title: Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats.
abstract: Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry. This CCI-induced CB1R upregulation was at least in part mediated through tyrosine kinase receptors (Trk), because intrathecal treatment with the Trk inhibitor K252a (1 microg) for postoperative days 1-6 significantly reduced the CB1R upregulation in CCI rats. At the intracellular level, the mitogen-activated protein kinase (ERK-MAPK) inhibitor PD98059 (1 microg) prevented, while the protein kinase C inhibitor chelerythrine (10 microg) partially reduced, the CCI-induced CB1R upregulation when each agent was administered intrathecally for postoperative days 1-6. Importantly, the CCI-induced upregulation of spinal CB1Rs enhanced the effects of Win 55,212-2 on both thermal hyperalgesia and mechanical allodynia, since inhibition of the CB1R upregulation by PD98059 resulted in a significant reduction of the effects of Win 55,212-2 in CCI rats. These results indicate that upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain.
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D008026:Ligation; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D009437:Neuralgia / Q000523:psychology*; D010146:Pain / Q000523:psychology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries*; D013116:Spinal Cord / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014947:Wounds and Injuries / Q000150:complications / Q000378:metabolism
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D020794:Receptor Protein-Tyrosine Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one