Resolvins, protectins, and chronic pain resolution.

描述（申请人提供）：超过3000万美国人患有未缓解的慢性疼痛，如神经损伤引起的神经性疼痛。虽然我们对慢性疼痛是如何诱发的有相当多的了解，但对急性疼痛如何自然消退却知之甚少。我们推测，局部主动促消退过程的中断将导致慢性疼痛。目前对慢性疼痛的治疗主要集中在两种类型的药物上，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缓解介质。这种方法的重点是新的内源性脂质介质，即resolvins和protectins，使受损的系统恢复到稳态，通过增强吞噬活性和清除局部巨噬细胞。我们最近的研究结果表明，resolvins和protectins是非常有效的促消退和抗炎激动剂。正在进行的工作表明，这些新的内源性介质在纳克剂量范围内在炎性疼痛和神经性疼痛的动物模型中产生抗痛觉过敏作用也非常有效。我们假设神经损伤后消退素和保护素的产生减少将导致慢性疼痛的发展。本申请的总体目标是研究消退素和保护素是否以及如何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，如新开发的脂质介体-脂质组学-信息学，动物行为学，电生理学，和几个新的生化系统，包括在体内和体外评估巨噬细胞吞噬作用，以确定神经病理性疼痛的动物模型中的消退素和保护素的抗痛觉过敏，促消退和抗炎作用。这些研究将涉及在同一部门的Ji博士的疼痛研究实验室和Serhan博士的炎症研究小组之间建立创新合作伙伴关系。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.