期刊
PAIN
卷 156, 期 6, 页码 1025-1035出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000000122
关键词
KCNQ; Benzbromarone; Peripheral nervous system; Gout; Pain
资金
- State Key Program of Basic Research of China [2013CB910604]
- National Science and Technology Major Project on Key New Drug Creation and Manufacturing Program [2013ZX09103001-016]
- National Natural Science Foundation of China [81123004, 61327014, 61175103]
- Shanghai Municipal Science and Technology Commission [13JC1406700]
- External Cooperation Program of BIC, Chinese Academy of Sciences [1536631KYSB20130003]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据