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: 10513813
• 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/10513813
• 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; Central Nervous System; 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; Head and neck structure; 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; Neurons; Opioid; Orofacial Pain; Outcome; Oxidative Stress; Pain; Patients; Peripheral Nervous System; Pharmacologic Substance; 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; antagonist; anxiety-related behavior; brain circuitry; care seeking; central pain; chronic constriction injury; chronic neuropathic pain; chronic pain; chronic pain management; clinically relevant; combat injury; design; efficacy evaluation; efficacy testing; endoplasmic reticulum stress; follow-up; histological studies; improved; in vivo; inhibitor; interest; misfolded protein; nerve injury; nerve supply; neural; neuropathology; non-opioid analgesic; noradrenergic; opioid overdose; oxidative damage; pain behavior; pain chronification; pain model; pain processing; pain reduction; painful neuropathy; pharmacologic; preclinical efficacy; promoter; protein expression; receptor; 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.

退伍军人的慢性疼痛比非兽医患者更严重，据报道死亡的可能性是 阿片类药物过量试图找到救济。这些后果在于确定大脑的关键需求 改变导致疼痛的年代化，这种变化常常发展为焦虑和抑郁症 我们的退伍军人自杀率提高。更好地理解驾驶基础机制 慢性疼痛对于开发更有效的非阿片类药物治疗方法至关重要。 在当前资助的VA绩效赠款期间，我们进行了锰增强MRI（MEMRI）研究 使用我们的实验性慢性神经性疼痛模型。 MEMRI允许可视化神经活化 使用7T布鲁克MRI扫描仪的小啮齿动物大脑。与临床fMRI研究一样，我们确定了特定的边缘 除了激活疼痛回路本身，慢性疼痛过分激活的情绪大脑区域。这是 在我们的初步数据组织学随访中明显看出，在边缘大脑中正在进行的细胞应激发生 电路。由于神经元过度活化，边缘脑疼痛回路的病理生理改变包括 细胞应激生物标志物的表达增加并改变了受保护的自噬生物标志物的表达。 自噬被定义为正在进行的细胞保护机制去除受损和折叠的蛋白质 在细胞应激期间产生。自噬稳态破坏，导致自噬功能障碍 不利地影响细胞功能，有时会生存力。拟议研究的目的是检查是否是否 促进细胞保护性自噬机制不仅可以减少与神经性疼痛变化有关的 行为，但可以想象可以减少相关的脑痛回路神经病理学。我们的研究在 诱导后8-10周，我们的慢性神经性疼痛模型允许显着临床相关。 我们将测试细胞应力/自噬机制是否与Noradrenagic alpha 1接收器有关 （Naα1R）信号我们在以前的优点授予融资期间确定为主要的慢性疼痛发生器。 我们将测试的Naα1R阻滞剂是临床治疗性毒素，也可以用作PTSD治疗。 多沙唑嗪比我们在上一批赠款期间在同一模型中测试的prazosin更长。 prazosin 我们在10周内观察到的慢性疼痛和厌恶性焦虑和抑郁症相关行为 时间点（请参阅进度报告）。我们将测试多克萨斯辛的效率，以减少慢性神经性疼痛引起的效率 机械性超敏反应，并执行动画和抑郁症相关的行为测定。比较 多沙唑嗪可以对吡唑嗪和细胞应激抑制剂/自噬增强剂的影响产生影响。 我们根据我们最近完成的MEMRI研究发现，在特定边缘皮质区域过度激活之后 持续的神经性疼痛10周导致细胞应激/自噬生物标志物表达改变 伴随着慢性疼痛与慢性疼痛相关的行为。此VA优点续签申请中提出的目的包括 慢性疼痛中细胞应力/自噬RNA/蛋白表达特征的鉴定/验证 10周的型号。细胞应力信号通路抑制剂和保护性自噬的试验效率测试 促进者发现慢性疼痛行为的逆转。增强受保护的自噬机制 通过量化将进一步证明针对细胞应激和细胞稳态破坏的防御 氧化应激/自噬RNA，蛋白质和其他神经病理学作为读数。成像分布 全身IVIS荧光红外成像的活动物中随着时间的流逝，炎症生物标志物组织B 将是周围和中枢神经系统中炎症成分的读数。 完成我们评估这些治疗效率以增强保护的效率的评估 慢性疼痛期间的自噬机制作为防御细胞应激和慢性疼痛与行为的防御 将增加对神经性疼痛回归的理解。提高理解将导致 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了更好的结果。