Kato Yuri, Hiasa Miki, Ichikawa Reiko, Hasuzawa Nao, Kadowaki Atsushi, Iwatsuki Ken, Shima Kazuhiro, Endo Yasuo, Kitahara Yoshiro, Inoue Tsuyoshi, Nomura Masatoshi, Omote Hiroshi, Moriyama Yoshinori, Miyaji Takaaki
Advanced Science Research Center, Okayama University, Okayama 700-8530, Japan.
Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):E6297-E6305. doi: 10.1073/pnas.1704847114. Epub 2017 Jul 18.
Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release.
尽管全球神经性和炎性疼痛的发病率很高，但目前尚无副作用少的有效药物用于治疗慢性疼痛。最近，研究人员提出，嘌呤能化学传递抑制剂在病理性疼痛反应中起关键作用，可能有助于针对性治疗病理性神经性和炎性疼痛。然而，此类治疗性镇痛剂尚未开发出来。在本研究中，我们证明了氯膦酸盐（一种第一代双膦酸盐，与传统治疗相比副作用相对较少）通过抑制囊泡核苷酸转运体（VNUT，嘌呤能化学传递起始的关键分子），可显著减轻与骨骼异常无关的神经性和炎性疼痛。体外分析表明，氯膦酸盐在半最大抑制浓度为15.6 nM时抑制VNUT，而不影响其他囊泡神经递质转运体，通过与Cl竞争作为变构调节剂。低浓度的氯膦酸盐会损害神经元、小胶质细胞和免疫细胞的囊泡ATP释放。体内分析显示，氯膦酸盐在减轻野生型而非 小鼠的神经性和炎性疼痛以及伴随的炎症方面比其他治疗剂更有效，且不影响基础痛觉。这些发现表明，氯膦酸盐可能代表一种通过抑制囊泡ATP释放来治疗慢性神经性和炎性疼痛的独特策略。
