Zheng Yueming, Xu Haiyan, Zhan Li, Zhou Xindi, Chen Xueqin, Gao Zhaobing
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Pain. 2015 Jun;156(6):1025-1035. doi: 10.1097/j.pain.0000000000000122.
Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK). Benzbromarone consistently attenuates BK-, formalin-, or monosodium urate-induced inflammatory pain in rat and mouse models. Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout.
关节及其他组织中的尿酸盐结晶所引发的强烈炎性疼痛是痛风的主要症状。在降低尿酸的治疗药物中，苯溴马隆（BBR）作为一种尿酸转运体抑制剂被广泛使用，因为它耐受性良好且疗效显著。我们证明BBR还是电压门控KCNQ钾通道的激活剂。在培养的重组细胞中，BBR对KCNQ通道表现出显著的增强作用，与先前报道的经典激活剂相当。在原代背根神经节神经元中，BBR有效克服了炎性介质（如缓激肽（BK））对KCNQ电流的抑制以及由此导致的神经元兴奋性过高。苯溴马隆持续减轻大鼠和小鼠模型中由BK、福尔马林或尿酸钠诱导的炎性疼痛。值得注意的是，BBR的镇痛作用主要通过外周而非中枢KCNQ通道介导，这一观察结果得到了药代动力学研究和体内实验的支持。此外，通过分子决定因素研究确定，KCNQ通道电压传感结构域表面部分的多个残基对BBR的增强活性至关重要。我们的数据表明，外周KCNQ通道的激活介导了BBR的止痛作用，这可能为开发更有效的痛风治疗方法提供新策略。
