Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain

调节慢性三叉神经病理性疼痛的疼痛发生器

• 批准号: 10012520
• 负责人: KARIN N. WESTLUND-HIGH
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012520
• 关键词: Ablation; Acute; Acute Pain; Affect; Afferent Neurons; American; Analgesics; Animals; Anxiety; Appearance; Automobile Driving; Autophagocytosis; Behavior; Behavioral; Behavioral Assay; Bioenergetics; Biological Markers; Brain; Brain region; Cathepsins B; Cell physiology; Cells; Cellular Stress; Chronic; Clinical; Confocal Microscopy; Data; Development; Doxazosin; Emotional; Enhancers; Experimental Models; Fluorescent Probes; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Gene Expression Profile; Goals; Grant; Headache; Healthcare Systems; Heat shock proteins; Histologic; Homeostasis; Hypersensitivity; Image; Immunohistochemistry; Inflammatory; Knowledge; Literature; Magnetic Resonance Imaging; Manganese; Measures; Mechanics; Mental Depression; Military Personnel; Mitochondria; Modeling; Mus; Neck Pain; Nerve; Nervous system structure; Neuraxis; Neurons; Opioid; Orofacial Pain; Outcome; Oxidative Stress; Pain; Patients; Peripheral; Pharmacologic Substance; Pharmacology; Post-Traumatic Stress Disorders; Prazosin; Process; Progress Reports; Prosencephalon; Proteins; RNA; Rattus; Receptor Signaling; Reporting; Rodent; Signal Pathway; Signal Transduction; Sirolimus; Testing; Therapeutic; Time; Treatment Efficacy; Trigeminal System; Validation; Veterans; Visualization; Western Blotting; anxiety-related behavior; base; brain circuitry; care seeking; central pain; chronic constriction injury; chronic neuropathic pain; chronic pain; clinically relevant; combat injury; design; efficacy evaluation; efficacy testing; endoplasmic reticulum stress; follow-up; histological studies; improved; in vivo; inhibitor/antagonist; interest; misfolded protein; nerve injury; nerve supply; neuropathology; non-opioid analgesic; noradrenergic; opioid overdose; oxidative damage; pain behavior; pain chronification; pain model; pain processing; pain reduction; painful neuropathy; preclinical efficacy; promoter; protein expression; receptor; relating to nervous system; suicide rate; transcriptome sequencing; treatment response; vehicular accident

Veterans have more severe chronic pain than non-veteran patients and are reportedly twice as likely to die of an opioid overdose in attempts to find relief. These consequences lie behind the critical need to determine brain alterations causing chronification of pain that are too often progressing to the anxiety and depression responsible for the increased suicide rate among our veterans. Better understanding of underlying mechanisms driving chronic pain is imperative to development of more effective non-opioid treatment approaches for chronic pain. During the currently funded VA Merit grant period, we performed manganese enhanced MRI (MEMRI) studies using our experimental chronic neuropathic pain model. MEMRI allows visualization of neural activation in the small rodent brain using a 7T Bruker MRI scanner. As in clinical fMRI studies, we identified specific limbic emotional brain regions overactivated by chronic pain in addition to activation of the pain circuitry itself. It is apparent in our Preliminary Data histological follow-up that ongoing cellular stress is occurring in limbic brain circuitry. Due to the neuronal overactivation, pathophysiological alterations in limbic brain pain circuitry include increased expression of cellular stress biomarkers and altered expression of protective autophagy biomarkers. Autophagy is defined as the ongoing cellular protective mechanisms removing damaged and misfolded proteins generated during cellular stress. Disrupted autophagy homeostasis that produces autophagic dysfunction adversely affects cell function and eventually viability. The goal of the proposed studies is to examine whether boosting cell protective autophagy mechanisms can not only reduce neuropathic pain chronification related behaviors but can conceivably reduce the related brain pain circuitry neuropathology. Our studies performed at 8-10 weeks after induction in our chronic neuropathic pain model allows salient clinical relevance. We will test whether cellular stress/autophagy mechanisms are related to the noradrenergic alpha 1 receptor (NAα1R) signaling we identified as a primary chronic pain generator in the previous Merit grant funding period. The NAα1R blocker we will test is the clinical therapeutic doxazosin that might also be used as PTSD therapy. Doxazosin is longer lasting than the prazosin we tested in the same model in the previous grant period. Prazosin reduced chronic pain and aversive anxiety and depression related behaviors we observed through the 10 week time points (see Progress Report). We will test efficacy of doxazosin to reduce chronic neuropathic pain induced mechanical hypersensitivity, and perform anxiety and depression related behavioral assays. Comparisons of the efficacy of doxazosin can be made to prazosin and the effects of cellular stress inhibitors/autophagy enhancers. We find based on our recently completed MEMRI study that overactivation in specific limbic cortical regions after 10 weeks of ongoing neuropathic pain results in altered cellular stress/autophagy biomarker expression that accompanies the chronic pain related behaviors. The Aims proposed in this VA Merit renewal application include identification/validation of the cellular stress/autophagy RNA/protein expression signature in the chronic pain model at 10 weeks. Pilot efficacy testing of a cellular stress signaling pathway inhibitor and protective autophagy promotor finds reversal of chronic pain behaviors. Enhancement of protective autophagy mechanisms as defense against cellular stress and disrupted cellular homeostasis will be further demonstrated by quantifying oxidative stress/autophagy RNA, proteins, and other neuropathology as readouts. Imaging the distribution of inflammatory biomarker cathepsin B over time in live animals with whole body IVIS fluorescent infrared imaging will be a readout of the inflammatory component in peripheral and central nervous system. Completion of our assessment of the efficacy of these treatments to provide enhancement of protective autophagy mechanisms during chronic pain as defense against cellular stress and chronic pain related behaviors will increase the understanding of the chronification of neuropathic pain. Improved understanding will lead to better non-opioid treatments for chronic pain that provide better outcomes for veterans living with chronic pain.

退伍军人比非退伍军人患者有更严重的慢性疼痛，据报道，死于 试图寻求缓解的阿片类药物过量。这些后果背后隐藏着确定大脑的迫切需要 导致疼痛慢性化的改变，往往进展为焦虑和抑郁 我们退伍军人自杀率的上升。更好地理解潜在的驱动机制 慢性疼痛是开发更有效的非阿片类药物治疗慢性疼痛的必要手段。 在目前资助的VA奖励金期间，我们进行了锰增强磁共振成像(MEMRI)研究 使用我们的实验性慢性神经病理性疼痛模型。MEMRI可以可视化显示大脑中的神经活动 使用7T布鲁克核磁共振扫描仪的小型啮齿动物大脑。在临床fmri研究中，我们确定了特定的边缘。 除了疼痛回路本身的激活外，慢性疼痛还会激活情绪大脑区域。它是 在我们的初步数据组织学随访中，很明显，边缘脑中正在发生持续的细胞应激 电路。由于神经元过度激活，边缘脑痛觉回路的病理生理改变包括 细胞应激生物标记物的表达增加，保护性自噬生物标记物的表达改变。 自噬被定义为清除受损和错误折叠的蛋白质的持续细胞保护机制 在细胞应激过程中产生。自噬动态平衡紊乱，导致自噬功能障碍 对细胞功能和最终的生存能力产生不利影响。拟议研究的目标是检查是否 增强细胞保护性自噬机制不仅可以减少神经病理性疼痛相关的慢性化 行为，但可以想见，可以减少相关的大脑痛觉回路神经病理。我们的研究在 我们的慢性神经病理性疼痛模型在诱导后8-10周允许显著的临床相关性。 我们将测试细胞应激/自噬机制是否与去甲肾上腺素能阿尔法1受体有关。 (NAα1R)信号，我们在上一个功绩拨款资助期确定为主要的慢性疼痛产生因素。 我们将测试的NAα1R阻滞剂是临床治疗多沙唑嗪，它也可能用于创伤后应激障碍的治疗。 多沙唑嗪的持续时间比我们在上一次赠款期间在同一型号中测试的哌唑嗪更长。哌唑嗪 通过10周的观察，我们观察到慢性疼痛、厌恶焦虑和抑郁相关行为减少 时间点(见进度报告)。我们将测试多沙唑嗪对减轻慢性神经病理性疼痛的疗效。 机械过敏症，并进行焦虑和抑郁相关的行为分析。两个版本之间的比较 多沙唑嗪的疗效可以与哌唑嗪和细胞应激抑制剂/自噬促进剂的效果相媲美。 我们发现，基于我们最近完成的MEMRI研究，在 持续10周的神经病理性疼痛导致细胞应激/自噬生物标记物表达改变 伴随着慢性疼痛相关行为。在这份退伍军人奖励续签申请中提出的目标包括 慢性疼痛中细胞应激/自噬RNA/蛋白表达特征的识别/验证 在10周时做模特。一种细胞应激信号通路抑制剂和保护性自噬的初步疗效测试 促进剂发现慢性疼痛行为的逆转。增强保护性自噬机制，如 对细胞应激和被破坏的细胞动态平衡的防御将通过量化进一步证明 氧化应激/自噬RNA、蛋白质和其他神经病理读数。想象的分布情况 全身IVIS荧光红外成像活体动物体内炎症生物标志物组织蛋白酶B随时间的变化 将读出外周和中枢神经系统中的炎症成分。 完成我们对这些治疗效果的评估，以提供加强保护 慢性疼痛中防御细胞应激和慢性疼痛相关行为的自噬机制 将增加对神经病理性疼痛慢性化的理解。更好的理解将导致 更好的非阿片类药物治疗慢性疼痛，为患有慢性疼痛的退伍军人提供更好的结果。