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.
Showing the most recent 10 out of 24 publications
