Dynorphin-independent spinal cannabinoid antinociception.
Spinal antinociception produced by delta 9-tetrahydro-cannabinol (Delta(9)-THC) and other cannabinoid agonists has been suggested to be mediated by the release of dynorphin acting at the kappa opioid receptor. Alternatively, as cannabinoid receptors are distributed appropriately in the pain transmission pathway, cannabinoid agonists might act directly at the spinal level to inhibit nociception, without requiring dynorphin release. Here, these possibilities were explored using mice with a deletion of the gene encoding prodynorphin. Antinociceptive dose-response curves were constructed for spinal Delta(9)-THC and WIN 55,212-2 in prodynorphin knock-out mice and in wild-type littermates. WIN 55,212-2 and Delta(9)-THC were equipotent in the wild-type and prodynorphin knock-out mice. Spinal pretreatment with a kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), did not alter the dose-response curves for either WIN 55,212-2 or Delta(9)-THC in prodynorphin knock-out and wild-type mice. However, the same dose of nor-BNI used blocked U50,488H-induced antinociception in both wild-type and prodynorphin knock-out mice, confirming kappa opioid receptor activity. Pretreatment with SR141716A, a cannabinoid receptor antagonist blocked the antinociceptive actions of both WIN 55,212-2 and Delta(9)-THC. These data support the conclusion that antinociception produced by spinal cannabinoids are likely to be mediated directly through activation of cannabinoid receptors without the requirement for dynorphin release or activation of kappa opioid receptors.
Gardell
L R
LR
Department of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, 85724 Tucson, AZ, USA Department of Anesthesiology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ, USA.
Ossipov
M H
MH
Vanderah
T W
TW
Lai
J
J
Porreca
F
F
D000700:Analgesics / Q000008:administration & dosage; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage; D000818:Animals; D048588:Benzoxazines; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage*; D004399:Dynorphins / Q000172:deficiency*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000008:administration & dosage*; D009271:Naltrexone / Q000031:analogs & derivatives*; D009281:Naphthalenes / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016037:Single-Blind Method; D013045:Species Specificity; D013116:Spinal Cord / Q000187:drug effects*
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; C051844:norbinaltorphimine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D009271:Naltrexone; D004399:Dynorphins; D013759:Dronabinol