Pronociceptive effects of spinal dynorphin promote cannabinoid-induced pain and antinociceptive tolerance.
Recent studies indicate that sustained opioid administration produces increased expression of spinal dynorphin, which promotes enhanced sensitivity to non-noxious and noxious stimuli. Such increased "pain" may manifest behaviorally as a decrease in spinal antinociceptive potency. Here, the possibility of similar mechanisms in the antinociception of spinal cannabinoids was explored. Response thresholds to non-noxious mechanical and noxious thermal stimuli were assessed. Antinociception was determined using the 52 degrees C tail-flick test. Mice received repeated WIN 55,212-2, its inactive enantiomer, WIN 55,212-3 or vehicle (i.th., bid, 5 days). WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced a time-related increased sensitivity to non-noxious and noxious stimuli. WIN 55,212-2, but not WIN 55,212-3 or vehicle, elicited a significant increase in lumbar spinal dynorphin content at treatment day 5. Increased sensitivity to mechanical and thermal stimuli produced by WIN 55,212-2 was reversed to baseline levels by i.th. MK-801 or dynorphin antiserum; control serum had no effect. WIN 55,212-2, but not WIN 55,212-3 or vehicle, produced dose-related antinociception and repeated administration resulted in antinociceptive tolerance. While MK-801 and dynorphin antiserum did not alter acute antinociception produced by WIN 55,212-2, these substances significantly blocked antinociceptive tolerance when given immediately prior to WIN 55,212-2 challenge on day 5. Daily MK-801 pretreatments, prior to WIN 55,212-2 injection, also produced a significant block of antinociceptive tolerance. These data suggest that like opioids, repeated spinal administration of a cannabinoid CB1 agonist elicits abnormal pain, which results in increased expression of spinal dynorphin. Manipulations that block cannabinoid-induced pain also block the behavioral manifestation of cannabinoid tolerance.
Gardell
L R
LR
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Burgess
S E
SE
Dogrul
A
A
Ossipov
M H
MH
Malan
T P
TP
Lai
J
J
Porreca
F
F
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D003429:Cross Reactions; D004357:Drug Synergism; D004361:Drug Tolerance; D004399:Dynorphins / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D006358:Hot Temperature; D007124:Immunoenzyme Techniques; D007278:Injections, Spinal; D007536:Isomerism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology*; D010146:Pain / Q000139:chemically induced*; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D013116:Spinal Cord / Q000378:metabolism
D000700:Analgesics; D000906:Antibodies; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D004399:Dynorphins