Plasticity of adenylyl cyclase-related signaling sequelae after long-term morphine treatment.
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.
Department of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA.
Michael
M
Shy
Sumita
S
Chakrabarti
Alan R
AR
Gintzler
D000255:Adenosine Triphosphate / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009020:Morphine / Q000008:administration & dosage*; D009473:Neuronal Plasticity; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013223:Statistics as Topic; D013997:Time Factors; D014162:Transfection
D000067956:Adenylyl Cyclase Inhibitors; D044387:GTP-Binding Protein beta Subunits; D007527:Isoenzymes; D017450:Receptors, Opioid, mu; D009020:Morphine; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; C087857:protein kinase C gamma; D011493:Protein Kinase C; D000262:Adenylyl Cyclases