Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain.
OBJECTIVE
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.


METHODS
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.


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
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.
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Chang.Z.Zhu@abbott.com
C Z
CZ
Zhu
J P
JP
Mikusa
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Y
Fan
P R
PR
Hollingsworth
M
M
Pai
P
P
Chandran
A V
AV
Daza
B B
BB
Yao
M J
MJ
Dart
M D
MD
Meyer
M W
MW
Decker
G C
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Hsieh
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Honore
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005528:Foot / Q000473:pathology; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D010149:Postoperative Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects
D000700:Analgesics; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone