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Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain.
Br J Pharmacol 2009; 157(4):645-55BJ

Abstract

BACKGROUND AND PURPOSE

Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain.

EXPERIMENTAL APPROACH

WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB(1) and CB(2) receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB(1) and CB(2) receptor antagonists.

KEY RESULTS

WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB(1) versus CB(2) receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB(1) receptor antagonist, but not with a CB(2) receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB(1) and CB(2) antagonists blocked systemic WIN-induced analgesic activity.

CONCLUSIONS AND IMPLICATIONS

Both CB(1) and CB(2) receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB(1) but not CB(2) receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB(1) receptors in the brain.

Authors+Show Affiliations

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Chang.Z.Zhu@abbott.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 availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19371344

Citation

Zhu, C Z., et al. "Peripheral and Central Sites of Action for the Non-selective Cannabinoid Agonist WIN 55,212-2 in a Rat Model of Post-operative Pain." British Journal of Pharmacology, vol. 157, no. 4, 2009, pp. 645-55.
Zhu CZ, Mikusa JP, Fan Y, et al. Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain. Br J Pharmacol. 2009;157(4):645-55.
Zhu, C. Z., Mikusa, J. P., Fan, Y., Hollingsworth, P. R., Pai, M., Chandran, P., ... Honore, P. (2009). Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain. British Journal of Pharmacology, 157(4), pp. 645-55. doi:10.1111/j.1476-5381.2009.00184.x.
Zhu CZ, et al. Peripheral and Central Sites of Action for the Non-selective Cannabinoid Agonist WIN 55,212-2 in a Rat Model of Post-operative Pain. Br J Pharmacol. 2009;157(4):645-55. PubMed PMID: 19371344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain. AU - Zhu,C Z, AU - Mikusa,J P, AU - Fan,Y, AU - Hollingsworth,P R, AU - Pai,M, AU - Chandran,P, AU - Daza,A V, AU - Yao,B B, AU - Dart,M J, AU - Meyer,M D, AU - Decker,M W, AU - Hsieh,G C, AU - Honore,P, Y1 - 2009/04/03/ PY - 2009/4/18/entrez PY - 2009/4/18/pubmed PY - 2009/10/16/medline SP - 645 EP - 55 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 157 IS - 4 N2 - BACKGROUND AND PURPOSE: Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain. EXPERIMENTAL APPROACH: WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB(1) and CB(2) receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB(1) and CB(2) receptor antagonists. KEY RESULTS: WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB(1) versus CB(2) receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB(1) receptor antagonist, but not with a CB(2) receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB(1) and CB(2) antagonists blocked systemic WIN-induced analgesic activity. CONCLUSIONS AND IMPLICATIONS: Both CB(1) and CB(2) receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB(1) but not CB(2) receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB(1) receptors in the brain. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/19371344/Peripheral_and_central_sites_of_action_for_the_non_selective_cannabinoid_agonist_WIN_55212_2_in_a_rat_model_of_post_operative_pain_ L2 - https://doi.org/10.1111/j.1476-5381.2009.00184.x DB - PRIME DP - Unbound Medicine ER -