Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat
Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat
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DOI：
10.1111/bph.14177
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发表时间：
2018-05-01
影响因子：
7.3
通讯作者：
Brandolini, Laura
中科院分区：
文献类型：
--
作者：
De Caro, Carmen;Russo, Roberto;Brandolini, Laura
瞬时受体电位（TRP）通道是参与外周感觉信号传导的非选择性阳离子渗透性通道的超家族。动物研究表明，几种TRP在疼痛调节中起重要作用。其中，TRP melastatin 8（TRPM 8）因其在伤害感受中的争议性作用而引起了更多的兴趣。该通道由背根神经节（DRG）和三叉神经节（TG）中的感觉神经元亚群表达，被低温和冷却剂激活。在实验性神经性疼痛模型中，已经观察到该受体在DRG和TG中的上调，表明TRPM8在疼痛的发展和维持中的关键作用。实验方法在这项研究中，两种新型TRPM8拮抗剂DFL23693和DFL23448的治疗潜力和疗效进行了测试。关键词两种有效的和选择性的TRPM8拮抗剂具有不同的药代动力学特征，DFL23693和DFL23448，已经在体外充分表征。在完善的模型中的体内研究，即湿狗摇动试验和体温变化，证实了它们阻断TRPM 8通道的能力。最后，TRPM8阻滞导致在福尔马林引起的orofacial疼痛和慢性压迫性损伤引起的神经性疼痛的显着的抗伤害性作用，证实了这个通道在疼痛perception.CONCLUSION和IMPLICATIONSOUR的研究结果，与以前的文献一致，鼓励进一步的研究更好地理解TRPM8阻滞剂作为疼痛管理的新药物的治疗潜力。
BACKGROUND AND PURPOSETransient receptor potential (TRP) channels are a superfamily of non-selective cation permeable channels involved in peripheral sensory signalling. Animal studies have shown that several TRPs are important players in pain modulation. Among them, the TRP melastatin 8 (TRPM8) has elicited more interest for its controversial role in nociception. This channel, expressed by a subpopulation of sensory neurons in dorsal root ganglia (DRG) and trigeminal ganglia (TG), is activated by cold temperatures and cooling agents. In experimental neuropathic pain models, an up-regulation of this receptor in DRG and TG has been observed, suggesting a key role for TRPM8 in the development and maintenance of pain. Consistent with this hypothesis, TRPM8 knockout mice are less responsive to pain stimuli.EXPERIMENTAL APPROACHIn this study, the therapeutic potential and efficacy of two novel TRPM8 antagonists, DFL23693 and DFL23448, were tested.KEY RESULTSTwo potent and selective TRPM8 antagonists with distinct pharmacokinetic profiles, DFL23693 and DFL23448, have been fully characterized in vitro. In vivo studies in well-established models, namely, the wet-dog shaking test and changes in body temperature, confirmed their ability to block the TRPM8 channel. Finally, TRPM8 blockage resulted in a significant antinociceptive effect in formalin-induced orofacial pain and in chronic constriction injury-induced neuropathic pain, confirming an important role for this channel in pain perception.CONCLUSION AND IMPLICATIONSOur findings, in agreement with previous literature, encourage further studies for a better comprehension of the therapeutic potential of TRPM8 blockers as novel agents for pain management.