Repurposing of Maraviroc for the treatment of neuropathic pain

重新利用马拉韦罗治疗神经性疼痛

• 批准号: 10586296
• 负责人: Jun Wang
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10586296
• 关键词: Adenylate Cyclase; Adrenal Cortex Hormones; Adult; Adverse effects; Affect; Amygdaloid structure; Animal Model; Anterior; Antiepileptic Agents; Anxiety; Blood; Brain; CCR5 gene; Cannabinoids; Cells; Cellular Structures; Centers for Disease Control and Prevention (U.S.); Chemotactic Factors; Clinical; Data; Development; Economics; Emotional; FDA approved; Female; Fiber; Filament; Flow Cytometry; Future; Gene Chips; Gene Expression; General Population; Health; Health care facility; Healthcare Systems; Human; Immune; Immunologics; Inflammation; Injections; Injury; Intervention; Lesion; Ligands; MAP Kinase Gene; Mechanics; Mental Depression; Mental disorders; Metabolism; Molecular; Mus; Natural Killer Cells; Nerve; Nerve Degeneration; Nervous system structure; Neuraxis; Neuroglia; Neuronal Plasticity; Neurons; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Opiate Addiction; Opioid; Outcome; Outcome Study; PI3K/AKT; Pain; Pain intensity; Pain management; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Play; Prevalence; Primary Health Care; Quality of life; RANTES; Randomized; Reporting; Role; Safety; Sampling; Signal Transduction; Spinal Ganglia; Steroids; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Tricyclic Antidepressive Agents; Trigeminal Neuralgia; Tumor Cell Invasion; Up-Regulation; Veterans; Weight-Bearing state; Well in self; antagonist; atypical facial pain; base; cancer pain; cell type; chemokine; chemokine receptor; chemotherapy; chronic pain; clinically significant; comorbidity; cytokine; discogenic pain; follow-up; macrophage; male; migration; monocyte; mouse model; nano-string; nerve injury; neural stimulation; neurobehavioral test; neuroinflammation; neuropathology; neurotransmission; novel; novel therapeutic intervention; pain reduction; pain relief; pain sensitivity; painful neuropathy; pre-clinical; receptor; response; sciatic nerve; sham surgery; side effect; social; spared nerve; spontaneous pain; suicidal; synaptic function; translational study; treatment group

SUMMARY/ABSTRACT Chronic pain is one of the most common health problems in adult and has profound impact on physical as well as mental wellbeing. According to CDC data brief in 2020, 20.4% of adults in the U.S. have chronic pain. The prevalence is even higher in veterans. Among Veterans receiving primary care in VA healthcare facilities, as many as 50% of male veterans and as many as 75% of female veterans report the presence of pain. In a sample of OEF and OIF veterans, approximately 47% reported at least a mild level of pain and 28% reported moderate to severe pain intensity. Chronic pain is often associated with limitation in mobility and daily activities and frequently comorbid with opioids dependency, anxiety and depression. Current available treatments medications such as NSAIDs, antiepileptic drugs, tricyclic antidepressants, corticosteroids, opioids, and cannabinoids are associated with a range of negative side effects. Invasive and surgical procedures such as peripheral nerve blockers, epidural steroid injections and neural stimulations are also used to provide effective pain relief. The long-term use of these medications often increases the potential for adverse or side effects. Thus, there is urgent needs to develop novel, efficacious and safe interventions for treating neuropathic pain. It is well established that chronic pain, such as inflammation pain, neuropathic pain, and cancer pain, is an expression of neural plasticity both in the peripheral nervous system (PNS) and in the central nervous system (CNS). A large body of evidence indicates that proinflammatory cytokines and chemokines make important contributions to the initiation and persistence of pain. Preliminary studies in our lab using a spared nerve injury (SNI) mouse model of neuropathic pain showed increased expression of CCL5 in the blood and pain phenotypes are significantly correlated with peripheral levels of CCL5. Moreover, analysis of CNS showed increased expression of CCL5 and CCR5 in the brain in the SNI mice, suggesting that CCL5/CCR5 axis may contribute to nerve injury-induced neuropathic pain. In humans, CCL5 was reported to be upregulated in patients with various pain conditions including atypical facial pain and trigeminal neuralgia, discogenic back pain and small fiber neuropathy, indicating its clinical significance in pain development. Based on these observations, we hypothesize that injury-induced increase of CCL5 and its interaction with CCR5 in the periphery and the CNS may dysregulate neural plasticity and promotes the development and persistency of pain. We propose to pharmacologically target CCL5/CCR5 using FDA approved CCR5 antagonist maraviroc in the SNI mouse mode, and use a battery of neurobehavioral tests, immunological and molecular techniques to test its efficacy and to investigate underlying mechanisms. We believe our approach will greatly enhance our understanding of the contribution of CCL5/CCR5 in chronic pain and the potential benefits of targeting CCL5/CCR5 axis as novel therapeutic intervention.

摘要/摘要 慢性疼痛是成年人最常见的健康问题之一，对身体健康有深远的影响 以及精神健康。根据美国疾病控制与预防中心2020年的数据简报，20.4%的美国成年人患有慢性疼痛。 退伍军人的患病率甚至更高。在退伍军人医疗机构接受初级护理的退伍军人中， 多达50%的男性退伍军人和多达75%的女性退伍军人报告存在疼痛。在一个 OEF和OIF退伍军人样本中，约47%的人报告至少有轻微疼痛，28%的人报告 中度至重度疼痛强度。慢性疼痛通常与行动能力和日常活动受限有关。 并经常合并阿片类药物依赖、焦虑和抑郁。目前可用的治疗方法 非甾体抗炎药、抗癫痫药、三环类抗抑郁药、皮质类固醇、阿片类药物和 大麻类药物与一系列负面副作用有关。侵入性和外科手术，如 周围神经阻滞剂、硬膜外类固醇注射和神经刺激也被用来提供有效的 止痛药。长期使用这些药物往往会增加不良反应或副作用的可能性。 因此，迫切需要开发新的、有效的、安全的干预措施来治疗神经病理性疼痛。 众所周知，慢性疼痛，如炎症疼痛、神经病理性疼痛和癌症疼痛，是一种 神经可塑性在周围神经系统和中枢神经系统中的表达 (CNS)。大量证据表明，促炎细胞因子和趋化因子在 对疼痛的开始和持久的贡献。我们实验室使用备用神经损伤的初步研究 (SNI)小鼠神经病理性疼痛模型显示血和疼痛中CCL5表达增加 表型与外周血CCL5水平显著相关。此外，对CNS的分析表明 CCL5和CCR5在SNI小鼠脑内的表达增加，提示CCL5/CCR5轴可能 导致神经损伤引起的神经病理性疼痛。据报道，在人类中，CCL5在 有各种疼痛情况的患者，包括不典型的面部疼痛和三叉神经痛，间盘性背部 疼痛和小纤维神经病，表明其在疼痛发展中的临床意义。基于这些 我们假设，损伤诱导的CCL5的增加及其与CCR5的相互作用在 外周和中枢神经系统可能调节神经可塑性，促进神经性痴呆的发生和持续 疼痛。我们建议使用FDA批准的CCR5拮抗剂马拉韦罗在药理学上靶向CCL5/CCR5 SNI小鼠模式，并使用一系列神经行为测试、免疫学和分子技术来 测试其有效性，并研究其潜在的机制。 我们相信，我们的方法将大大加强我们对CCL5/CCR5在 慢性疼痛和以CCL5/CCR5轴为靶点作为新的治疗干预的潜在好处。