Mechanisms of Zinc Regulation of Pain-initiating TRP Channels

锌对疼痛引发 TRP 通道的调节机制

• 批准号: 8505830
• 负责人: Hongzhen Hu
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505830
• 关键词: Ablation; Accounting; Acute; Adverse effects; Afferent Neurons; Agonist; Analgesics; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Behavior; Behavioral; Biological Models; Bradykinin; Calcium; Capsaicin; Carrageenan; Cell membrane; Cells; Chronic; Chronic inflammatory pain; Complex; Data; Esthesia; Event; Freund' s Adjuvant; Genetic; Goals; Human; Hyperalgesia; Image; In Vitro; Inflammatory; Injection of therapeutic agent; Irritants; Light; Measures; Mechanics; Mediating; Medical Assistance; Metals; Modeling; Molecular; Molecular Target; Mus; Nerve Growth Factors; Neurogenic Inflammation; Neuronal Injury; Nociception; Nociceptors; Pain; Patients; Peripheral; Pilot Projects; Process; Proteins; Reactive Oxygen Species; Regulation; Second Messenger Systems; Sensory; Side; Signal Pathway; Signal Transduction; Signaling Molecule; Site-Directed Mutagenesis; Stimulus; TRPA1 Channel; TRPV1 gene; Testing; Therapeutic Intervention; Tissues; Transition Elements; Translating; United States; Work; Wound Healing; Zinc; Zinc Acetate; antiarthritic agent; attenuation; behavior test; desensitization; extracellular; in vivo; inflammatory pain; interdisciplinary approach; novel; novel therapeutics; pain inhibition; patch clamp; public health relevance; receptor; relating to nervous system; research study; response; second messenger

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.

描述（由申请人提供）： 锌作为抗炎和抗关节炎剂被广泛使用已有 3000 多年的历史。它在许多模型系统中显示出有希望的镇痛效果。先前的研究发现，锌激活疼痛启动 TRPA1 通道并诱导急性伤害行为。因此，锌必须通过替代机制发挥其抗伤害作用。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 的脱敏一样。我们还表明，锌在体外和体内均抑制 TRPV1 功能，并且 TRPA1 的基因消除显着降低了锌对 TRPV1 功能的抑制。拟议的实验将验证细胞外锌在急性和慢性炎症模型中抑制 TRPA1/V1 介导的热痛和机械痛的假设。我们将研究 TRPV1 锌抑制的分子决定因素。我们还将检查 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对于限制体内锌的作用是否重要 以及一种特定的 TRPA1 阻断剂 HC-030031。这些实验产生的数据将通过抑制主要伤害感受器上的两个主要的疼痛引发 TRP 通道，将锌确立为一种新型抗伤害剂，并将揭示锌抑制 TRPV1 功能的分子机制。我们的研究结果将揭示以 TRP 通道为靶点的新治疗策略，用于治疗外周伤害感受器中的疼痛，而不促进人类患者的靶向副作用。