Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation - by protons - is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and - via the acido-antithermogenic and acido-antivasoconstrictor reflexes - modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist's potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed.

中文翻译：

---

在人类临床试验中由瞬时受体电位Vanilloid-1（TRPV1）拮抗剂引起的热疗：数学建模和荟萃分析的见解。

瞬态受体电位香草酸1（TRPV1）通道的拮抗剂会改变实验动物和人类的体温（Tb）。一些产生体温过低；但是其他都没有效果。可以通过辣椒素（CAP），质子（低pH）和热量激活TRPV1。第一代（多峰型）TRPV1拮抗剂有效地阻断了所有三种TRPV1激活模式。第二代（模式选择性）TRPV1拮抗剂可有效阻止CAP激活通道，但在质子模式，加热模式或两者中均发挥不同的作用（例如，增强作用，无作用或低效抑制）。根据我们在大鼠中的早期研究，质子激活TRPV1的方式仅涉及一种对TRPV1拮抗剂的温度调节反应。在大鼠中，可能有效阻断，增强，或对质子激活无影响分别导致体温过高，体温过低或对Tb无影响。当TRPV1拮抗剂阻断（如果发生体温过高）或增强（体温过低）时，躯干中某处的质子（可能是肌肉）中的质子激活补品TRPV1激活，并且-通过酸-抗生热和酸-抗血管收缩剂反射-调节生热，就会发生Tb反应。和皮肤血管收缩。在这项工作中，我们使用了数学模型来分析TRPV1拮抗剂的人体临床试验中的Tb数据。分析表明，在人类中，高热效应取决于拮抗剂的作用能力，不仅可以通过质子，而且可以通过热量阻止TRPV1激活，而无需涉及CAP激活模式。在大鼠中，TRPV1通过介导躯干的pH信号而不是Tb信号来驱动热效应器，我们的分析表明，TRPV1介导pH和热信号，从而驱动人类的体温调节。因此，在人类（但不是在大鼠中）中，TRPV1可能充当温度调节系统的热传感器。我们还对人体试验中的Tb数据进行了荟萃分析，发现多峰TRPV1拮抗剂（ABT-102，AZD1386和V116517）可增加Tb，而模式选择阻滞剂NEO6860则不会。讨论了利用TRPV1拮抗剂对人的体温调节作用的几种策略。AZD1386和V116517）增加了Tb，而模式选择阻止程序NEO6860没有。讨论了利用TRPV1拮抗剂对人的体温调节作用的几种策略。AZD1386和V116517）增加了Tb，而模式选择阻止程序NEO6860没有。讨论了利用TRPV1拮抗剂对人的体温调节作用的几种策略。