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A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833.
Eur J Pharmacol. 2005 Dec 28; 528(1-3):65-72.EJ

Abstract

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.

Authors+Show Affiliations

Purdue Pharma Discovery Research, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA. whitesg@wyeth.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16316650

Citation

Whiteside, Garth T., et al. "A Role for Cannabinoid Receptors, but Not Endogenous Opioids, in the Antinociceptive Activity of the CB2-selective Agonist, GW405833." European Journal of Pharmacology, vol. 528, no. 1-3, 2005, pp. 65-72.
Whiteside GT, Gottshall SL, Boulet JM, et al. A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833. Eur J Pharmacol. 2005;528(1-3):65-72.
Whiteside, G. T., Gottshall, S. L., Boulet, J. M., Chaffer, S. M., Harrison, J. E., Pearson, M. S., Turchin, P. I., Mark, L., Garrison, A. E., & Valenzano, K. J. (2005). A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833. European Journal of Pharmacology, 528(1-3), 65-72.
Whiteside GT, et al. A Role for Cannabinoid Receptors, but Not Endogenous Opioids, in the Antinociceptive Activity of the CB2-selective Agonist, GW405833. Eur J Pharmacol. 2005 Dec 28;528(1-3):65-72. PubMed PMID: 16316650.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW405833. AU - Whiteside,Garth T, AU - Gottshall,Susan L, AU - Boulet,Jamie M, AU - Chaffer,Suzanne M, AU - Harrison,James E, AU - Pearson,Michelle S, AU - Turchin,Paul I, AU - Mark,Lilly, AU - Garrison,Augusta E, AU - Valenzano,Kenneth J, Y1 - 2005/11/28/ PY - 2005/05/23/received PY - 2005/10/14/revised PY - 2005/10/25/accepted PY - 2005/12/1/pubmed PY - 2006/3/10/medline PY - 2005/12/1/entrez SP - 65 EP - 72 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 528 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/16316650/A_role_for_cannabinoid_receptors_but_not_endogenous_opioids_in_the_antinociceptive_activity_of_the_CB2_selective_agonist_GW405833_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(05)01109-X DB - PRIME DP - Unbound Medicine ER -