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Plasticity of Adenylyl Cyclase-Related Signaling Sequelae after Long-Term Morphine Treatment

Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, New York

Adaptations to long-term morphine treatment resulting in tolerance are protective by counteracting the consequences of sustained opioid receptor activation. Consequently, the manifestation of specific adenylyl cyclase (AC)-related neurochemical sequelae of long-term morphine treatment should depend on the consequences of short-term µ-opioid receptor (MOR) activation. We tested this by comparing complementary chemical sequelae of long-term morphine treatment among cells in which short-term MOR activation inhibited instead of stimulated AC activity. Short-term activation of MOR in Chinese hamster ovary (CHO) cells stably transfected with MOR (MOR-CHO) inhibits AC activity. Long-term morphine treatment of these cells increased AC and Gβ phosphorylation, membrane protein kinase C (PKC) translocation, and MOR G_s association. All converge, shifting the consequences of short-term MOR activation from G_i/G_o inhibitory to AC stimulatory signaling. In contrast, overexpression of the Gβ-stimulated AC isoform AC2 (which converted MOR-coupled inhibition to stimulation of AC) eliminated or reversed these adaptations to long-term morphine treatment; it negated the increase in Gβ phosphorylation and PKC translocation while reversing the increase in AC phosphorylation and MOR G_s association. These adaptations greatly attenuated MOR-coupled stimulation of AC activity. Altered overexpression of AC protein per se was not a confounding factor because MOR-CHO overexpressing AC1, which is inhibited by short-term MOR activation, manifested adaptations to long-term morphine treatment qualitatively identical with those of MOR-CHO. These results reveal that adaptations elicited by long-term morphine treatment depend on the effects of short-term MOR activation. This dynamic and pliable nature of tolerance mechanisms could represent a new paradigm for pharmacotherapeutics.

Address correspondence to: Dr. Alan Gintzler, Box 8, Department of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. E-mail: alan.gintzler{at}downstate.edu

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