TY - JOUR T1 - Calmodulin-Stimulated Adenylyl Cyclase Gene Deletion Affects Morphine Responses JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1742 LP - 1749 DO - 10.1124/mol.106.025783 VL - 70 IS - 5 AU - Shuang Li AU - Michael L. Lee AU - Michael R. Bruchas AU - Guy C. Chan AU - Daniel R. Storm AU - Charles Chavkin Y1 - 2006/11/01 UR - http://molpharm.aspetjournals.org/content/70/5/1742.abstract N2 - To define the roles of the calmodulin-stimulated adenylyl cyclases (AC1 and AC8) in morphine-induced analgesia, tolerance, physical dependence, and conditioned place preference, we used mice having targeted disruptions of either the AC1 or AC8 genes or both genes [double knockout mice (DKO)]. Mice lacking either AC1 or AC8 genes or DKO did not differ from wild-type mice in short-term antinociceptive responses to morphine measured in the tail-flick analgesia assay. Morphine tolerance that developed immediately within 3 h of morphine administration (10 mg/kg s.c.) was significantly attenuated in DKO mice and AC8 single knockout mice. Tolerance induced continually by daily injections of morphine (10 mg/kg s.c.) was also reduced in DKO mice. In DKO mice continually treated with morphine, there was a significant reduction in withdrawal behaviors, including reduced wet-dog shakes and forepaw tremor after naloxone injection (10 mg/kg i.p.). Morphine produced hyperlocomotion and conditioned place preference in wild-type mice, whereas DKO mice displayed significantly less hyperlocomotion and conditioned place preference. Furthermore, the significant increase in phosphorylated cAMP-response element binding protein (CREB) staining in ventral tegmental area induced by long-term morphine treatment was not evident in DKO mice, suggesting that CREB activation by morphine requires cAMP generated by AC1 and AC8. These results support the hypothesis that calmodulin-stimulated adenylyl cyclases are important mediators of the neuronal responses to morphine. The American Society for Pharmacology and Experimental Therapeutics ER -