Resolving functional pain by complementary approaches

通过补充方法解决功能性疼痛

• 批准号: 9703534
• 负责人: Andrea G Nackley
• 金额: $ 26.44万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9703534
• 关键词: Acupuncture Therapy; Adrenergic Agents; Adrenergic Antagonists; Affect; American; Animal Model; Antigens; Astrocytes; Behavior; Behavioral; Biological Availability; Biological Markers; Blood; Calcium; Catechol O-Methyltransferase; Catecholamines; Characteristics; Clinical; Complementary Medicine; Corticosterone; Data; Development; Ear; Electroacupuncture; Enzymes; Exhibits; Fatigue; Female; Fibromyalgia; Fish Oils; Genotype; Homeostasis; Hypotension; Immune; Immune response; Immunohistochemistry; Individual; Inflammation; Inflammatory; Interleukin-6; Knowledge; Lead; Link; Low Back Pain; Maintenance; Manuals; Measures; Methyltransferase Gene; Molecular; Motor Activity; Mus; Nerve; Neuraxis; Neuroglia; Neuronal Plasticity; Neurons; Nociceptors; Opioid; Pain; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Persistent pain; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Population; Quality of life; Regimen; Reporting; Resolution; Rodent; Rodent Model; Site; Sleep Disorders; Spinal Cord; Spinal cord injury; Stress; Stressful Event; Swimming; Syndrome; T-Lymphocyte; TNF gene; Temporomandibular Joint Disorders; Testing; Time; Variant; Ventilatory Depression; Volition; Work; beta-adrenergic receptor; calcium indicator; cost; course development; cytokine; effective therapy; genetic variant; glial activation; imaging modality; immune activation; immune function; improved; in vivo calcium imaging; inflammatory pain; insight; macrophage; male; mechanical allodynia; men' s group; neuroinflammation; p38 Mitogen Activated Protein Kinase; painful neuropathy; prevent; response; sex; side effect; tissue injury; treatment strategy

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.

抽象的 功能性疼痛综合征（FPS）影响超过1亿人，但仍被无效治疗，因为 原因在很大程度上未知。积累的证据表明，这些综合症在很大程度上是由于 儿茶酚-O-甲基转移酶（COMT）的活性降低，这是一种代谢儿茶酚胺的酶。一个 估计有66％的功能性疼痛综合征患者（例如纤维肌痛）在COMT中具有变异性 导致COMT酶活性低的基因。具有“低COMT活动”基因型报告的个人 压力事件可能释放的压力事件后，基线时更大的疼痛和增加的疼痛 来自交感神经。与临床综合征一致，我们的实验室表明药物口语抑制 啮齿动物中的COMT在多个身体部位会产生疼痛，并在重复应力后增加疼痛。 随后的研究，我们证明了依赖性疼痛是由周围β-肾上腺素引发的 通过释放促炎性细胞因子（例如TNFα和IL-6）的受体，并保持 通过中枢神经系统的神经塑性变化，其特征是TNFα和 脊髓中神经胶质和伤害感受器的激活增加。这些发现一起表明 肾上腺张力促进FPS患者的疼痛，感染和神经炎症。针灸和 建议对FPS的鱼油衍生物DHA进行治疗，但是它们对 与COMT缺陷有关的炎症和神经炎症仍然未被研究。我们 假设针灸，DHA和DHA衍生的Resolvin D1（RVD1）都产生了有益的效果 通过调节免疫反应和 伤害感受器活性。初步数据表明，ST36针灸会逆转COMT依赖性疼痛和 脊髓中神经胶质细胞的相应激活。其他数据显示DHA逆转COMT- 依赖性疼痛和伤害性活性因应力加剧。拟议的研究将将这项工作扩展到1） 确定功能疼痛的开发，维护和解决的时间过程（例如， 机械性异常性和运动活性），炎症（例如，细胞因子和活化的巨噬细胞和T 血浆中的细胞）和神经炎症（例如，CSF中的细胞因子和脊髓中的激活神经胶质）由 低COMT活性并因压力而加剧，2）测试电针，DHA和RVD1在 在不存在或存在的情况下，防止和逆转功能性疼痛，感染和神经炎症 压力和3）测试电针（与手动针灸），DHA和RVD1的影响 机械和热敏性伤害感受器的活性增加了，使功能性疼痛在 不存在和存在压力。这些研究的结果将提高我们对 儿茶酚胺调高对免疫功能的后果，并确定效用 完成医学疗法以恢复免疫稳态并减轻功能性疼痛。