Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA.
Pain. 2013 Oct;154(10):2169-2177. doi: 10.1016/j.pain.2013.06.043. Epub 2013 Jun 29.
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, although 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 that 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.
薄荷醇是薄荷的清凉天然产物，广泛用于运动损伤、关节炎和其他疼痛情况下急性和炎症性疼痛的药物制剂中。薄荷醇通过激活冷敏外周感觉神经元中的离子通道 TRPM8 来诱导清凉感。最近的研究确定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一个有助于薄荷醇诱导的镇痛，或者与薄荷醇治疗相关的刺激性副作用有关。在这里，我们使用遗传和药理学方法在小鼠中探究 L-薄荷醇诱导的镇痛中 TRPM8 的作用，L-薄荷醇是药物制剂中主要的镇痛薄荷醇异构体。L-薄荷醇有效地减轻了化学刺激（辣椒素、丙烯醛、乙酸）、有害热和炎症（完全弗氏佐剂）引起的疼痛行为。在所有这些模型中，TRPM8 的遗传缺失完全消除了 L-薄荷醇的镇痛作用，尽管其他镇痛药（对乙酰氨基酚）仍然有效。用选择性 TRPM8 抑制剂 AMG2850 治疗的小鼠中也重现了 L-薄荷醇诱导的镇痛作用丧失。用 WS-12（一种我们在培养的感觉神经元和体内鉴定为特异性 TRPM8 激动剂的薄荷醇衍生物）选择性激活 TRPM8，也可诱导急性和炎症性疼痛的 TRPM8 依赖性镇痛。纳洛酮阻断 L-薄荷醇和 WS-12 诱导的镇痛，表明激活了内源性阿片依赖的镇痛途径。我们的数据表明，TRPM8 是薄荷醇诱导的急性和炎症性疼痛镇痛的主要介导物。与薄荷醇不同，选择性 TRPM8 激动剂可能更有效地产生镇痛作用，副作用更小。
