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)： 摘要外周神经和大脑中持续的神经可塑性障碍对疼痛体验有很大的影响。例如，军人遭受的面部创伤可能会痊愈，但几个月后会进展为慢性神经病理性疼痛状态。我们利用面部撕裂三叉神经创伤模型(CCI-ION)来寻求机械支持，以重新调整去甲肾上腺素(NA)疗法的用途，目前正用于治疗现役军人和退伍军人的创伤后应激障碍(PTSD)，以减少慢性疼痛。拟议的研究提出了新的假设，以探索导致蓝斑核(LC)神经元过度激活的机制变化，这些神经元调制疼痛及其在两个目标脑区功能失调的NA受体信号。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中的神经可塑性变化调节向慢性疼痛的转变。在我们的临床前模型中，这也会导致焦虑和抑郁相关的行为测量。我们的研究的独特之处在于，与使用急性损伤的研究相比，我们通过更长的时间段进行测试，以提供更多临床相关信息。我们已经发现，从疼痛抑制到促进的转换发生在NA LC神经元矛盾的持续失调(目标1)，这可以从药物上逆转(目标2)。长期阻断NAα1受体易化被建议用于慢性疼痛行为、过度激活和适应不良神经病理的治疗(目标3)。目的1验证慢性三叉神经病理性疼痛通过LC NA神经元的过度激活和失调而促进中枢敏感化的假说，从而导致从疼痛抑制到易化的功能转变。在慢性疼痛过程中，已经确定了适应不良的信号机制。生物标志物的变化表明LC过度激活，LC是疼痛处理的重要NA调节器。侧脑室或三叉神经背角(SpVc)微量注射神经毒性皂苷结合的多巴胺-β-羟基酶抗体消除LC NA的影响可特异性地消融NA神经元，降低机械超敏反应。目的2验证三叉神经损伤将NAα2受体介导的抑制作用转变为NAα1受体介导的慢性疼痛易化作用的假说。药理学结果表明，在慢性疼痛期间，GABA发生去抑制。因此，在慢性疼痛中，配体门控的GABAA受体氯信号变得兴奋而不是抑制。损伤诱导的长期神经元兴奋导致细胞内氯蓄积和平衡电位移动。伴随而来的从NAα2受体抑制到NAα1受体促进的功能障碍导致内侧前额叶边缘皮质和 以NA LC神经元为靶点的spVc。目的3验证长期使用哌唑嗪可降低NA-LC信号转导失调效应的假说。口服临床使用的NA受体拮抗剂哌唑嗪的长期疗效将在慢性阻塞性肺疾病患者中进行测试。 面部撕裂伤和神经损伤模型。根据其对退伍军人创伤后应激障碍的治疗效果，预计减量可用于过敏、焦虑、抑郁和认知相关措施。慢性疼痛引起的组织病理学改变，即细胞过度激活、皮质神经元死亡和胶质瘢痕形成的生物标记物的表达，有望通过长期的哌唑嗪治疗而得到改善。这项拟议研究的长期目标是更好地了解疼痛产生因素和神经可塑性变化，这些变化会引发产生慢性疼痛的功能失调的神经元信号。这些研究的完成将为FDA批准的去甲肾上腺素疗法提供科学依据，这些疗法(1)有可能减少慢性神经性疼痛，(2)将迅速通过监管批准。这将提高生活质量，退伍军人的复员率，并降低退伍军人制度的成本。