哺乳动物有害热感知的神经元和离子通道机制：感觉生理学和药理学的谜题

摘要(中文译文)

瞬时受体电位香草酸亚型1（TRPV1）是首个被发现的伤害性热敏感通道。在啮齿类动物中，其在多模态伤害感受器胞体热反应中的作用十分显著，但在皮肤外周终末的热反应中作用却出人意料地小。TRPV1对热阈值的贡献取决于解剖定位，在小鼠尾部普遍存在，而在后爪中则缺失。在啮齿类动物的行为学测试中，TRPV1的作用在较低温度下较为微弱，但在较高温度下则显著。与基础热反应不同，炎症性热痛觉过敏/异常性疼痛严重依赖于TRPV1。与大鼠和小鼠不同，TRPV1受体拮抗剂可提高人类的热痛阈值，可能导致烫伤，从而妨碍了其临床应用。TRPM3和anoctamin 1是其他热敏感通道，在啮齿类动物的伤害性热反应性中作用有限。冷和热激活的TRPA1通道在热感觉中的功能尚存争议。相比之下，TRPV2、TRPV3、TRPV4和TRPM2通道不太可能是伤害性热感觉的主要决定因素。在小鼠中联合基因敲除TRPV1、TRPA1和TRPM3可导致热反应近乎完全丧失；然而，热阈值保持不变。然而在人类中，联合药理学阻断这三种TRP通道仅使皮肤伤害性热阈值升高1°C。TRPV1似乎是唯一已知的热传感器，其在热痛感觉中具有已确立但有限的作用；因此，其他热传感器也必定参与其中。

Abstract

Transient receptor potential vanilloid 1 (TRPV1) was the first noxious heat-sensitive channel discovered. In rodents, its role is robust in the heat response of the cell body of polymodal nociceptors, but surprisingly small in that of the peripheral terminals in the skin. TRPV1's contribution to the heat threshold depends on anatomical localisation, being prevalent in the tail while absent in the hind paw of the mouse. In behavioural tests of rodents, the role of TRPV1 is marginal with lower, but significant with higher, temperatures. In contrast to the basal heat response, inflammatory heat hyperalgesia/allodynia critically depends on TRPV1. In contrast to rats and mice, TRPV1 receptor antagonists elevate the heat pain threshold in humans, potentially leading to scald injuries and precluding their clinical use. TRPM3 and anoctamin 1 are other heat-sensitive channels that play limited roles in rodents' noxious heat responsiveness. The function of the cold- and heat-activated TRPA1 channel in heat sensation is a matter of debate. In contrast, TRPV2, TRPV3, TRPV4 and TRPM2 channels are unlikely to be major determinants of noxious heat sensation. Combined genetic ablation of TRPV1, TRPA1 and TRPM3 in the mouse results in a near-complete reduction of the heat response; however, the heat threshold remains unchanged. In humans, however, combined pharmacological block of the three TRP channels elevates the noxious heat threshold in skin by only 1°C. TRPV1 appears to be the only known heat sensor with an established but limited role in heat pain sensation; thus, other heat sensor must also contribute.

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