The goal of the product is to determine how chronic opiate treatment disrupts opioid control of endocrine function during ontogeny. We will identify the relative ontogeny of receptor subtype-specific systems, their changing neurotransmitter interactions and specific adaptation during chronic treatment. We hypothesize that these characteristics will determine the vulnerability or resistance of these systems to disruption during chronic opiate exposure. Basal and drug-evoked hormone secretion will be used as indices of opiate receptor function. The first goal of the proposed studies is to test the hypothesis that opiate receptor control of anterior pituitary hormone secretion appears in ontogeny in the sequence of kappa > mu > delta. The second goal will be to determine if dopamine mediates the early-developing kappa receptor controls of hormone secretion. The ability of dopaminergic antagonists to prevent morphine and U50,488-induced endocrine responses will be compared to the action of noradrenergic and serotonergic antagonists, and dopamine turnover following administration of morphine and U50,488 will be measured in vivo and in a median eminence explant. The third goal is to investigate mu and kappa tolerance in immature and adult rats. Two problems will be studied. We will test the hypothesis that specific mu tolerance of endocrine function appears developmentally before kappa tolerance by assessing mu and kappa receptor function during chronic administration of morphine and U50,488 to adult and developing rats. In addition, the effects of chronic etorphine administration on mu and kappa receptor control of HPA function will be determined. In adults, tolerance of PRL, GH and TSH responses to mu and kappa agonists will be measured to test the generality of our observation that rapid, specific mu and kappa tolerance of ACTH secretion develops after chronic morphine and U50,488 treatment. (4) The fourth goal is to test the hypothesis that kappa and mu tolerance affect different aspects of nonopioid control of HPA axis function. ACTH and CS responses to cholinergic, serotonergic, dopaminergic and noradrenergic agents, novelty and diurnal changes will be determined after chronic morphine and U50,488 treatment to test this hypothesis. The results of this study should provide insight into basic mechanisms of opiate tolerance in both adult and developing rats. The implications should transcend simple """"""""risk assessment"""""""" for perinatal opiate addiction, to include basic insight into CNS adaptation to any pharmacologic insult during development.

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National Institute on Drug Abuse (NIDA)
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Duke University
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Rincavage, Heather L; McDonnell, Donald P; Kuhn, Cynthia M (2003) Expression of functional estrogen receptor beta in locus coeruleus-derived Cath.a cells. Endocrinology 144:2829-35
Ceger, P; Kuhn, C M (2000) Opiate withdrawal in the neonatal rat: relationship to duration of treatment and naloxone dose. Psychopharmacology (Berl) 150:253-9
Hepburn, M J; Little, P J; Gingras, J et al. (1997) Differential effects of naltrindole on morphine-induced tolerance and physical dependence in rats. J Pharmacol Exp Ther 281:1350-6
Little, P J; Price, R R; Hinton, R K et al. (1996) Role of noradrenergic hyperactivity in neonatal opiate abstinence. Drug Alcohol Depend 41:47-54
Little, P J; Kuhn, C M; Wilson, W A et al. (1996) Differential effects of ethanol in adolescent and adult rats. Alcohol Clin Exp Res 20:1346-51
Windh, R T; Little, P J; Kuhn, C M (1995) The ontogeny of mu opiate tolerance and dependence in the rat: antinociceptive and biochemical studies. J Pharmacol Exp Ther 273:1361-74
Little, P J; Kuhn, C M (1995) Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis. Psychopharmacology (Berl) 122:78-84
Windh, R T; Kuhn, C M (1995) Increased sensitivity to mu opiate antinociception in the neonatal rat despite weaker receptor-guanyl nucleotide binding protein coupling. J Pharmacol Exp Ther 273:1353-60
Blackford, S P; Little, P J; Kuhn, C M (1992) Mu- and kappa-opiate receptor control of prolactin secretion in rats: ontogeny and interaction with serotonin. Endocrinology 131:2891-7
Ignar, D M; Windh, R T; Kuhn, C M (1992) Chronic administration of U50,488H fails to produce hypothalamo-pituitary-adrenal axis tolerance in neonatal rats. Neuropharmacology 31:143-8

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