Mechanisms of Zinc Regulation of Pain-initiating TRP Channels

描述（由申请人提供）：锌已被广泛用作抗炎和抗关节炎剂超过3000年。它已在许多模型系统中显示出有希望的镇痛作用。以往的研究发现，锌激活痛起始TRPA1通道，诱导急性疼痛反应行为。因此，锌必须通过替代机制来执行其抗伤害性作用。我们的初步研究表明，锌的预处理使TRPA1脱敏，这表明锌可以通过诱导受体脱敏来抑制TRPA1，就像辣椒素对TRPV1一样。我们还表明，锌抑制TRPV1功能在体外和体内和TRPA1的基因消融显着减少锌抑制TH TRPV1功能。所提出的实验将测试细胞外锌抑制TRPA1/V1介导的热和机械性疼痛在急性和慢性炎症模型中的假设。我们将研究锌抑制TRPV1的分子决定因素。我们还将研究TRPA1激活是否是TRPV1抑制的上游事件，并使用trpa1-/-小鼠测试这种调节机制是否对体内限制锌的作用很重要 和一种特异性TRPA1阻断剂HC-030031。从这些实验中得到的数据将通过抑制初级伤害感受器处的两个主要疼痛起始TRP通道来确立锌作为新型抗伤害感受剂，并将揭示锌抑制TRPV 1功能的分子机制。我们的研究结果将阐明靶向TRP通道的新治疗策略，用于治疗外周伤害感受器中的疼痛，而不会促进人类患者的靶向副作用。

DESCRIPTION (provided by applicant): Zinc has been widely used as an anti-inflammatory and anti-arthritic agent for more than 3000 years. It has shown promising analgesic effect in a number of model systems. Previous studies found that zinc activated the pain-initiating TRPA1 channels and induced acute nocifensive behaviors. Therefore, zinc must execute its anti-nociceptive effect via alternative mechanisms. Our pilot studies show that pre-treatment of zinc desensitized TRPA1, suggesting that zinc can inhibit TRPA1 by inducing receptor desensitization like capsaicin to TRPV1. We also show that zinc suppressed TRPV1 function both in vitro and in vivo and genetic ablation of TRPA1 significantly reduced zinc inhibition of th TRPV1 function. The proposed experiments will test the hypothesis that extracellular zinc suppresses TRPA1/V1-mediated thermal and mechanical pain in both acute and chronic inflammatory models. We will investigate molecular determinants of zinc inhibition of TRPV1. We will also examine if TRPA1 activation is an upstream event of TRPV1 inhibition and test whether this regulatory mechanism is important for limiting zinc action in vivo using trpa1-/- mice and a specific TRPA1 blocker, HC-030031. The data resulting from these experiments will establish zinc as a novel anti-nociceptive agent by inhibiting two major pain-initiating TRP channels at the primary nociceptors and will reveal the molecular mechanisms by which zinc suppresses TRPV1 function. Our results will shed light on novel therapeutic strategies to target TRP channels for treatment of pain in the peripheral nociceptors without promoting on-target side effects in human patients.