic group ; and rata receiving either morphine (25 ug) pimozide (0 .5 ug) or vehicle (1 ul) intracerebrally, the central group. Withdrawal behavior was assessed for 1 hr before and 1 hr after naloxone . For chewing, licking, teeth chatter, facial tremor, grooming, sneezing and writhing each 1 hr observation period was divided into 20 3 min sessions and the number of sessions in which each sign occurred were counted . The proportion of rata in the group with diarrhea was calculated and head shakes and wet dog shakes were counted individually . The withdrawal score was corrected by subtracting the pre-naloxone score for apomorphine, pimozide or vehicle pretreated groups . Results Fig. 1 illustrates the temperature changes. Naloxone caused a 1.37°C fall in morphine dependent rate which was similar in magnitude to that seen after apomorphine. Pimozide produced only a small, non-significant, fall in morphine dependent rate . When apomorphine and naloxone were injected together a fall in rectal temperature occurred which was not significantly different from the effect when either was injected alone. Pimozide pretreatment caused a significant (p < 0 .05) antagonism of the withdrawal hypothermia . Injection of morphine (25 ug) or pimozide (0 .5 ug) into the PO/AH nuclei immediately before systemic naloxone caused a significant antagonism of the hypothermia . Apomorphine (1 .25 mg/kg) significantly reduced wet dog shakes, teeth chatter and 1 Supported by USPHS Fellowship 1, F05, TWO 2130-01 2Supported by USPHS MH-6415

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Dopamine and Morphine Withdrawal

Vol . 17, No . 1

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1, Naloxone (1 mg/kg ip) 2, Apomorphine (1 .25 mg/kg ip) 3, Naloxone (1 mg/kg ip) + Apomorphine (1 .25 mg/kg ip) 4, Pimozide (0 .5 mg/kg ip) 5, Naloxone (I mg/kg ip) + Pimozide (0 .5 mg/kg ip) 6, 0 .9~ NaCl (1 ul ic) 7, Morphine (25 ug ic) 8, Pimozide (0 .5 ug ic) *Significantly different (p < 0 .05) from corresponding control

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Effects of apomorphine and pimozide on naloxone induced withdrawal

Pimozide (0 .5 writhing and gave an almost significant reduction in chewing . mg/kg) significantly increased chewing, headshakea and writhing . Diarrhea, facial tremor, grooming, licking and sneezing were unaffected by either pimozide or apomorphine . Discussion By using rata which had developed a medium degree of dependence it was possible to demonstrate dopaminergic involvement in naloxone precipitated withdrawal in both directions . Thus, whilst the hypothermia appeared to be dop amine mediated (blocked by pimozide), other signs - chewing, head shakes and writhing - appeared to be under a dopaminergic inhibitory influence (potentiated by pimozide) . Apomorphine significantly antagonized the writhing, and reduced the chewing, providing further evidence for a dopamine inhibitory mechanism . Although wet dog shakes and teeth chatter were not affected by pimozide, they vere markedly reduced by apomorphine suggesting that stimulation of dopamine receptors can also reduce these signs . The fact that central injection of morphine antagonized naloxone precipitated withdrawal hypothermia indicated that not only was this a centrally mediated response but probably that it occurred in the PO/AH region . Pimozide was also an effective antagonist at this central site confirming the peripheral studies and implicating a dopaminergic mechanism in the PO/AH area . For a number of the signs there was no evidence of any dopaminergic involvement . These results emphasize the need to be specific about the particular sign They further demonunder study when discussing the mechanisms of withdrawal . atrate that not only may different neurotransmitters be involved but that the same neurotransmitter can exert either a facilitatory or inhibitory influence depending on the sign measured . References 1. 2. 3. 4.

A. H. S. G.

E. TAREMORI, Ann . Rev. Biochem . 43 : 15-33 (1974) . LAL, S . K. PURI, and Y . KARKAi .AS,pharmacologiet 13 : 263 (1971) . R. PURI and H. hAL, Psychopharmacologia _32 : 113-120 (1973) . GUINUTSOS, M. D. HYNES, S . R. PURI, R. B . DRAWBAUGH and A. LAL, Peychopharmacologia 34 : 37-44 (1974) .