PKCepsilon regulates behavioral sensitivity, binding and tolerance to the CB1 receptor agonist WIN55,212-2.
The cannabinoid CB1 receptor (CB1) is one of the most abundant G protein-coupled receptors in the brain, but little is known about the mechanisms that modulate CB1 receptor signaling. Here, we show that inhibition or null mutation of the epsilon isozyme of protein kinase C (PKCepsilon) selectively enhances behavioral responses to the CB1 agonist WIN55,212-2 in mice, but not to the structurally unrelated CB1 agonist CP55,940. Binding affinity for [(3)H] WIN55,212-2 was increased in brain membranes from PKCepsilon(-/-) mice compared with PKCepsilon(+/+) mice. There was no difference in binding of the inverse agonist [(3)H] SR141716A. In addition, repeated administration of WIN55,212-2 produced greater analgesic and thermal tolerance in PKCvarepsilon(-/-) mice compared with PKCepsilon(+/+)mice. These results indicate that PKCvarepsilon selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.
Wallace
Melisa J
MJ
Department of Neurology, The Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA 94608, USA.
Newton
Philip M
PM
McMahon
Thomas
T
Connolly
Jacklyn
J
Huibers
Anne
A
Whistler
Jennifer
J
Messing
Robert O
RO
D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D048588:Benzoxazines / Q000494:pharmacology*; D003164:Competitive Bidding / Q000379:methods; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007035:Hypothermia / Q000139:chemically induced / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000172:deficiency / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D000700:Analgesics; D048588:Benzoxazines; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D010455:Peptides; D043884:Receptor, Cannabinoid, CB1; D014316:Tritium; D012694:Serine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D051744:Protein Kinase C-epsilon