Soga Masahiko, Izumi Takaya, Nanchi Isamu, Horita Narumi, Yamamoto Miyuki, Kawasaki Shiori, Ogawa Koichi, Fujita Masahide, Morioka Yasuhide
Department of Pharmacological Efficacy Evaluation, Shionogi TechnoAdvance Research Co. Ltd., Toyonaka, Japan.
Laboratory for Drug Discovery and Disease Research, Shionogi & Co. Ltd., Toyonaka, Japan.
Pain Rep. 2021 Aug 9;6(3):e951. doi: 10.1097/PR9.0000000000000951. eCollection 2021 Sep-Oct.
Transient receptor potential vanilloid 4 (TRPV4) modulates osteoarthritic (OA) pain in animal models. However, the pathophysiological function of TRPV4 in regulating OA pain remains poorly understood.
We developed TRPV4-knockout (TRPV4-KO) rats and assessed the effects of gene deficiency in a monoiodoacetate (MIA)-induced OA pain model (MIA rats) by examining pain-related behavior, pathological changes, and electrophysiological changes in dorsal root ganglion (DRG) neurons. The changes detected in TRPV4-KO rats were confirmed in wild-type rats using a TRPV4 antagonist.
Transient receptor potential vanilloid 4-KO rats showed the same pain threshold as wild-type rats for thermal or pressure stimuli under normal conditions. gene deletion did not suppress the development of osteoarthritis pathologically in MIA rats. However, the OA-related mechanical pain behaviors observed in MIA rats, including decreased grip strength, increased mechanical allodynia, and reduced weight-bearing on the ipsilateral side, were completely suppressed in TRPV4-KO rats. The DRG neurons in wild-type but not TRPV4-KO MIA rats were depolarized with increased action potentials. Transient receptor potential vanilloid 4 antagonist treatments recapitulated the effects of genetic deletion.
Transient receptor potential vanilloid 4 was sensitized in the DRG neurons of MIA rats and played a critical role in the development of OA pain. These results suggest that the inhibition of TRPV4 might be a novel potent analgesic strategy for treating OA pain.
瞬时受体电位香草酸亚型4（TRPV4）在动物模型中调节骨关节炎（OA）疼痛。然而，TRPV4在调节OA疼痛中的病理生理功能仍知之甚少。
我们培育了TRPV4基因敲除（TRPV4-KO）大鼠，并通过检查背根神经节（DRG）神经元的疼痛相关行为、病理变化和电生理变化，评估基因缺陷在单碘乙酸盐（MIA）诱导的OA疼痛模型（MIA大鼠）中的作用。在野生型大鼠中使用TRPV4拮抗剂证实了在TRPV4-KO大鼠中检测到的变化。
在正常条件下，TRPV4基因敲除大鼠对热刺激或压力刺激的疼痛阈值与野生型大鼠相同。基因缺失在病理上并未抑制MIA大鼠骨关节炎的发展。然而，在MIA大鼠中观察到的与OA相关的机械性疼痛行为，包括握力下降、机械性异常性疼痛增加和同侧负重减少，在TRPV4-KO大鼠中完全受到抑制。野生型MIA大鼠而非TRPV4-KO MIA大鼠的DRG神经元去极化，动作电位增加。TRPV4拮抗剂治疗重现了基因缺失的效果。
TRPV4在MIA大鼠的DRG神经元中被致敏，并在OA疼痛的发展中起关键作用。这些结果表明，抑制TRPV4可能是治疗OA疼痛的一种新型有效镇痛策略。
