title: Antinociceptive effect of intrathecal cannabinoid receptor agonist WIN 55,212-2 in a rat bone tumor pain model.
abstract: Bone tumor pain is a poorly controlled pain comprising background and severe pain on moving or weight-bearing postures that decreases the quality of life for cancer patients; thus, more effective analgesics are clearly needed. This study evaluated the efficacy of a cannabinoid (CB) receptor agonist (WIN 55,212-2) on bone tumor pain in the spinal cords of rats, and clarified the roles of the CB1 and CB2 receptors in WIN 55,212-2-induced antinociception at the spinal level. Bone tumor pain was induced by injecting MRMT-1 tumor cells (1×10(5)) into the right tibias of female Sprague-Dawley rats under sevoflurane anesthesia. Bone tumor development was monitored radiologically. Under sevoflurane anesthesia, a polyethylene catheter was inserted into the intrathecal space for drug administration. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cell inoculation site. The effect of intrathecal WIN 55,212-2 was investigated. Next, the WIN 55,212-2-mediated antinociception was reversed using CB1 (AM 251) and CB2 (AM 630) receptor antagonists. The intratibial injection of MRMT-1 tumor cells produced radiologically confirmed bone tumors. The paw withdrawal threshold decreased significantly (mechanical allodynia) with tumor development; however, intrathecal WIN 55,212-2 dose-dependently increased the withdrawal threshold. The antinociceptive effect of WIN 55,212-2 was reversed by both CB1 and CB2 receptor antagonists. Intrathecal WIN 55,212-2 reduced bone tumor-related pain behavior mediated via spinal CB1 and CB2 receptors. Therefore, spinal CB receptor agonists may be novel analgesics in the treatment of bone tumor pain.
authors.affiliation: The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jin Hua
authors.initials: JH
authors.lastname: Cui
authors.forename: Woong Mo
authors.initials: WM
authors.lastname: Kim
authors.forename: Hyung Gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Ye Ok
authors.initials: YO
authors.lastname: Kim
authors.forename: Chang Mo
authors.initials: CM
authors.lastname: Kim
authors.forename: Myung Ha
authors.initials: MH
authors.lastname: Yoon
mesh_terms: D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002186:Cannabinoids / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007278:Injections, Spinal; D009025:Morpholines / Q000008:administration & dosage*; D009281:Naphthalenes / Q000008:administration & dosage*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000502:physiology; D013125:Spinal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D014407:Tumor Cells, Cultured
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; 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