Menthol, which acts as an agonist for transient receptor potential melastatin 8 (TRPM8), has complex effects on nociceptive transmission, including pain relief and hyperalgesia. Here, we addressed the effects of menthol on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs, respectively) in medullary dorsal horn neurons, using a whole-cell patch-clamp technique. Menthol significantly increased sEPSC frequency, in a concentration-dependent manner, without affecting current amplitudes. The menthol-induced increase in sEPSC frequency could be completely blocked by AMTB, a TRPM8 antagonist, but was not blocked by HC-030031, a transient receptor potential ankyrin 1 (TRPA1) antagonist. Menthol still increased sEPSC frequency in the presence of Cd²⁺, a general voltage-gated Ca²⁺ channel blocker, suggesting that voltage-gated Ca²⁺ channels are not involved in the menthol-induced increase in sEPSC frequency. However, menthol failed to increase sEPSC frequency in the absence of extracellular Ca²⁺, suggesting that TRPM8 on primary afferent terminals is Ca²⁺ permeable. On the other hand, menthol also increased sIPSC frequency, without affecting current amplitudes. The menthol-induced increase in sIPSC frequency could be completely blocked by either AMTB or CNQX, an AMPA/KA receptor antagonist, suggesting that the indirect increase in excitability of inhibitory interneurons may lead to the facilitation of spontaneous GABA and/or glycine release. The present results suggested that menthol exerts analgesic effects, via the enhancement of inhibitory synaptic transmission, through central feed-forward neural circuits within the medullary dorsal horn region.

薄荷醇作为瞬时受体电位 melastatin 8 (TRPM8) 的激动剂，对伤害性传递具有复杂的作用，包括缓解疼痛和痛觉过敏。在这里，我们使用全细胞膜片钳技术解决了薄荷醇对延髓背角神经元中自发兴奋性和抑制性突触后电流（分别为 sEPSC 和 sIPSC）的影响。薄荷醇以浓度依赖的方式显着增加 sEPSC 频率，而不影响电流幅度。薄荷醇诱导的 sEPSC 频率增加可以被 TRPM8 拮抗剂 AMTB 完全阻断，但不能被瞬时受体电位锚蛋白 1 (TRPA1) 拮抗剂 HC-030031 阻断。在 Cd ²⁺存在的情况下，薄荷醇仍会增加 sEPSC 频率，Cd ²⁺是一种通用的电压门控 Ca²⁺通道阻滞剂，表明电压门控 Ca ²⁺通道不参与薄荷醇诱导的 sEPSC 频率增加。然而，在没有细胞外 Ca ²⁺的情况下，薄荷醇未能增加 sEPSC 频率，这表明初级传入末梢上的 TRPM8 是 Ca ²⁺透水。另一方面，薄荷醇还增加了 sIPSC 频率，而不影响电流幅度。薄荷醇诱导的 sIPSC 频率增加可以被 AMTB 或 CNQX（一种 AMPA/KA 受体拮抗剂）完全阻断，这表明抑制性中间神经元兴奋性的间接增加可能导致自发 GABA 和/或甘氨酸释放的促进。目前的结果表明，薄荷醇通过延髓背角区域内的中枢前馈神经回路增强抑制性突触传递，从而发挥镇痛作用。