Primary afferent plasticity in chronic pain

慢性疼痛的初级传入可塑性

基本信息

批准号：
10187545
负责人：
Man-Kyo Chung
金额：
$ 49.99万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187545
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 efficacious treatment 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

项目摘要

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.

项目概要三叉神经性疼痛（TNP）是一个主要的医学问题。三叉神经区受伤或手术会导致使人衰弱的持续性神经性疼痛。由于 TNP 通常对当前的药物治疗有耐药性，因此存在一种迫切需要开发更有效且副作用更少的 TNP 治疗方法。神经性疼痛是由涉及外周和神经回路的多种分子和神经回路的无数机制维持中枢神经系统。最近的一项研究发现，敏感的伤害感受器可能会在大约三分之一的神经性疼痛患者。因此，识别和确定主导外周的机制造成疼痛的因素对于为这部分慢性疼痛患者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的作用的详细机制具有重要意义改善慢性疼痛患者的伤害感受器靶向疼痛管理的障碍。 TRPV1 是一种伤害感受器富集辣椒素受体。外用辣椒素总是会引起灼痛。矛盾的是，这样的伤害感受后通常会进行长时间的镇痛，以减轻先前存在的持续性疼痛。外用辣椒素已获得 FDA 批准用于治疗带状疱疹后神经痛，并提供长达数月的缓解。然而，辣椒素诱导镇痛的机制尚不清楚。尽管明确辣椒素的治疗作用，TRPV1 和 TRPV1+ 伤害感受器参与神经性疼痛是有争议的。我们最近在小鼠模型中报告了 TRPV1 和 TRPV1+ 伤害感受器发挥作用的证据三叉神经病变后的机械性痛觉过敏和异常性疼痛。机械通常在遭受眶下慢性缩窄损伤的小鼠中观察到痛觉过敏和异常性疼痛使用树脂毒素（一种超强 TRPV1 激动剂）进行全身预处理可预防神经损伤 (ION-CCI) 它使 TRPV1+ 传入神经变得不敏感。我们还发现 TRPV1 的局部药理学抑制作用初级传入神经的中央末端足以减轻机械性痛觉过敏和异常性疼痛。我们的这里的目标是确定 TRPV1 和 TRPV1+ 伤害感受器在 TNP 中的作用并阐明辣椒素诱导 TNP 镇痛的机制。我们的中心假设是三叉神经的可塑性变化分别由神经损伤和香草酸化合物引起的 TRPV1+ 伤害感受器对于慢性 TNP 的维持和治疗。为了测试这一点，我们将确定消融或抑制的效果 TRPV1+ 传入神经对 ION-CCI 小鼠机械痛觉过敏或自发性疼痛的影响（目标 1），定义决定辣椒素诱导的 TRPV1+ 外周末端消融的主要分子途径传入神经和辣椒素诱导的镇痛（目标 2），并剖析不同基因定义的作用通过条件 TRPV1 敲低和阐明 TRPV1+ 传入 TNP 的亚群神经化学和功能可塑性（目标 3）。这项研究可能会确定潜在的神经生物学机制 TRPV1+伤害感受器对 TNP 的贡献，这可能将 TRPV1 定义为一个有吸引力的目标条件，并揭示辣椒素治疗的机制，这是一个数百年之谜。