The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation
The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation
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DOI：
10.1523/jneurosci.4833-06.2007
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发表时间：
2007-03-28
影响因子：
5.3
通讯作者：
Louis, Jean-Claude
中科院分区：
文献类型：
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作者：
Gavva, Narender R.;Bannon, Anthony W.;Louis, Jean-Claude
香草素受体TRPV1（瞬时受体电位香草素1）是一种阳离子通道，作为产生疼痛刺激的多模态探测器，如辣椒素、质子（pH < 5.7）和热。TRPV1拮抗剂阻断炎性、神经性和癌性疼痛啮齿动物模型的疼痛行为，提示其作为镇痛药的效用。在这里，我们报告了代表各种化学型的TRPV1拮抗剂导致体温升高（热疗），确定了其临床发展的潜在问题。外周限制拮抗剂并不能消除高热，这表明作用部位主要在血脑屏障外。对质子激活无效的拮抗剂也会引起热疗，这表明阻断辣椒素和TRPV1的热激活足以产生热疗。本研究评估的所有TRPV1拮抗剂均引起热疗，提示TRPV1在体内被强直性激活，TRPV1拮抗剂与热疗是不可分离的。TRPV1拮抗剂在多个物种（大鼠、狗和猴子）中引起高热，表明TRPV1在体温调节中的功能从啮齿动物到灵长类动物都是保守的。总之，这些结果表明，强直性TRPV1激活调节体温。
The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH < 5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics. Here, we report that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development. Peripheral restriction of antagonists did not eliminate hyperthermia, suggesting that the site of action is predominantly outside of the blood-brain barrier. Antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. All TRPV1 antagonists evaluated here caused hyperthermia, suggesting that TRPV1 is tonically activated in vivo and that TRPV1 antagonism and hyperthermia are not separable. TRPV1 antagonists caused hyperthermia in multiple species (rats, dogs, and monkeys), demonstrating that TRPV1 function in thermoregulation is conserved from rodents to primates. Together, these results indicate that tonic TRPV1 activation regulates body temperature.