Evidence for a role of CaMKIV in the development of opioid analgesic tolerance.
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.
Ko
Shanelle W
SW
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.
Jia
Yongheng
Y
Xu
Hui
H
Yim
Se-Jeong
SJ
Jang
Dong-Hyuk
DH
Lee
Yong-Seok
YS
Zhao
Ming-Gao
MG
Toyoda
Hiroki
H
Wu
Long-Jun
LJ
Chatila
Talal
T
Kaang
Bong-Kiun
BK
Zhuo
Min
M
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
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