Journal article
Plasticity of adenylyl cyclase-related signaling sequelae after long-term morphine treatment
Molecular pharmacology, Vol.73(3), pp.868-879
03/2008
DOI: 10.1124/mol.107.042184
PMID: 18045853
Abstract
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 mu-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 Gbeta phosphorylation, membrane protein kinase Cgamma (PKCgamma) translocation, and MOR G(s) association. All converge, shifting the consequences of short-term MOR activation from Galpha(i)/Galpha(o) inhibitory to AC stimulatory signaling. In contrast, overexpression of the Gbetagamma-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 Gbeta phosphorylation and PKCgamma 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.
Details
- Title: Subtitle
- Plasticity of adenylyl cyclase-related signaling sequelae after long-term morphine treatment
- Creators
- Michael Shy - Department of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USASumita ChakrabartiAlan R Gintzler
- Resource Type
- Journal article
- Publication Details
- Molecular pharmacology, Vol.73(3), pp.868-879
- Publisher
- United States
- DOI
- 10.1124/mol.107.042184
- PMID
- 18045853
- ISSN
- 0026-895X
- eISSN
- 1521-0111
- Language
- English
- Date published
- 03/2008
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984020758302771
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