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: 8869234
• 负责人: Hongzhen Hu
• 金额: $ 26.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869234
• 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; Health; 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; 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.

说明(申请人提供)：锌被广泛用作消炎和抗关节炎药物已有3000多年的历史。它已在许多模型系统中显示出良好的镇痛效果。以往的研究发现，锌激活了痛觉启动的TRPA1通道，并诱导了急性致痛行为。因此，锌必须通过其他机制发挥其抗伤害性作用。我们的初步研究表明，锌可以使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。我们还发现，锌在体外和体内都抑制了TRPV1的功能，基因消融TRPA1显著降低了锌对TH TRPV1功能的抑制。拟议的实验将在急性和慢性炎症模型中检验细胞外锌抑制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。我们还将检查TRPA1的激活是否是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重要 和一种特定的TRPA1阻滞剂，HC-030031。这些实验数据将通过抑制初级伤害性感受器上两个主要的痛觉启动Trp通道，确立锌作为一种新型的抗伤害感受剂，并将揭示锌抑制TRPV1功能的分子机制。我们的结果将阐明靶向Trp通道的新治疗策略，用于治疗周围伤害性感受器的疼痛，而不会促进人类患者的靶向副作用。