Primary afferent plasticity in chronic pain

慢性疼痛的初级传入可塑性

• 批准号: 10020475
• 负责人: Man-Kyo Chung
• 金额: $ 21.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020475
• 关键词: Ablation; Absence of pain sensation; Agonist; Area; Attenuated; Burning Pain; Caliber; Calpain; Capsaicin; Chronic; Development; FDA approved; Goals; Hyperalgesia; Injections; Injury; Maintenance; Mechanics; Mediating; Medical; Methods; Molecular; Mus; Nerve; Neuraxis; Neuropathy; Nociception; Nociceptors; Operative Surgical Procedures; Outcome; Pain; Pain management; Pathologic; Pathway interactions; Peptide Hydrolases; Peripheral; Persistent pain; Pharmacology; Pharmacotherapy; Postherpetic neuralgia; Prevention; Reporting; Resiniferatoxin; Resistance; Role; Specificity; Structure; TRPV1 gene; Testing; Therapeutic Effect; Trigeminal System; Trigeminal nerve structure; Up-Regulation; Vanilloid; allodynia; attenuation; capsaicin receptor; cell type; chronic constriction injury; chronic pain; chronic pain patient; desensitization; face skin; functional plasticity; improved; knock-down; mouse model; nerve injury; neural circuit; neurobiological mechanism; neurochemistry; new therapeutic target; novel; pain patient; pain receptor; painful neuropathy; prevent; side effect; spontaneous pain

PROJECT SUMMARY Trigeminal neuropathic pain (TNP) is a major medical problem. Injury or surgery in the trigeminal area induces debilitating persistent neuropathic pain. Since TNP is often resistant to current pharmacotherapy, there is a pressing need to develop more efficacious treatments for TNP with fewer side effects. Neuropathic pain is maintained by a myriad of mechanisms involving multiple molecules and neural circuits across peripheral and central nervous systems. A recent study found that sensitized nociceptors likely maintain pain in approximately one third of neuropathic pain patients. Thus, identifying and determining mechanisms of dominant peripheral contributors to pain is critical for developing selective treatment for this subset of chronic pain patients. Lack of understanding of detailed mechanisms underlying the role of nociceptors in neuropathic pain poses a significant hurdle to improving nociceptor-targeted pain management in chronic pain sufferers. TRPV1 is a nociceptor- enriched receptor for capsaicin. Topical capsaicin invariably induces burning pain. Paradoxically, such nociception is often followed by prolonged analgesia attenuating pre-existing persistent pain. Topical capsaicin has been approved by the FDA for treatment of post-herpetic neuralgia, and provides months-long relief. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Despite clear therapeutic effects of capsaicin, the involvement of TRPV1 and TRPV1+ nociceptors in neuropathic pain is controversial. We recently reported evidence in a mouse model that TRPV1 and TRPV1+ nociceptors contributed to mechanical hyperalgesia and allodynia following neuropathy in the trigeminal area. The mechanical hyperalgesia and allodynia usually observed in mice subjected to chronic constriction injury of the infraorbital nerve (ION-CCI) was prevented by systemic pretreatment with resiniferatoxin, an ultrapotent TRPV1 agonist which desensitizes TRPV1+ afferents. We also found that local pharmacological inhibition of TRPV1 at the central terminals of primary afferents was sufficient to attenuate mechanical hyperalgesia and allodynia. Our objectives here are to determine the roles of TRPV1 and TRPV1+ nociceptors in TNP and to elucidate mechanisms of capsaicin-induced analgesia for TNP. Our central hypothesis is that plastic changes in trigeminal TRPV1+ nociceptors caused by nerve injury and vanilloid compounds, respectively, are critical for the maintenance and treatment of chronic TNP. To test this, we will determine the effects of ablation or inhibition of TRPV1+ afferents on mechanical hyperalgesia or spontaneous pain in mice with ION-CCI (Aim 1), define the major molecular pathway determining both capsaicin-induced ablation of peripheral terminals of TRPV1+ afferents and capsaicin-induced analgesia (Aim 2) and dissect the contribution of distinct genetically defined subpopulations of TRPV1+ afferents to TNP through conditional TRPV1 knockdown and elucidation of neurochemical and functional plasticity (aim 3). This study may identify neurobiological mechanisms underlying the contributions of TRPV1+ nociceptors to TNP, which may define TRPV1 as an attractive target for this condition, and reveal mechanisms of capsaicin therapy, a centuries-old enigma.

项目摘要 三叉神经性疼痛（TNP）是一个主要的医学问题。三叉神经区域的受伤或手术诱导 使持续的神经性疼痛使人衰弱。由于TNP通常对当前药物疗法有抵抗力，因此有一个 迫切需要开发更有效的TNP治疗方法，而副作用较少。神经性疼痛是 通过涉及周围和周围和神经回路的多种机制维护 中枢神经系统。最近的一项研究发现，敏化的伤害感受器可能会大约保持疼痛 三分之一的神经性疼痛患者。因此，识别和确定主要外围的机制 疼痛的贡献者对于为此子集开发选择性治疗至关重要。缺乏 了解伤害感受器在神经性疼痛中作用的详细机制带来了重要 在慢性疼痛患者中改善伤害感受器的疼痛管理的障碍。 TRPV1是伤害感受器 - 辣椒素的富集受体。局部辣椒素总是会诱发灼痛。矛盾的是，这样 伤害感受之后，长时间的镇痛抑制了先前存在的持续疼痛。局部辣椒素 FDA已批准治疗疗程后神经痛，并提供了长达数月的缓解。 但是，尚未很好地了解辣椒素诱导的镇痛的机制。尽管很清楚 辣椒素的治疗作用，TRPV1和TRPV1+伤害感受器在神经性疼痛中的参与是 有争议的。我们最近在鼠标模型中报道了TRPV1和TRPV1+伤害感受器的证据 在三叉神经区域的神经病之后，机械性痛觉过敏和异常性症。机械 炎性和异常性疾病通常在炎症的小鼠中观察到 通过使用树脂毒素（一种超能力的TRPV1激动剂）进行全身预处理来预防神经（离子-CCI） 脱敏TRPV1+传入。我们还发现，局部药理抑制TRPV1在 初级传入的中央末端足以减弱机械性痛觉过敏和异常性。我们的 这里的目的是确定TRPV1和TRPV1+伤害感受器在TNP中的作用，并阐明 辣椒素诱导的TNP镇痛的机制。我们的中心假设是三叉神经的塑料变化 由神经损伤引起的TRPV1+伤害感受器，分别对 慢性TNP的维护和治疗。为了测试这一点，我们将确定消融或抑制的影响 ION-CCI的小鼠机械性痛觉过敏或自发疼痛的TRPV1+传入（AIM 1）定义 确定辣椒素诱导的TRPV1+外周末端的消融的主要分子途径 传入剂和辣椒素诱导的镇痛（AIM 2）并剖析了不同遗传定义的贡献 通过条件TRPV1敲低和阐明TRPV1+传入TNP的亚群 神经化学和功能可塑性（AIM 3）。这项研究可能确定基础的神经生物学机制 TRPV1+伤害感受器对TNP的贡献，可以将TRPV1定义为有吸引力的目标 状况和揭示辣椒素疗法的机制，是一个世纪以上的谜。