Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain
Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain
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DOI：
10.1073/pnas.1704847114
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发表时间：
2017-08-01
影响因子：
11.1
通讯作者：
Miyaji, Takaaki
中科院分区：
文献类型：
--
作者：
Kato, Yuri;Hiasa, Miki;Miyaji, Takaaki
尽管神经性疼痛和炎性疼痛在世界范围内的发病率很高，但目前还没有有效的药物用于治疗慢性疼痛。最近，研究人员提出，嘌呤能化学传递的抑制剂，这在病理性疼痛反应中起着关键作用，可能允许有针对性地治疗病理性神经性疼痛和炎性疼痛。然而，此类治疗性镇痛剂尚未开发。在本研究中，我们证明，氯膦酸盐，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蛋白（VNUT），一个关键分子的嘌呤能化学传递的启动，显着减弱与骨异常无关的神经性和炎症性疼痛。体外分析表明，氯膦酸盐抑制VNUT在半最大抑制浓度为15.6 nM，而不影响其他囊泡神经递质转运蛋白，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，氯膦酸盐在减弱野生型但非VNUT-/-小鼠中的神经性疼痛和炎性疼痛以及伴随的炎症方面比其他治疗剂更有效，而不影响基础伤害感受。这些研究结果表明，氯膦酸盐可能是一种独特的治疗策略，慢性神经性疼痛和炎症性疼痛通过抑制囊泡ATP释放。
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 VNUT-/- 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.