Gavva Narender R, Bannon Anthony W, Surapaneni Sekhar, Hovland David N, Lehto Sonya G, Gore Anu, Juan Todd, Deng Hong, Han Bora, Klionsky Lana, Kuang Rongzhen, Le April, Tamir Rami, Wang Jue, Youngblood Brad, Zhu Dawn, Norman Mark H, Magal Ella, Treanor James J S, Louis Jean-Claude
Department of Neuroscience, Amgen, Thousand Oaks, California 91320-1799, USA.
J Neurosci. 2007 Mar 28;27(13):3366-74. doi: 10.1523/JNEUROSCI.4833-06.2007.
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.
香草酸受体TRPV1（瞬时受体电位香草酸亚型1）是一种阳离子通道，可作为辣椒素、质子（pH<5.7）和热等致痛刺激的多模式检测器。TRPV1拮抗剂可阻断炎症性、神经性和癌痛啮齿动物模型中的疼痛行为，表明它们可作为镇痛药。在此，我们报告代表各种化学类型的TRPV1拮抗剂会导致体温升高（发热），这为它们的临床开发指出了一个潜在问题。拮抗剂的外周限制并不能消除发热，这表明作用部位主要在血脑屏障之外。对质子激活无效的拮抗剂也会导致发热，这表明阻断TRPV1的辣椒素和热激活足以产生发热。此处评估的所有TRPV1拮抗剂都会导致发热，这表明TRPV1在体内被持续激活，并且TRPV1拮抗作用和发热是不可分割的。TRPV1拮抗剂在多个物种（大鼠、狗和猴子）中都会导致发热，这表明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TRPV1的持续激活调节体温。
