Opioid Mediated Adenylyl Cyclase Supersensitization

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Adverse withdrawal effects often result from discontinuation of opioid use. Upon chronic treatment and subsequent removal of opioids, cells exhibit an enhanced sensitivity to cAMP accumulation, termed adenylyl cyclase supersensitization. It is hypothesized that opioid induced adenylyl cyclase supersensitization results from stimulation of specific Galpha subtypes and subsequent activation of the MAP kinase pathway. This hypothesis will be tested in cellular models, in ex vivo tissue preparations, and in whole animal behavioral models. Supersensitization may be supported by specific oj/o subtypes, and this will be investigated through the use of pertussis toxin insensitive Galpha proteins expressed in SH-SY5Y and C6n cells.The role of MAP kinase in adenylyl cyclase supersensitization will be examined by relating the time courses of supersensitization and MAP kinase induction, and using inhibitors of the MAP kinase pathway in cellular and animal models. Through the use of various jo,- and 8-opioid agonists, it will be determined if mu- and delta-opioid receptors, or interactions between them, differently modulate supersensitization. Understanding the cellular responses to opioids and how this relates to the whole animal is essential in providing both analgesic treatment and therapy for the consequences of chronic opioid abuse and withdrawal.