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: 10642699
• 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/10642699
• 关键词: Affect; Aftercare; American; Anatomy; Animal Model; Anxiety; Astrocytes; Behavior; CXC Chemokines; Central Nervous System Agents; Chronic; Chronic Phase; Data; Dose; Encephalomyelitis; Exhibits; Experimental Genetics; Exposure to; Extinction; Female; General Population; 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; Pharmaceutical Preparations; Pharmacologic Substance; 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; experience; experimental study; functional improvement; glial activation; 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; pharmacologic; 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过慢性疼痛，其严重程度不成比例。 2500 万美国人患有严重的慢性疼痛，这是一种常见现象。 军事和恐怖相关伤害的后遗症 大多数战场伤口都是暴露在外的伤害。 四肢，导致阿片类药物使用障碍引起的神经性疼痛的发生率很高。 持续存在的“阿片类药物流行病”部分是由于合法使用用于治疗神经病的阿片类药物所致 部署后，15% 的退伍军人使用阿片类药物，而普通人群的这一比例为 4%。 退伍军人，使用阿片类药物和自杀之间存在直接相关性。 使用非成瘾药物控制疼痛的途径是神经病理性疼痛研究的主要目标。 神经损伤（PNI），细胞因子和趋化因子集中上调，包括背角星形胶质细胞， 它们在机制上促进了背侧反应性星形胶质细胞的发病机制。 角表现出慢性激活的促炎分泌（CAPS）表型，其特征在于 分泌多种因子，包括白细胞介素 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)，其中每一个均已被证明会导致神经病 PNI 后星形胶质细胞 CAPS 表型会导致炎症和神经元行为。 通过神经元趋化因子受体过度激活，导致神经性疼痛。 新发现表明，在神经性疼痛的小鼠坐骨神经袖带模型中，抑制磺酰脲类受体 1 (SUR1) 每天服用低剂量格列本脲，持续几周，治疗期间开始 PNI 后第 21 天的慢性期，导致以下方面显着减少：(i) 机械性异常性疼痛、热痛觉过敏 以及地点逃避/回避；(ii) 背角星形胶质细胞 IL-6、CCL2 和 CXCL1 的表达。 描述：该项目的临床相关目标是确定治疗潜力、持久性、 和格列本脲治疗 PNI 诱发的神经性疼痛行为的关键作用位点 四个独立的。 计划使用小鼠坐骨神经袖带模型在男性和女性中进行实验，并进行治疗 仅在慢性期，即 PNI 后 3 周，在这些实验中，我们将检查： (a) 各种能力。 全身和鞘内注射格列本脲的剂量可有效逆转神经性疼痛行为（机械性疼痛） 异常性疼痛、热痛觉过敏、地方逃避/回避、焦虑和抑郁样行为）以及相关 运动功能障碍；（b）全身性格列本脲逐渐消除神经炎症的能力 DRG/背角，与观察到的异常性疼痛的逐渐消失相关；(c) 的持久性； 停止治疗后的格列本脲治疗；以及 (d) 作用的解剖学和细胞部位； 将对小鼠进行长达 11 周的神经性疼痛行为和运动功能研究； 将研究背角组织的神经炎症，包括星形胶质细胞和小胶质细胞的激活，以及 该项目是第一个研究 SUR1-TRPM4、IL-6、CCL2 和 CXCL1 表达对神经病变的影响的项目。 格列本脲抑制 SUR1 带来的疼痛，安全、非成瘾性，可重新用于治疗 神经性疼痛，从而大大改善受影响退伍军人的功能。