TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.
TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.
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DOI：
10.1016/j.pain.2013.06.043
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发表时间：
2013-10
期刊：
影响因子：
7.4
通讯作者：
Jordt SE
中科院分区：
文献类型：
--
作者：
Liu B;Fan L;Balakrishna S;Sui A;Morris JB;Jordt SE
薄荷醇是薄荷的冷却天然产物，广泛用于药物制剂中，用于缓解运动损伤、关节炎和其他疼痛情况下的急性和炎症性疼痛。薄荷醇通过激活TRPM8，一种冷敏感的外周感觉神经元上的离子通道，来诱导降温的感觉。最近的研究发现了薄荷醇的其他靶点，包括刺激性受体、TRPA1、电压门控离子通道和神经递质受体。目前尚不清楚这些靶点中的哪些参与了薄荷醇诱导的止痛，或者与薄荷醇治疗相关的刺激性副作用。在这里，我们使用遗传学和药理学方法在小鼠身上探讨TRPM8在L-薄荷醇的镇痛中的作用。薄荷醇是药物制剂中的主要止痛异构体。L-薄荷醇有效地减轻化学刺激(辣椒素、丙烯醛、醋酸)、毒热和炎症(完全弗氏佐剂)引起的疼痛行为。在所有这些模型中，TRPM8基因缺失完全取消了L-薄荷脑的镇痛作用，而其他镇痛剂(对乙酰氨基酚)仍然有效。在用选择性TRPM8抑制剂AMG2850治疗的小鼠中，重述了L薄荷醇诱导的镇痛作用的丧失。在培养的感觉神经元和体内，用WS-12选择性地激活TRPM8，也诱导了TRPM8依赖的急性和炎症性疼痛的镇痛。纳洛酮阻断L薄荷脑和WS-12的镇痛作用，提示内源性阿片依赖的镇痛通路被激活。我们的数据显示，TRPM8是薄荷醇诱导的急性和炎症性疼痛镇痛的主要介体。与薄荷醇相比，选择性的TRPM8激动剂可能产生更有效的镇痛作用，副作用减少。
Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations. L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic acid), noxious heat and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8 completely abolished analgesia by L-menthol in all these models, while other analgesics (acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a menthol derivative we characterized as a specific TRPM8 agonist in cultured sensory neurons and in vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L-menthol and WS-12 induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively with diminished side effects.
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影响因子：
3.3
作者：
Gavva NR;Davis C;Lehto SG;Rao S;Wang W;Zhu DX
通讯作者：
Zhu DX
DOI：
10.1152/physiol.00026.2008
发表时间：
2008-12
期刊：
Physiology (Bethesda, Md.)
影响因子：
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通讯作者：
Jordt SE
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作者：
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