Primary afferent plasticity in chronic pain

慢性疼痛的初级传入可塑性

• 批准号: 9766271
• 负责人: Man-Kyo Chung
• 金额: $ 50.09万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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/9766271
• 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.

项目总结 三叉神经病理性疼痛(TNP)是一个主要的医学问题。三叉神经区的损伤或手术导致 衰弱的持续性神经病理性疼痛。由于TNP通常对当前的药物治疗具有耐药性，因此有一种 迫切需要开发更有效、副作用更少的TNP治疗方法。神经病理性疼痛是 由涉及多个分子和神经电路的无数机制维持，这些机制涉及外周和 中枢神经系统。最近的一项研究发现，敏化的伤害性感受器可能在大约 三分之一的神经病理性疼痛患者。因此，识别和确定优势外周的机制 疼痛的贡献者对于为这类慢性疼痛患者开发选择性治疗至关重要。缺乏 对伤害感受器在神经病理性疼痛中作用的详细机制的理解具有重要意义 改善慢性疼痛患者伤害性感受器靶向疼痛管理的障碍。TRPV1是一个伤害性感受器- 辣椒素的富含受体。外用辣椒素总是会引起灼痛。矛盾的是，这样的 痛觉之后往往伴随着长时间的止痛，以减轻先前存在的持续性疼痛。外用辣椒素 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，辣椒素的镇痛机制还不是很清楚。尽管很清楚 辣椒素的治疗作用及TRPV1和TRPV1+伤害性感受器在神经病理性疼痛中的作用 有争议的。我们最近在小鼠模型中报告了TRPV1和TRPV1+伤害性感受器参与 三叉神经病后的机械性痛觉过敏和痛觉异常。机械的 慢性眶下缩窄伤小鼠常出现痛觉过敏和痛觉过敏 用超强TRPV1激动剂白藜芦醇预防神经(离子-CCI) 使TRPV1+传入细胞脱敏。我们还发现，TRPV1的局部药理抑制在 初级传入的中央终末足以减轻机械性痛觉过敏和痛觉过敏。我们的 目的是确定TRPV1和TRPV1+伤害性感受器在TNP中的作用，并阐明 辣椒素对TNP的镇痛作用机制。我们的中心假设是三叉神经可塑性改变 分别由神经损伤和香草类化合物引起的TRPV1+伤害性感受器在 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+对离子-CCI小鼠机械性痛敏或自发性疼痛的传入作用(目标1)，定义 决定辣椒素对TRPV1+外周末端消融的主要分子途径 传入和辣椒素诱导的镇痛(目标2)，并剖析不同的基因定义的贡献 TRPV1+亚群通过条件性TRPV1基因敲除与TNP的关系 神经化学和功能可塑性(目标3)。这项研究可能确定神经生物学机制 TRPV1+伤害性感受器对TNP的贡献，这可能使TRPV1成为一个有吸引力的靶标 状况，并揭示了辣椒素治疗的机制，一个数百年的谜团。