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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：
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
项目类别：
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

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.

项目摘要三叉神经痛（TNP）是一个主要的医学问题。三叉神经区域的损伤或手术会导致使人衰弱的持续性神经性疼痛。由于TNP通常对目前的药物治疗有抗性，因此存在一种迫切需要开发更有效的TNP治疗方法，副作用更少。神经性疼痛是维持的无数机制，涉及多个分子和神经回路跨越外周和中枢神经系统最近的一项研究发现，致敏的伤害感受器可能维持大约三分之一的神经性疼痛患者。因此，识别和确定主导性外周神经系统的机制，疼痛的主要原因是对慢性疼痛患者的这一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病理性疼痛中作用的详细机制，在慢性疼痛患者中改善伤害感受器靶向疼痛管理的障碍。TRPV 1是一种伤害感受器- 富含辣椒素的受体。局部使用辣椒素总是会引起灼痛。巧合的是，这样的伤害感受之后通常是延长的镇痛，减轻预先存在的持续疼痛。局部辣椒素已被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还不清楚。尽管有明确辣椒素的治疗作用，TRPV 1和TRPV 1+伤害感受器在神经性疼痛中的参与，争议我们最近报道了在小鼠模型中的证据，TRPV 1和TRPV 1+伤害感受器有助于机械性痛觉过敏和三叉神经区神经病变后的异常性疼痛。机械通常在经受眶下慢性收缩损伤的小鼠中观察到痛觉过敏和异常性疼痛通过全身性预处理树脂毒素（一种超强效TRPV 1激动剂）来预防神经（ION-CCI）使TRPV 1+传入神经脱敏。我们还发现，TRPV 1的局部药理学抑制作用，初级传入纤维的中枢终末足以减弱机械性痛觉过敏和异常性疼痛。我们目的是确定TRPV 1和TRPV 1+伤害感受器在TNP中的作用，并阐明TRPV 1+伤害感受器在TNP中的作用。辣椒素诱导的TNP镇痛机制。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素化合物引起的TRPV 1+伤害感受器对于神经元的功能是至关重要的。维持和治疗慢性TNP。为了验证这一点，我们将确定消融或抑制 TRPV 1+传入对ION-CCI小鼠机械性痛觉过敏或自发性疼痛的影响（目的1），定义了决定辣椒素诱导的TRPV 1+外周末端消融的主要分子途径传入和辣椒素诱导的镇痛（目的2），并剖析不同的遗传定义的贡献，通过条件性TRPV 1敲低和阐明TRPV 1+传入TNP的亚群神经化学和功能可塑性（目的3）。这项研究可能会确定神经生物学机制， TRPV 1+伤害感受器对TNP的贡献，这可能将TRPV 1定义为一个有吸引力的靶点，条件，并揭示辣椒素治疗的机制，一个百年之谜。