A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833.
Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.
Whiteside
Garth T
GT
Purdue Pharma Discovery Research, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA. whitesg@wyeth.com
Gottshall
Susan L
SL
Boulet
Jamie M
JM
Chaffer
Suzanne M
SM
Harrison
James E
JE
Pearson
Michelle S
MS
Turchin
Paul I
PI
Mark
Lilly
L
Garrison
Augusta E
AE
Valenzano
Kenneth J
KJ
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000517:prevention & control; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics; D043882:Receptors, Cannabinoid / Q000187:drug effects* / Q000235:genetics; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery
C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D000700:Analgesics; D007211:Indoles; D009025:Morpholines; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011957:Receptors, Opioid; D009271:Naltrexone; D005620:Freund's Adjuvant