Resolvins, protectins, and chronic pain resolution.

描述(申请人提供)：3000多万美国人患有未缓解的慢性疼痛，如神经损伤引起的神经病理性疼痛。虽然有相当多的人知道慢性疼痛是如何诱发的，但对急性疼痛如何自然缓解却知之甚少。我们假设，局部主动前分解过程的中断将导致慢性疼痛。目前慢性疼痛的治疗主要集中在两类药物上，一种是通过阻断神经传递来治疗疼痛症状的药物，另一种是通过抑制神经炎症来改变疾病进展的药物。我们现在提出了一种新的慢性疼痛治疗方法，使用新发现的内源性促分解介质。这种方法侧重于新的内源性脂质介质，即分解素和保护素，它们通过增强局部巨噬细胞的吞噬活性和清除能力，使受损的系统恢复动态平衡。我们最近的研究结果表明，溶血素和保护素是非常有效的促消炎和抗炎激动剂。正在进行的工作表明，这些新型内源性介质在纳克剂量范围内，在炎症性疼痛和神经病理性疼痛的动物模型中也非常有效地产生抗痛敏效应。我们假设神经损伤后分解素和保护素的产生减少将导致慢性疼痛的发展。这项应用的总体目标是调查解决素和保护素是否以及如何可以预防和逆转神经损伤后的神经病理性疼痛。我们将采用多学科的方法，如新开发的脂质介导物-脂质组学-信息学，动物行为，电生理学，以及几个新的生化系统，包括体内和体外巨噬细胞吞噬功能的评估，以确定在神经病理性疼痛的动物模型中，溶血素和保护素的抗痛敏、促分解和抗炎作用。这些研究将包括在纪万昌博士的疼痛研究实验室和Serhan博士在同一部门的炎症研究小组之间建立创新的合作伙伴关系。鉴于正在进行的工作的结果，拟议研究的结果将是变革性的，并对整个疼痛社区产生相当大的影响，从急性术后疼痛到慢性炎症性疼痛和神经病理性疼痛。 与公共卫生相关：虽然关于慢性疼痛是如何诱发的已知相当多，但对急性疼痛如何自然缓解知之甚少。我们提出了一种新的治疗慢性疼痛的方法，使用新发现的内源性促分解脂质介质，即分解素和保护素。我们将使用多学科方法来确定在神经病理性疼痛的动物模型中，解决素和保护素的抗痛敏、促进分解和抗炎作用。拟议的研究结果将是变革性的，并对整个疼痛社区产生相当大的影响，从急性术后疼痛到慢性炎症性和神经病理性疼痛。

DESCRIPTION (provided by applicant): More than 30 million Americans suffer from unrelieved chronic pain, such as nerve injury-induced neuropathic pain. Although a considerable amount is known about how chronic pain is induced, little is known about how acute pain naturally resolves. We hypothesize that disruption of local active pro-resolving processing will result in chronic pain. Current management of chronic pain mainly focuses on two types of drugs, ones that treat pain symptoms by blocking neurotransmission and those that modify disease progression by suppressing neuroinflammation. We now propose a novel approach for chronic pain therapy, using newly uncovered endogenous pro-resolving mediators. This approach focuses on novel endogenous lipid mediators namely resolvins and protectins that bring damaged system back to homeostasis by enhancing the phagocytic activity and clearance of local macrophages. Our recent results show that resolvins and protectins are very potent pro-resolving and anti-inflammatory agonists. Work in progress demonstrates that these novel endogenous mediators are also very effective, in nanogram dose range, in producing anti- hyperalgesic effects in animal models of inflammatory pain and neuropathic pain. We hypothesize that diminished production of resolvins and protectins after nerve injury will lead to the development of chronic pain. The overall goal of this application is to investigate whether and how resolvins and protectins can prevent and reverse neuropathic pain after nerve injury. We will employ multidisciplinary approaches, such as newly developed lipid mediator-lipidomics-informatics, animal behavior, electrophysiology, and several new biochemical systems including in vivo and in vitro assessment of macrophage phagocytosis to define the anti- hyperalgesic, pro-resolving, and anti-inflammatory roles of resolvins and protectins in animal models of neuropathic pain. These studies will involve formation of innovative partnership between Dr. Ji's pain research laboratory and Dr. Serhan's inflammation research group in the same department. In view of the results from work in progress, the results from the proposed studies will be transformative and have considerable impact on the entire pain community, from acute postoperative pain to chronic inflammatory pain and neuropathic pain. PUBLIC HEALTH RELEVANCE: Although a considerable amount is known about how chronic pain is induced, little is known about how acute pain naturally resolves. We propose a novel approach for chronic pain therapy, using newly uncovered endogenous pro-resolving lipid mediators, namely resolvins and protectins. We will employ multidisciplinary approaches to define the anti-hyperalgesic, pro-resolving, and anti-inflammatory roles of resolvins and protectins in animal models of neuropathic pain. The results from the proposed studies will be transformative and have considerable impact on the entire pain community, from acute postoperative pain to chronic inflammatory and neuropathic pain.