Interaction between SCI and Noxious Input: Modulation of Pain Hypersensitivity

SCI 与有害输入之间的相互作用：疼痛超敏反应的调节

• 批准号: 8583152
• 负责人: Sandra M. Garraway
• 金额: $ 24.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583152
• 关键词: Acute Pain; Adult; Afferent Neurons; Animals; Attenuated; Behavior monitoring; Behavioral; C Fiber; Capsaicin; Chronic Phase; Clinical; Clinical Research; Contusions; Data; Development; Electric Stimulation; Experimental Models; Freund' s Adjuvant; Genes; Goals; Healed; Human; Hypersensitivity; Incidence; Individual; Inflammation; Inflammatory; Injury; Investigation; Lead; Link; Literature; Long-Term Effects; Maintenance; Mechanical Stimulation; Mediating; Mediator of activation protein; Modeling; Molecular; Nociception; Pain; Patients; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Play; Procedures; Production; Rattus; Reporting; Research; Research Personnel; Role; Shock; Signal Pathway; Signal Transduction; Source; Spinal; Spinal Cord Plasticity; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Staging; TNF gene; TNFRSF1A gene; TRPV1 gene; Techniques; Testing; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; Variant; Work; allodynia; autocrine; cellular targeting; central sensitization; chronic neuropathic pain; chronic pain; clinically relevant; cytokine; early onset; effective therapy; healing; human TNF protein; inflammatory pain; injured; innovation; mechanical allodynia; novel; novel strategies; pain behavior; painful neuropathy; prevent; protective effect; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): In examining the conditions under which neuropathic pain develops following spinal cord injury (SCI), we propose that the presence of noxious input plays an important role. Specifically, we suggest that nociceptive input accompanying SCI may determine if and when neuropathic pain develops. The studies described in this proposal will investigate the interaction between SCI and nociceptive input, derived from peripheral inflammation, to further our understanding of its consequence on pain hypersensitivity. Prior clinical and experimental studies have shown that there is a tremendous amount of variability in both the onset and incidence of chronic pain following SCI. Because current studies attempting to identify the mechanisms underlying SCI-induced pain hypersensitivity have not been successful, additional studies are warranted. Recently, we observed that noxious input given shortly after SCI significantly increases behavioral signs of neuropathic pain for at least 3 weeks following injury. We also found that the pro-inflammatory cytokine TNFalpha, which is implicated in inflammatory pain, is up-regulated by the stimulation and appears to play a role in pain hypersensitivity following SCI. These observations are consistent with our past work showing the negative effects of noxious stimulation on spinal cord plasticity in adult rats with a transection SCI. Consequently, we hypothesize that noxious input derived from peripheral inflammation or electrical stimulation enhances the development of chronic neuropathic pain through a spinal TNFalpha signaling pathway. This proposal, consisting of three aims, will introduce a novel approach to investigate the mechanisms underlying pain following SCI. We will combine behavioral, pharmacological and molecular techniques to study the interaction between SCI and peripherally-derived nociceptive input as a potential predictor of chronic pain. In the first aim, we will assess the effect of noxious input induced by peripheral inflammation on the induction and maintenance of pain hypersensitivity following SCI. The second aim will assess the effects of noxious stimulation on the spatial and temporal expression of TNFalpha signaling genes. In aim 3, we will explore the role TNFalpha signaling plays in the induction of enhanced pain behaviors following SCI, by administering a TNFR1 blocker. These studies will establish the feasibility of this novel approach of investigation and advance our understanding of the mechanisms producing pain. This work is innovative in that it combines clinically relevant models of peripheral sensitization and SCI to investigate the centrally mediated mechanisms underlying pain following SCI, a combination that has been under-studied in prior studies. It will allow us to more accurately associate nociceptive input to the development of pain hypersensitivity following SCI and also identify potential cellular targets, which play a critical ole in these mechanisms. If successful, this work could lead to new procedures to prevent the development of neuropathic pain after SCI.

描述（由申请人提供）：在检查脊髓损伤（SCI）后神经性疼痛发生的条件时，我们提出有害输入的存在起着重要作用。具体来说，我们认为，伤害性输入伴随SCI可能会决定是否以及何时神经性疼痛的发展。本研究将探讨脊髓损伤与外周炎症引起的伤害性输入之间的相互作用，以进一步了解其对疼痛超敏反应的影响。先前的临床和实验研究表明，SCI后慢性疼痛的发作和发生率存在巨大的差异。由于目前的研究试图确定SCI引起的疼痛超敏反应的机制尚未成功，因此需要进行更多的研究。最近，我们观察到SCI后短时间内给予伤害性输入可显著增加神经病理性疼痛的行为体征，持续至少3周 受伤后。我们还发现，与炎性疼痛有关的促炎细胞因子TNF α受刺激上调，似乎在SCI后的疼痛超敏反应中发挥作用。这些观察结果与我们过去的工作一致，表明伤害性刺激对成年大鼠脊髓可塑性的负面影响。因此，我们假设来自外周炎症或电刺激的有害输入通过脊髓TNF α信号通路增强慢性神经性疼痛的发展。该提案包括三个目标，将介绍一种新的方法来研究SCI后疼痛的潜在机制。我们将结合联合收割机行为学、药理学和分子技术来研究SCI和外周源性伤害性输入之间的相互作用，作为慢性疼痛的潜在预测因子。在第一个目标中，我们将评估外周炎症诱导的伤害性输入对SCI后疼痛超敏反应的诱导和维持的影响。第二个目标是评估伤害性刺激对TNF α信号基因的空间和时间表达的影响。在目标3中，我们将通过给予TNFR1阻断剂来探索TNF α信号传导在诱导SCI后增强的疼痛行为中所起的作用。这些研究将确立这种新的研究方法的可行性，并促进我们对疼痛产生机制的理解。这项工作是创新的，因为它结合了临床相关的外周敏化和SCI模型，以研究SCI后疼痛的中枢介导机制，这是一种在先前研究中研究不足的组合。这将使我们能够更准确地将伤害性输入与SCI后疼痛超敏反应的发展联系起来，并确定在这些机制中起关键作用的潜在细胞靶点。如果成功的话，这项工作可能会导致新的程序，以防止SCI后神经性疼痛的发展。