Li Ziping, Zhang Haoyue, Wang Yigang, Li Yize, Li Qing, Zhang Linlin
The Graduate School, Tianjin Medical University, Tianjin, China.
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.
Front Mol Neurosci. 2022 Oct 5;15:1006908. doi: 10.3389/fnmol.2022.1006908. eCollection 2022.
Menthol is an important flavoring additive that triggers a cooling sensation. Under physiological condition, low to moderate concentrations of menthol activate transient receptor potential cation channel subfamily M member 8 (TRPM8) in the primary nociceptors, such as dorsal root ganglion (DRG) and trigeminal ganglion, generating a cooling sensation, whereas menthol at higher concentration could induce cold allodynia, and cold hyperalgesia mediated by TRPM8 sensitization. In addition, the paradoxical irritating properties of high concentrations of menthol is associated with its activation of transient receptor potential cation channel subfamily A member 1 (TRPA1). Under pathological situation, menthol activates TRPM8 to attenuate mechanical allodynia and thermal hyperalgesia following nerve injury or chemical stimuli. Recent reports have recapitulated the requirement of central group II/III metabotropic glutamate receptors (mGluR) with endogenous κ-opioid signaling pathways for menthol analgesia. Additionally, blockage of sodium channels and calcium influx is a determinant step after menthol exposure, suggesting the possibility of menthol for pain management. In this review, we will also discuss and summarize the advances in menthol-related drugs for pathological pain treatment in clinical trials, especially in neuropathic pain, musculoskeletal pain, cancer pain and postoperative pain, with the aim to find the promising therapeutic candidates for the resolution of pain to better manage patients with pain in clinics.
薄荷醇是一种能引发清凉感的重要调味添加剂。在生理条件下，低至中等浓度的薄荷醇会激活初级伤害感受器（如背根神经节和三叉神经节）中的瞬时受体电位阳离子通道亚家族M成员8（TRPM8），产生清凉感，而高浓度的薄荷醇会诱发冷觉异常和由TRPM8敏化介导的冷痛觉过敏。此外，高浓度薄荷醇的反常刺激特性与其对瞬时受体电位阳离子通道亚家族A成员1（TRPA1）的激活有关。在病理情况下，薄荷醇会激活TRPM8，以减轻神经损伤或化学刺激后的机械性异常性疼痛和热痛觉过敏。最近的报告概括了中枢II/III组代谢型谷氨酸受体（mGluR）与内源性κ-阿片信号通路对薄荷醇镇痛的必要性。此外，阻断钠通道和钙内流是薄荷醇暴露后的一个决定性步骤，这表明薄荷醇具有用于疼痛管理的可能性。在这篇综述中，我们还将讨论和总结薄荷醇相关药物在临床试验中治疗病理性疼痛方面的进展，特别是在神经性疼痛、肌肉骨骼疼痛、癌症疼痛和术后疼痛方面，旨在找到有前景的治疗候选药物，以解决疼痛问题，从而在临床上更好地管理疼痛患者。
