title: Evidence for a role of CaMKIV in the development of opioid analgesic tolerance.
abstract: cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV). Here, we show that CaMKIV-knockout (KO) mice developed less analgesic tolerance after chronic morphine administration with no alteration in physical dependence or acute morphine-induced analgesia. The increase in phosphorylated CREB expression observed in wild-type mice after chronic morphine was absent in CaMKIV-KO mice, while there was no difference in the expression or phosphorylation of the micro-opioid receptor between groups. Morphine-treated CaMKIV-KO mice showed less G-protein uncoupling from the micro-opioid receptor than did wild-type mice, while uncoupling was similar in control wild-type and KO mice. In addition, morphine reduced inhibitory transmission to a greater degree in CaMKIV-KO mice than in controls after chronic morphine exposure. Our results provide novel evidence for the role of CaMKIV in the development of opioid analgesic tolerance but not physical dependence.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, 1 King's College Circle, Medical Sciences Building Rm3342, Toronto, Canada, M5S 1A8.
authors.forename: Shanelle W
authors.initials: SW
authors.lastname: Ko
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Jia
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Se-Jeong
authors.initials: SJ
authors.lastname: Yim
authors.forename: Dong-Hyuk
authors.initials: DH
authors.lastname: Jang
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Lee
authors.forename: Ming-Gao
authors.initials: MG
authors.lastname: Zhao
authors.forename: Hiroki
authors.initials: H
authors.lastname: Toyoda
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
authors.forename: Talal
authors.initials: T
authors.lastname: Chatila
authors.forename: Bong-Kiun
authors.initials: BK
authors.lastname: Kaang
authors.forename: Min
authors.initials: M
authors.lastname: Zhuo
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D011869:Radioligand Assay / Q000379:methods; D013116:Spinal Cord / Q000166:cytology; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D017362:Cyclic AMP Response Element-Binding Protein; D013460:Sulfur Isotopes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse