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2015 ; 156
(6
): 1025-1035
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Activation of peripheral KCNQ channels relieves gout pain
#MMPMID25735002
Zheng Y
; Xu H
; Zhan L
; Zhou X
; Chen X
; Gao Z
Pain
2015[Jun]; 156
(6
): 1025-1035
PMID25735002
show ga
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.
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