Resolving functional pain by complementary approaches

摘要 功能性疼痛综合征(FPS)影响着1亿多人，但仍然没有得到有效的治疗，因为 原因在很大程度上是未知的。越来越多的证据表明，这些症状在很大程度上是由于 儿茶酚-O-甲基转移酶(COMT)活性降低，这是一种代谢儿茶酚胺的酶。一个 据估计，66%的功能性疼痛综合征患者，如纤维肌痛，在COMT中存在变异 导致COMT酶活性低的基因。COMT活性低的个体的基因报告 基线时疼痛更大，紧张性事件后疼痛加剧，从而促进儿茶酚胺释放 来自交感神经。与临床症状一致，我们的实验室已经表明，药物抑制 在啮齿类动物中，COMT会在多个身体部位产生疼痛，并在反复应激后疼痛加剧。在……里面 随后的研究表明，COMT依赖的疼痛是由外周β-肾上腺素能启动的 受体通过在血浆中释放促炎细胞因子(例如，肿瘤坏死因子α和IL-6)，并维持 通过中枢神经系统的神经可塑性改变，特征是肿瘤坏死因子α和 脊髓中神经胶质细胞和伤害性感受器的激活增加。总而言之，这些发现表明， 肾上腺素能促进FPS患者的疼痛、炎症和神经炎症。针灸和 鱼油衍生物DHA是治疗FPS的推荐药物，但它们对FPS的机理影响 与COMT缺陷相关的炎症和神经炎症仍未得到研究。我们 假设针灸、DHA和DHA衍生的解析素D_1(RvD_1)各自产生有益的效果 在通过调节免疫反应和治疗应激加剧的功能性疼痛方面 伤害性感受器活动。初步数据显示，ST36针刺可逆转COMT依赖的疼痛和 脊髓内神经胶质细胞的相应激活。更多数据显示，DHA逆转了COMT- 依赖性疼痛和伤害性感受器活动因压力而加剧。拟议的研究将把这项工作扩展到1) 确定功能性疼痛的发展、维持和解决的时间进程(例如， 机械性疼痛和运动异常)、炎症(如细胞因子和活化的巨噬细胞和T细胞)。 引起的神经炎症(如脑脊液中的细胞因子和脊髓中激活的胶质细胞)。 COMT活性降低并因应激而加重，2)检测电针、DHA和RvD1对小鼠的影响 预防和逆转功能性疼痛、炎症和神经性炎症 应激，以及3)测试电针(与手动针刺相比)、DHA和Rvd1的逆转效果 机械敏感和温度敏感伤害性感受器活动增加，从而驱动功能性疼痛 没有压力，没有压力。这些研究的结果将增进我们对 儿茶酚胺浓度升高对免疫功能的影响及应用 补充药物疗法，以恢复免疫动态平衡和缓解功能性疼痛。

ABSTRACT Functional pain syndromes (FPS) affect over 100 million people, yet remain ineffectively treated because the causes are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to reduced activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated 66% of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that lead to low activity of the COMT enzyme. Individuals with the ‘low COMT activity’ genotype report greater pain at baseline and enhanced pain following stressful events that potentiate catecholamine release from sympathetic nerves. Consistent with clinical syndromes, our lab has shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites and enhanced pain following repeated stress. In subsequent studies, we demonstrated that COMT-dependent pain is initiated by peripheral β-adrenergic receptors through the release of pro-inflammatory cytokines (e.g., TNFα and IL-6) in plasma, and maintained by neuroplastic changes in the central nervous system, characterized by increased expression of TNFα and increased activation of glia and nociceptors in the spinal cord. Together, these findings suggest that heightened adrenergic tone promotes pain, inflammation, and neuroinflammation in patients with FPS. Acupuncture and the fish oil derivative DHA are recommended treatments for FPS, however their mechanistic effects on inflammation and neuroinflammation associated with deficiencies in COMT have remained unstudied. We hypothesize that acupuncture, DHA, and the DHA-derived resolvin D1 (RvD1) each produce beneficial effects in preventing and treating functional pain exacerbated by stress via modulating immune response and nociceptor activity. Preliminary data reveal that ST36 acupuncture reverses COMT-dependent pain and corresponding activation of glial cells in the spinal cord. Additional data reveal that DHA reverses COMT- dependent pain and nociceptor activity exacerbated by stress. The proposed studies will extend this work to 1) determine the time course for the development, maintenance, and resolution of functional pain (e.g., mechanical allodynia and locomotor activity), inflammation (e.g., cytokines and activated macrophages and T cells in plasma), and neuroinflammation (e.g., cytokines in CSF and activated glia in spinal cord) caused by low COMT activity and exacerbated by stress, 2) test the effects of electroacupuncture, DHA, and RvD1 in preventing and reversing functional pain, inflammation, and neuroinflammation in the absence or presence of stress, and 3) test the effects of electroacupuncture (versus manual acupuncture), DHA, and RvD1 in reversing increased activity of mechanosensitive and thermosensitive nociceptors that drive functional pain in the absence and presence of stress. Results from these studies will advance our knowledge about the consequences of heightened catecholamine tone on immune function and determine the utility of complementary medicine therapies to restore immune homeostasis and alleviate functional pain.