The overall goal of this project is to investigate the consequences of perinatal opiate addiction. The specific hypothesis we plan to test in the present proposal is that chronic opiate agonist administration produces less tolerance in opiate receptor function in developing than in adult rats. The second hypothesis we plan to test is that opiate abstinence will precede tolerance to opiate-induced antinociception in ontogeny and will correlate with adaptations in opioid receptor signal transduction. To test the first hypothesis, dose response curves for mu agonists (morphine and sufentanil)-induced neuroendocrine (ACTH, GH, PRL and TSH) or antinociceptive responses after administration of one of three increasingly rigorous chronic morphine treatment regimens during several different postnatal treatment windows (days 1-5, 6-10, 11-15, 16- 20, 21-25) will be compared. To test the second hypothesis, dose response curves for naloxone-precipitated changes in behavior, ACTH and corticosterone secretion and increases in the norepinephrine metabolite 3-methoxy-4-hydroxphenylglycol will be assessed. finally, the effect of chronic morphine administration on mu receptor number, GTP-modulation of agonist binding and adenylate cyclase activity will be determined. If confirmed, these hypotheses predict that previous studies of perinatal opiate addiction may have underestimated the impact of perinatal opiate exposure by focusing on opiate responsivity only in adult offspring that were exposed gestationally. The proposed studies suggest that new insight will be obtained by evaluating the effects of opiate exposure during rat rather than after the end of treatment. Furthermore, this hypothesis predicts that ontogeny might provide a critical tool in establishing the relationship between described biochemical changes in opioid receptor function and behavioral changes associated with chronic opiate administration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002739-13
Application #
2116636
Study Section
Special Emphasis Panel (SRCD (20))
Project Start
1990-02-01
Project End
1998-01-31
Budget Start
1994-03-01
Budget End
1995-01-31
Support Year
13
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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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