Wong Gilbert Y, Gavva Narender R
Clinical Research, Anesiva, South San Francisco, CA 94080, USA.
Brain Res Rev. 2009 Apr;60(1):267-77. doi: 10.1016/j.brainresrev.2008.12.006. Epub 2008 Dec 25.
The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions.
香草酸受体TRPV1是一种同源四聚体、非选择性阳离子通道，在伤害感受器（C纤维）中大量表达。TRPV1被认为是一个经过高度验证的疼痛靶点，原因如下：其一，其激动剂如辣椒素可使TRPV1通道脱敏，从而缓解临床前动物的疼痛行为；其二，其拮抗剂可缓解炎症、骨关节炎和癌症的啮齿动物模型中的疼痛行为。因此，TRPV1的激动剂和拮抗剂都正在作为潜在的镇痛药进行临床试验评估。已报道了TRPV1激动剂如树脂毒素用于间质性膀胱炎、NGX 4010用于带状疱疹后神经痛以及4975（Adlea）用于骨关节炎、拇囊炎切除术和 Morton 神经瘤的临床试验结果。同样，TRPV1拮抗剂如SB - 705498和AMG 517的临床试验结果最近也已发表。总体而言，一些分子（如辣椒素）在某些情况下（术后疼痛、带状疱疹后神经痛、糖尿病性神经病变疼痛、骨关节炎、拇囊炎切除术和 Morton 神经瘤）显示出潜在的镇痛作用，而其他一些分子则由于靶点相关不良反应退出临床试验或未能证明其疗效。本综述总结了TRPV1激动剂和拮抗剂在临床上的最新进展和挫折，并预测了未来的方向。
