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）：尽管我们对中央和周围敏化的病理生理学的了解最近进步，但神经性疼痛仍然是未满足的医学需求。但是，神经损伤也可以提高某些药物的镇痛功效，包括旋转的12-肾上腺素受体激动剂。在探索提高功效的基础机制时，我们发现周围神经损伤导致皮肤上的脊髓中的去甲肾上腺素能纤维发芽，这些脊髓会从损伤中获得输入。初步数据表明，周围神经损伤后的脊柱去甲肾上腺素能发芽是由于脑衍生的生长因子（BDNF）引起的，具体目标1将检查脊柱去甲肾上腺素能纤维双侧发芽的机制。很少有疗法可有效治疗神经性疼痛，大多数模仿或增强了脊髓中去甲肾上腺素释放的活性。初步数据表明，神经性疼痛与脊柱去甲肾上腺素的新作用有关激活局部脊柱胆碱能回路以进行镇痛。具体的目标2将检查周围神经损伤后12-肾上腺素受体对脊柱胆碱能神经元的新型兴奋作用的机制，重点是激活的12-肾上腺素受体亚型和G蛋白质物种。这些解剖结构和降级抑制作用的变化表明了治疗神经性疼痛的新方法。我们提供了初步数据，这些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柱乙酰胆碱在神经损伤后释放镇痛，因此可以通过去甲肾上腺素转运蛋白和胆碱酯酶抑制剂来增强该途径。人类令人兴奋的新初步数据表明，胆碱酯酶抑制剂Donepezil（Aricept。）提供镇痛，并改善慢性神经性疼痛患者的认知。特定的目标3将使用临床上可用的口服药物在动物和患者中对去甲肾上腺素能发芽的治疗后果进行测试。这些研究将改善我们的理解，并为更好地治疗神经性疼痛提供实际指导。公共卫生相关性：神经损伤，无论是癌症，糖尿病还是创伤，都可能导致慢性疼痛，即使使用麻醉品也很难治疗。这些在大鼠和患有慢性疼痛的人中的研究将探索使用药物来帮助人体自身缓解疼痛系统的新方法，以更好地缓解疼痛。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activation of glutamate transporters in the locus coeruleus paradoxically activates descending inhibition in rats.

DOI：
10.1016/j.brainres.2009.12.086
发表时间：
2010-03-04
期刊：
BRAIN RESEARCH
影响因子：
2.9
作者：
Hayashida, Ken-ichiro;Parker, Renee A.;Eisenach, James C.
通讯作者：
Eisenach, James C.

Reply to: The G protein preference of orexin receptors is currently an unresolved issue.

DOI：
10.1038/s41467-023-38765-2
发表时间：
2023-06-01
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Yin, Jie;Kang, Yanyong;McGrath, Aaron P.;Chapman, Karen;Sjodt, Megan;Kimura, Eiji;Okabe, Atsutoshi;Koike, Tatsuki;Miyanohana, Yuhei;Shimizu, Yuji;Rallabandi, Rameshu;Lian, Peng;Bai, Xiaochen;Flinspach, Mack;De Brabander, Jef K.;Rosenbaum, Daniel M.
通讯作者：
Rosenbaum, Daniel M.

Riluzole and gabapentinoids activate glutamate transporters to facilitate glutamate-induced glutamate release from cultured astrocytes.