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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：
8265958
负责人：
James Eisenach
金额：
$ 31.73万
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265958
关键词：
Absence of pain sensation Acetylcholine Acute Pain Adrenergic Receptor Agonist Alzheimer&apos s Disease Analgesics Anatomy Animals Antidepressive Agents Aricept Bilateral Brain Cholinesterase Inhibitors Cholinesterases Chronic Clinical Clonidine Cognition Data Development Diabetes Mellitus Fiber Functional disorder GTP-Binding Proteins Human Hypersensitivity Injury Malignant Neoplasms Mechanics Medical Medicine Narcotics Nerve Growth Factors Neuroglia Norepinephrine Oral Pain Pathway interactions Patients Peripheral Peripheral nerve injury Pharmaceutical Preparations Rattus Signal Transduction Source Spinal Spinal Cord Spinal cord posterior horn Stimulus System Testing Therapeutic Time Trauma Work brain-derived growth factor central sensitization cholinergic cholinergic neuron chronic neuropathic pain chronic pain donepezil duloxetine effective therapy gabapentin improved inhibitor/antagonist nerve injury noradrenaline transporter noradrenergic novel novel strategies painful neuropathy practical application public health relevance

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）：尽管最近我们对中枢和外周致敏的病理生理学的理解有所进展，但神经性疼痛仍然是一个未满足的医学需求。但是神经损伤也可以增加一些药物的镇痛效果，包括脊髓给药的12-肾上腺素能受体激动剂。在探索这种疗效增加的机制时，我们发现周围神经损伤导致皮节处脊髓中去甲肾上腺素能纤维的萌发。初步数据表明，周围神经损伤后脊髓去甲肾上腺素能芽化是由脑源性生长因子（BDNF）引起的，特异性目的1将研究周围神经损伤节段两侧脊髓去甲肾上腺素能纤维芽化的机制，重点研究胶质细胞作为BDNF的来源和TrkB信号作为芽化的原因。