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: 10293538
• 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/10293538
• 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; antagonist; anxiety-related behavior; base; 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; 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.

退伍军人的慢性疼痛比非退伍军人更严重，据报道，死于慢性疼痛的可能性是非退伍军人的两倍