Spinal Noradrenergic Sprouting after Nerve Injury

神经损伤后脊髓去甲肾上腺素能出芽

基本信息

批准号：
8133206
负责人：
James Eisenach
金额：
$ 6.63万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8133206
关键词：
Absence of pain sensation Acetylcholine Acute Address Adrenergic Receptor Agonist Analgesics Anatomy Anesthesiology Animals Aricept Bilateral Brain-Derived Neurotrophic Factor Breakthrough Pain Cholinesterase Inhibitors Clinical Clinical Research Clinical Trials Cognition Data Diabetes Mellitus Dose Drug Interactions Ethics Fiber Figs - dietary Functional disorder GTP-Binding Proteins Grant Review Process Human Hypersensitivity Injury Intake Intervention Malignant Neoplasms Measures Mechanical Stimulation Mechanics Medical Medicine Methods Muscarinic Acetylcholine Receptor Narcotics Neuroglia Non-Steroidal Anti-Inflammatory Agents Norepinephrine Operative Surgical Procedures Opioid Oral Oral Administration Outcome Measure Pain Pain Clinics Pain Measurement Paper Pathway interactions Patients Peripheral Peripheral nerve injury Pharmaceutical Preparations Publications Published Comment Publishing Rattus Right-On Signal Transduction Source Spinal Spinal Cord Stimulus System Testing Text Therapeutic Trauma Withdrawal Work brain-derived growth factor cholinergic cholinergic neuron chronic neuropathic pain chronic pain design donepezil duloxetine effective therapy experience gabapentin heat stimulus improved inhibitor/antagonist innovation nerve injury noradrenaline transporter noradrenergic novel novel strategies painful neuropathy primary outcome public health relevance response reuptake synergism

项目摘要

DESCRIPTION (provided by applicant): Neuropathic pain remains an unmet medical need, despite recent advances in our understanding of the pathophysiology of central and peripheral sensitization. But nerve injury can also increase the analgesic efficacy of some drugs, including spinally administered 12-adrenoceptor agonists. In exploring the mechanisms underlying this increased efficacy, we have discovered that peripheral nerve injury results in sprouting of noradrenergic fibers in the spinal cord at the dermatomes receiving inputs from injury. Preliminary data suggest that spinal noradrenergic sprouting after peripheral nerve injury is due to brain derived growth factor (BDNF), and Specific Aim 1 will examine mechanisms for bilateral sprouting of spinal noradrenergic fibers at the segments of peripheral nerve injury, with focus on glia as a source of BDNF and TrkB signaling as a cause of sprouting. Few therapies are effective to treat neuropathic pain, and most of these mimic or augment the activity of the release of norepinephrine in the spinal cord. Preliminary data demonstrate that neuropathic pain is associated with a novel action of spinal norepinephrine to activate local spinal cholinergic circuits for analgesia. Specific Aim 2 will examine mechanisms for novel excitatory actions of 12-adrenoceptors on spinal cholinergic neurons after peripheral nerve injury, with focus on 12-adrenoceptor subtype and G protein species activated. These changes in anatomy and circuitry of descending inhibition suggest novel approaches to the treatment of neuropathic pain. We present preliminary data which show that this pathway can be activated by gabapentin. Since norepinephrine also stimulates spinal acetylcholine release for analgesia after nerve injury, this pathway could be augmented by norepinephrine transporter and cholinesterase inhibitors. Exciting new preliminary data in humans suggests that the cholinesterase inhibitor, donepezil (Aricept.) provides analgesia and improves cognition in patients with chronic neuropathic pain. Specific Aim 3 will test in animals and patients the therapeutic consequences of noradrenergic sprouting, using clinically available, oral drugs. These studies will improve our understanding and provide practical guidance for better treatment of neuropathic pain. PUBLIC HEALTH RELEVANCE: Nerve injury, whether from cancer, diabetes, or trauma, can result in chronic pain which is difficult to treat, even with narcotics. These studies in rats and in people with chronic pain will explore new ways to use medicines to help the body's own pain relieving system to work better to relieve pain.

描述（由申请人提供）：尽管我们对中枢和外周敏化的病理生理学的理解最近取得了进展，但神经性疼痛仍然是一个未满足的医疗需求。但神经损伤也会增加一些药物的镇痛效果，包括脊髓注射 12-肾上腺素受体激动剂。在探索这种功效增强的机制时，我们发现周围神经损伤会导致接受损伤输入的脊髓中去甲肾上腺素能纤维发芽。初步数据表明，周围神经损伤后脊髓去甲肾上腺素能纤维出芽是由于脑源性生长因子（BDNF）所致，具体目标1将研究周围神经损伤节段处脊髓去甲肾上腺素能纤维双侧出芽的机制，重点关注神经胶质细胞作为BDNF 和 TrkB 信号传导的来源是发芽的原因。很少有疗法能够有效治疗神经性疼痛，并且大多数疗法模拟或增强脊髓中去甲肾上腺素的释放活性。初步数据表明，神经性疼痛与脊髓去甲肾上腺素激活局部脊髓胆碱能回路进行镇痛的新作用有关。具体目标 2 将研究周围神经损伤后 12-肾上腺素受体对脊髓胆碱能神经元的新兴奋作用机制，重点关注 12-肾上腺素受体亚型和激活的 G 蛋白种类。下行抑制的解剖学和回路的这些变化提出了治疗神经性疼痛的新方法。我们提供的初步数据表明该途径可以被加巴喷丁激活。由于去甲肾上腺素还刺激脊髓乙酰胆碱释放以在神经损伤后镇痛，因此去甲肾上腺素转运蛋白和胆碱酯酶抑制剂可以增强该途径。令人兴奋的人体新初步数据表明，胆碱酯酶抑制剂多奈哌齐 (Aricept.) 可为慢性神经性疼痛患者提供镇痛作用并改善认知能力。具体目标 3 将使用临床可用的口服药物在动物和患者中测试去甲肾上腺素能芽的治疗效果。这些研究将增进我们的理解，并为更好地治疗神经性疼痛提供实用指导。公共卫生相关性：神经损伤，无论是由于癌症、糖尿病还是外伤，都可能导致慢性疼痛，即使使用麻醉剂也难以治疗。这些针对老鼠和患有慢性疼痛的人的研究将探索使用药物帮助人体自身的疼痛缓解系统更好地发挥作用来缓解疼痛的新方法。