Spinal Noradrenergic Sprouting after Nerve Injury

描述（由申请人提供）：神经性疼痛仍然是一个未满足的医疗需求，尽管最近在我们的理解中枢和外周致敏的病理生理学的进展。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-肾上腺素受体激动剂。在探索这种增加的功效的机制时，我们发现周围神经损伤导致脊髓中接受损伤输入的皮节处的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发芽是由于脑源性生长因子（BDNF），具体目标1将检查周围神经损伤节段脊髓去甲肾上腺素能纤维双侧发芽的机制，重点是胶质细胞作为BDNF的来源和TrkB信号传导作为发芽的原因。 很少有疗法能有效治疗神经性疼痛，并且这些疗法中的大多数模仿或增强脊髓中去甲肾上腺素释放的活性。初步数据表明，神经性疼痛与脊髓去甲肾上腺素激活局部脊髓胆碱能回路镇痛的新作用有关。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，重点是12-肾上腺素受体亚型和G蛋白种类激活。 这些解剖学和下行抑制回路的变化提示了治疗神经病理性疼痛的新方法。我们目前的初步数据表明，这一途径可以激活加巴喷丁。由于去甲肾上腺素也刺激脊髓乙酰胆碱释放镇痛神经损伤后，这一途径可以增强去甲肾上腺素转运蛋白和胆碱酯酶抑制剂。令人兴奋的人类新的初步数据表明，胆碱酯酶抑制剂多奈哌齐（Aricept.）为慢性神经性疼痛患者提供镇痛和改善认知。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发芽的治疗结果。这些研究将提高我们对神经病理性疼痛的认识，并为更好地治疗神经病理性疼痛提供实践指导。 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，即使使用麻醉剂也难以治疗。这些对老鼠和慢性疼痛患者的研究将探索使用药物的新方法，以帮助人体自身的疼痛缓解系统更好地缓解疼痛。

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.