Calmodulin-stimulated adenylyl cyclase gene deletion affects morphine responses.
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.
Li
Shuang
S
Department of Pharmacology, Box 357280, University of Washington School of Medicine, Seattle, 98195-7280, USA.
Lee
Michael L
ML
Bruchas
Michael R
MR
Chan
Guy C
GC
Storm
Daniel R
DR
Chavkin
Charles
C
D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002147:Calmodulin / Q000378:metabolism*; D003214:Conditioning, Classical; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage*; D009043:Motor Activity / Q000502:physiology; D010147:Pain Measurement; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013375:Substance Withdrawal Syndrome; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000201:enzymology
D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D009020:Morphine; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8