Mechanisms of Zinc Regulation of Pain-initiating TRP Channels

描述（由申请人提供）：锌被广泛用作抗炎和抗关节炎的药物已有3000多年的历史。它在许多模型系统中显示出良好的镇痛效果。先前的研究发现，锌激活了引起疼痛的TRPA1通道，并诱导急性伤害行为。因此，锌必须通过其他机制来发挥其抗伤害性作用。我们的前期研究表明，锌预处理使TRPA1脱敏，表明锌可以通过诱导辣椒素等受体对TRPV1脱敏来抑制TRPA1。我们还发现锌在体内和体外都抑制了TRPV1的功能，TRPA1的基因消融显著降低了锌对TRPV1功能的抑制。本实验将验证细胞外锌在急性和慢性炎症模型中抑制TRPA1/ v1介导的热痛和机械性疼痛的假设。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

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.