Therapeutic potential and the critical site of action of non-addicting glibenclamide in neuropathic pain

非成瘾性格列本脲治疗神经性疼痛的治疗潜力和关键作用位点

• 批准号: 10359075
• 负责人: J. Marc Simard
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359075
• 关键词: Affect; Aftercare; American; Anatomy; Animal Model; Anxiety; Astrocytes; Behavior; CXC Chemokines; Chronic; Chronic Phase; Data; Dose; Encephalomyelitis; Exhibits; Exposure to; Extinction (Psychology); Female; General Population; Genetic; Glial Fibrillary Acidic Protein; Glyburide; Goals; Health; Hypersensitivity; Incidence; Individual; Inflammation; Inflammatory; Injury; Interleukin-6; Ipsilateral; Ligands; Limb structure; Link; Medication Management; Mental Depression; Military Personnel; Modeling; Motor; Mus; Neuroglia; Neurons; Opiate Addiction; Opioid; Pain Research; Pain management; Pathogenesis; Pathway interactions; Peripheral Nerves; Peripheral nerve injury; Pharmacologic Substance; Pharmacology; Phenotype; Population; RNA Interference; Site; Specificity; Spinal Ganglia; Suicide; Symptoms; Therapeutic; Thermal Hyperalgesias; Tissues; Up-Regulation; Veterans; Withholding Treatment; allodynia; beta-Chemokines; chemokine; chemokine receptor; chronic neuropathic pain; chronic pain; clinically relevant; cytokine; dorsal horn; drug action; experience; experimental study; glial activation; improved functioning; male; mechanical allodynia; military veteran; motor disorder; nerve injury; neuroinflammation; non-opioid analgesic; novel; opioid epidemic; opioid use; opioid use disorder; pain behavior; painful neuropathy; prescription opioid; sciatic nerve; sulfonylurea receptor; wound

BACKGROUND: Almost half of Veterans experience chronic pain, which is disproportionately greater than the 25 million Americans in the civilian population who suffer from significant chronic pain. Chronic pain is a common sequela of military- and terror-related injuries. The majority of battlefield wounds involve injuries to exposed limbs, resulting in high rates of neuropathic pain caused by damage to a peripheral nerve. Opioid use disorder and the ongoing “opioid epidemic” are driven in part by the legitimate use of opioids prescribed for neuropathic pain. Post-deployment, 15% of military Veterans use opioids, compared to 4% of the general population, and in Veterans, there is a direct correlation between the use of opioids and suicide. Targeting alternative non-opioid pathways for pain control using non-addicting drugs is a major goal of neuropathic pain research. After peripheral nerve injury (PNI), cytokines and chemokines are upregulated centrally, including in dorsal horn astrocytes, where they contribute mechanistically to the pathogenesis of neuropathic pain. Reactive astrocytes in the dorsal horn exhibit a chronically activated, pro-inflammatory secretory (CAPS) phenotype characterized by the secretion of numerous factors, including interleukin-6 (IL-6), chemokine C-C motif ligand 2 (CCL2) and chemokine C-X-C motif ligand 1 (CXCL1), each of which individually has been shown to contribute to neuropathic pain behaviors. The post-PNI astrocytic CAPS phenotype contributes to both inflammation and neuronal hyperactivation via neuronal chemokine receptors, leading to neuropathic pain. Our pilot data demonstrate the novel findings that, in the murine sciatic nerve cuff model of neuropathic pain, inhibiting sulfonylurea receptor 1 (SUR1) with low-dose glibenclamide administered daily over several weeks, with treatment beginning during the chronic phase at day21 after PNI, causes marked reductions in: (i) mechanical allodynia, thermal hyperalgesia and place escape/avoidance; (ii) dorsal horn astrocyte expression of IL-6, CCL2 and CXCL1. DESCRIPTION: This project has the clinically relevant aim of establishing the therapeutic potential, durability, and critical site of action of glibenclamide treatment in neuropathic pain behaviors induced by PNI. Four separate experiments are planned in males and females using the murine sciatic nerve cuff model, with treatments applied only during the chronic phase, 3 weeks after PNI. In these experiments, we will examine: (a) the ability of various doses of systemic and intrathecal glibenclamide to effectively reverse neuropathic pain behaviors (mechanical allodynia, thermal hyperalgesia, place escape/avoidance, anxiety and depression-like behaviors), and related motor dysfunction; (b) the ability of systemic glibenclamide to gradually extinguish neuroinflammation in the DRG/dorsal horn, for correlation with the observed gradual extinction of allodynia; (c) the durability of glibenclamide treatment after treatment cessation; and (d) the anatomical and cellular site of action of glibenclamide. Mice will be studied up to 11 weeks for neuropathic pain behaviors and motor function; DRG and dorsal horn tissues will be studied for neuroinflammation, including astrocyte and microglial activation, and expression of SUR1-TRPM4, IL-6, CCL2 and CXCL1. This project is the first to study the effects in neuropathic pain of SUR1 inhibition by glibenclamide, which is safe, non-addicting and could be repurposed for the treatment of neuropathic pain, thereby greatly improving the function of affected Veterans.

背景：几乎一半的退伍军人经历了慢性疼痛，这比 平民中有2500万美国人患有严重的慢性疼痛。慢性疼痛是常见的 军事和恐怖有关的续集。大多数战场伤口涉及暴露的伤害 四肢，导致神经性疼痛的高率是由周围神经系统损害引起的。阿片类药物使用障碍 持续的“阿片类流行病”部分是由针对神经疗法规定的阿片类药物的合法使用来驱动的。 疼痛。部署后，有15％的退伍军人使用阿片类药物，相比之下，有4％的一般人口，在 退伍军人，使用卵巢和自杀之间存在直接相关性。靶向替代非阿片类药物 使用非添加药物控制疼痛的途径是神经性疼痛研究的主要目标。外围 神经损伤（PNI），细胞因子和趋化因子的中调在中央上调，包括在背角星形胶质细胞中， 它们为神经性疼痛的发病机械做出了机械贡献。背侧的反应性星形胶质细胞 角表现出长期激活的促炎秘密（CAP）表型，其特征是 分泌多种因素，包括白介素6（IL-6），趋化因子C-C基序配体2（CCL2）和 趋化因子C-X-C基序配体1（CXCL1），每个配体单独证明有助于神经疗法 疼痛行为。 PNI后星形胶质帽表型有助于炎症和神经元 通过神经趋化因子受体过度激活，导致神经性疼痛。我们的飞行员数据证明了 新发现，在神经性疼痛的鼠坐骨神经袖口模型中，抑制磺酰尿受体1 （SUR1）每天使用低剂量的Glibenclamide在几周内进行治疗，从 PNI后第21天的慢性相导致标志性降低：（i）机械性异常，热痛觉过敏 并放置逃生/回避； （ii）IL-6，CCL2和CXCL1的背角星形胶质细胞表达。 描述：该项目的临床目的是建立治疗潜力，耐用性， Glibenclamide治疗在PNI引起的神经性疼痛行为中的关键作用部位。四个分开 使用鼠坐骨神经袖口模型计划在男性和女性中进行实验，并采用治疗 仅在慢性阶段，PNI后3周。在这些实验中，我们将研究：（a）各种能力 全身性和胸膜内glibenclamide的剂量有效逆转神经性疼痛行为（机械 异常性痛，热过敏，位置逃生/避免，动画和类似抑郁症的行为）及相关 电机功能障碍； （b）全身性glibenclamide逐渐消除神经炎症的能力 DRG/背喇叭，与观察到的异常性nia级延长相关； （c）耐用性 治疗后的Glibenclamide治疗； （d）解剖学和细胞的作用部位 Glibenclamide。小鼠的神经性疼痛行为和运动功能最多可长达11周。 drg和 背角组织将研究神经炎症，包括星形胶质细胞和小胶质细胞激活，以及 SUR1-TRPM4，IL-6，CCL2和CXCL1的表达。该项目是第一个研究神经疗法影响的项目 SUR1抑制Glibenclamide的疼痛，这是安全的，不添加的，可以重新用于治疗 神经性疼痛，从而大大改善了受影响的退伍军人的功能。