EFFECT OF OPIOIDS AND OTHER DRUGS IN A MODEL CIRCADIAN SYSTEM

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The avian pinealocyte model is a novel system in which to explore the linkage between environmental or pharmacologic stimuli and hormone synthesis. Unlike the mammalian pineal, the avian gland is inherently photosensitive and rhythmic in its production of melatonin, expresses these characteristics either in vivo or in vitro and responds to light or catecholamines (alpha2 agonists) with an acute suppression of melatonin synthesis. This acute, inhibitory effect should also be produced by agents, such as opioid and muscarinic agonists, which disrupt cyclic AMP synthesis by mechanisms which involve the G-i class of GTP-binding proteins. Melatonin, a hormone which has anti-reproductive activity in numerous species, has also been shown to modify the analgesic responses to various opioid agents, suggesting that melatonin may be an endogenous modifier of opioid receptor activity. The primary hypothesis underlying this proposal is that the melatonin synthetic pathway is a logical target for pharmacologic agents which may exert feedback, inhibitory control on melatonin production, such as opioids. In this proposal, the effects of opioids and other related pharmacologic agents will be examined on pineal melatonin production, serotonin-N-acetyltransferase activity, cyclic AMP synthesis and light-dependent changes in G-protein subunit methylation, distribution and expression. In conclusion, as the avian pinealocyte model is both endogenously rhythmic and photosensitive, the investigations outlined in this proposal will determine whether opioid agonists and related compounds alter the pineal's acute biochemical responses and circadian behavior. As such, these studies will enhance our understanding of two critical physiological processes, response to pain and biological rhythmicity.