Staton Penny C, Hatcher Jon P, Walker Deborah J, Morrison Alastair D, Shapland Ellen M, Hughes Jane P, Chong Elizabeth, Mander Palwinder K, Green Paula J, Billinton Andy, Fulleylove Michael, Lancaster Hilary C, Smith Jason C, Bailey Leigh T, Wise Alan, Brown Andrew J, Richardson Jill C, Chessell Iain P
Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK Discovery Technology Group, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK Laboratory Animal Sciences, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK.
Pain. 2008 Sep 30;139(1):225-236. doi: 10.1016/j.pain.2008.04.006. Epub 2008 May 27.
It has been postulated that the G protein-coupled receptor, GPR55, is a third cannabinoid receptor. Given that the ligands at the CB(1) and CB(2) receptors are effective analgesic and anti-inflammatory agents, the role of GPR55 in hyperalgesia associated with inflammatory and neuropathic pain has been investigated. As there are no well-validated GPR55 tool compounds, a GPR55 knockout (GPR55(-/-)) mouse line was generated and fully backcrossed onto the C57BL/6 strain. General phenotypic analysis of GPR55(-/-) mice revealed no obvious primary differences, compared with wild-type (GPR55(+/+)) littermates. GPR55(-/-) mice were then tested in the models of adjuvant-induced inflammation and partial nerve ligation. Following intraplantar administration of Freund's complete adjuvant (FCA), inflammatory mechanical hyperalgesia was completely absent in GPR55(-/-) mice up to 14 days post-injection. Cytokine profiling experiments showed that at 14 days post-FCA injection there were increased levels of IL-4, IL-10, IFN gamma and GM-CSF in paws from the FCA-injected GPR55(-/-) mice when compared with the FCA-injected GPR55(+/+) mice. This suggests that GPR55 signalling can influence the regulation of certain cytokines and this may contribute to the lack of inflammatory mechanical hyperalgesia in the GPR55(-/-) mice. In the model of neuropathic hypersensitivity, GPR55(-/-) mice also failed to develop mechanical hyperalgesia up to 28 days post-ligation. These data clearly suggest that the manipulation of GPR55 may have therapeutic potential in the treatment of both inflammatory and neuropathic pain.
据推测，G蛋白偶联受体GPR55是第三种大麻素受体。鉴于CB(1)和CB(2)受体的配体是有效的镇痛和抗炎剂，人们对GPR55在与炎性疼痛和神经性疼痛相关的痛觉过敏中的作用进行了研究。由于没有经过充分验证的GPR55工具化合物，因此构建了GPR55基因敲除（GPR55(-/-)）小鼠品系，并使其完全回交到C57BL/6品系。与野生型（GPR55(+/+)）同窝小鼠相比，对GPR55(-/-)小鼠的一般表型分析未发现明显的主要差异。然后在佐剂诱导的炎症和部分神经结扎模型中对GPR55(-/-)小鼠进行测试。在足底注射弗氏完全佐剂（FCA）后，GPR55(-/-)小鼠在注射后长达14天完全没有炎性机械性痛觉过敏。细胞因子谱实验表明，与注射FCA的GPR55(+/+)小鼠相比，在FCA注射后14天，注射FCA的GPR55(-/-)小鼠爪中的IL-4、IL-10、IFNγ和GM-CSF水平升高。这表明GPR55信号传导可以影响某些细胞因子的调节，这可能是GPR55(-/-)小鼠缺乏炎性机械性痛觉过敏的原因。在神经性超敏反应模型中，GPR55(-/-)小鼠在结扎后长达28天也未出现机械性痛觉过敏。这些数据清楚地表明，操纵GPR55可能在治疗炎性疼痛和神经性疼痛方面具有治疗潜力。
