Peripheral and Central Pain Generators of Chronic Trigeminal Neuropathic Pain

慢性三叉神经病理性疼痛的周围和中枢疼痛发生器

• 批准号: 9031396
• 负责人: KARIN N. WESTLUND-HIGH
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031396
• 关键词: Acute; Acute Pain; Address; Animals; Anterior; Antibodies; Anxiety; Attenuated; Behavioral; Behavioral Assay; Biological Assay; Biological Markers; Blast Cell; Brain; Brain Injuries; Brain region; Cell Nucleus; Chloride Ion; Chlorides; Chronic; Cicatrix; Cognition; Cognitive; Craniocerebral Trauma; Data; Disinhibition; Dopamine-beta-monooxygenase; Dose; Effectiveness; Equilibrium; Excision; Explosion; FDA approved; Face; Facial Injuries; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Head; Healed; Healthcare Systems; Hippocampus (Brain); Hypersensitivity; Immunohistochemistry; Incidence; Injury; Laceration; Lesion; Ligands; Measures; Mechanics; Medial; Mediating; Mental Depression; Microinjections; Military Personnel; Modeling; Monitor; Neuronal Plasticity; Neurons; Pain; Patients; Peripheral Nerves; Pharmaceutical Preparations; Pharmacological Treatment; Post-Traumatic Stress Disorders; Prazosin; Pre-Clinical Model; Prefrontal Cortex; Process; Prosencephalon; Quality of life; Receptor Inhibition; Receptor Signaling; Role; Signal Transduction; Sleep disturbances; Staining method; Stains; Structure; Symptoms; System; Testing; Therapeutic; Time; Trauma; Treatment Efficacy; Trigeminal System; Trigeminal nerve structure; Ventricular; Veterans; Work; attenuation; base; behavior measurement; central pain; central sensitization; chloride-cotransporter potassium; chronic neuropathic pain; chronic pain; cingulate cortex; clinically relevant; cohort; combat; comparison group; constriction; cost; dorsal horn; drinking water; experience; follow-up; gamma-Aminobutyric Acid; healing; improved; in vivo; locus ceruleus structure; nerve injury; nerve supply; neuron loss; neuropathology; neurotoxic; neurotransmission; noradrenergic; novel; pain behavior; pain inhibition; painful neuropathy; peripheral pain; pre-clinical; public health relevance; receptor

 DESCRIPTION (provided by applicant): ABSTRACT Persisting dysfunctional neuroplasticity in peripheral nerves as well as in the brain exert powerful influences on the pain experience. For example, facial trauma suffered by military personnel may heal, yet months later progress to a chronic neuropathic pain state. A facial laceration trigeminal nerve trauma model (CCI-ION) is utilized in our pursuit of mechanistic support for repurposing a noradrenergic (NA) therapeutic currently in use for treatment of post-traumatic stress disorder (PTSD) in active duty and Veteran military personnel to reduce chronic pain. The proposed studies address novel hypotheses to explore mechanistic changes that cause overactivation of NA neurons in the nucleus locus coeruleus (LC) neurons that modulate pain and their dysfunctional NA receptor signaling in two targeted brain regions. Our Preliminary Data support our overall hypothesis that neuroplastic changes in the pain network and related limbic structures modulate a shift to chronic pain. This also causes anxiety and depression related behavioral measures in our preclinical model. Our studies are unique in that we test through an extended time course compared to studies using acute injuries, to provide more clinically relevant information. We have discovered that switch from pain inhibition to facilitatio occurs through paradoxical ongoing dysregulation of NA LC neurons (Aim 1) that can be reversed pharmacologically (Aim 2). Long-term block of NAα1 receptor facilitation is proposed as therapy for chronic pain behaviors, overactivation, and maladaptive neuropathology (Aim 3). Aim 1 tests the hypothesis that chronic trigeminal neuropathic pain facilitates central sensitization by overactivation and dysregulation of LC NA neurons producing a functional shift from pain inhibition to facilitation. Maladaptive signaling mechanisms have been identified during chronic pain. Biomarker changes indicate overactivation of the LC, an important NA modulator of pain processing. Removal of LC NA influence with intracerebroventricular or trigeminal dorsal horn (spVc) microinjections of neurotoxic saporin conjugated dopamine-beta-hydroxylase antibodies specifically ablates NA neurons, reducing mechanical hypersensitivity. Aim 2 tests the hypothesis that trigeminal nerve injury shifts NAα2 receptor mediated inhibition to NAα1 receptor mediated facilitation of chronic pain assisted by GABA dysregulation. Pharmacological findings indicate that during chronic pain GABA disinhibition occurs. Thus, in chronic pain ligand-gated GABAA receptor chloride signaling becomes excitatory instead of inhibitory. Injury-induced long-term neuronal excitation causes intracellular chloride accumulation and equilibrium potential shift. Concomitant dysfunctional shift from NAα2 receptor inhibition to NAα1 receptor facilitation results in the medial prefrontal limbic cortex (mPFC) and spVc targeted by the NA LC neurons. Aim 3 tests the hypothesis that long-term treatment with prazosin will reduce the effects of dysregulated NA LC signaling. Efficacy of long-term treatment with orally dosed prazosin, a clinically used NA receptor antagonist, will be tested in the chronic facial laceration and nerve injury model. Attenuation is anticipated of hypersensitivity, anxiety, depression, and cognition related measures based on its efficacy for the treatment of Veterans with PTSD. Chronic pain induced histopathological changes, i.e. biomarker expression of cellular overactivation, cortical neuronal death and glial scar formation, are expected to be improved by long-term treatment with prazosin. The long term goal of the proposed studies is greater understanding of pain generators and neuroplastic changes precipitating dysfunctional neuronal signaling that produce chronic pain. Completion of the studies will provide scientific justification for "repurposing" FDA approved noradrenergic therapies that (1) have potential to decrease chronic neuropathic pain and (2) will move quickly through regulatory approvals. This would improve quality of life, return to work rates for Veterans, and decrease costs for the VA system.

 描述（由申请人提供）： 在周围神经系统中以及大脑中的抽象持续性神经成形术对疼痛体验产生强大的影响。例如，军事人员遭受的面部创伤可能会愈合，但几个月后就发展为慢性神经性疼痛状态。面部裂伤三叉神经创伤模型（CCI-ION）用于我们寻求机械支持，以重新利用目前正在使用的诺氏肾上腺素（NA）治疗，以治疗现役军人和退伍军人军事人员，以减轻慢性疼痛。拟议的研究介绍了新的假设，以探索机械变化，从而导致NA神经元过度激活核基因座（LC）神经元，该神经元在两个靶向大脑区域中调节疼痛及其功能障碍的Na受体信号传导。我们的初步数据支持我们的总体假设，即疼痛网络和相关边缘结构的神经塑性变化调节向慢性疼痛的转变。这也会在我们的临床前模型中引起焦虑和抑郁相关的行为措施。与使用急性损伤的研究相比，我们的研究是独一无二的，因为我们通过延长的时间课程进行了测试，以提供更多临床相关的信息。我们发现，通过矛盾的Na LC神经元的矛盾持续失调（AIM 1），可以从疼痛抑制转换为促进症（AIM 2）发生（AIM 2）。 NAα1受体设施的长期阻滞被认为是慢性疼痛行为，过度激活和适应不良神经病理学的治疗（AIM 3）。 AIM 1检验了以下假设：慢性三叉神经性疼痛设施通过过度激活和失调LC NA神经元的失调，从而产生从疼痛抑制转换为支撑的功能转移。在慢性疼痛期间，已经确定了适应不良的信号传导机制。生物标志物变化表明LC过度活化，LC是疼痛处理的重要NA调节剂。用脑室内或三方背角（SPVC）对神经毒素糖蛋白结合的多巴胺β-羟化酶抗体的显微注射去除LC NA的影响，专门消除了NA神经元，从而降低了机械性降低的机械性降低。 AIM 2检验了三叉神经损伤的假设，即对Naα1受体介导的慢性疼痛介导的抑制作用抑制了GABA失调的慢性疼痛。药理学发现表明，在慢性疼痛期间，发生抑制作用。在慢性疼痛中，配体门控的GABAA受体受体慢性信号传导变得兴奋而不是抑制性。损伤引起的长期神经兴奋会导致细胞内氯化物的积累和等效的潜在转移。从Naα2受体抑制到Naα1受体设施的功能障碍转移导致培养基前额叶边缘皮层（MPFC）和 NA LC神经元靶向的SPVC。 AIM 3检验了以下假设：用曲霉素长期治疗将减少NA LC信号失调的影响。长期治疗用口服剂量的Pyrozosin（一种临床使用的Na受体拮抗剂）的疗效将在慢性中进行测试 面部撕裂和神经损伤模型。衰减预计会导致过敏性，焦虑，抑郁和与认知相关的措施基于其对PTSD治疗退伍军人的有效性。慢性疼痛引起的组织病理学变化，即细胞过度活化，皮质神经元死亡和神经胶质疤痕形成的生物标志物的表达，预计将通过长期治疗曲霉素治疗来改善。拟议研究的长期目标更大。了解疼痛发生器和神经塑性变化，导致功能失调的神经信号导致慢性疼痛。研究的完成将为“重新利用” FDA批准的NORADENAGIC疗法提供科学理由，因为（1）有可能减轻慢性神经性疼痛，并且（2）将通过法规批准迅速移动。这将提高生活质量，退伍军人的工作率，并降低VA系统的成本。