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得到满足的医学需求，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。但神经损伤也可以增加一些药物的止痛效果，包括脊髓注射的12-肾上腺素能受体激动剂。在探索这种提高疗效的机制时，我们发现周围神经损伤导致脊髓中去甲肾上腺素能纤维在接受损伤输入的皮肤处萌发。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脑源性生长因子(BDNF)引起的，具体目标1将研究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，重点放在胶质细胞作为BDNF的来源和TrkB信号发芽的原因。 很少有治疗神经病理性疼痛的有效疗法，而且大多数疗法都模拟或增强了脊髓中去甲肾上腺素的释放活性。初步数据表明，神经病理性疼痛与脊髓去甲肾上腺素激活局部脊髓胆碱能回路用于镇痛的一种新作用有关。具体目标2将研究12-肾上腺素受体对周围神经损伤后脊髓胆碱能神经元的新的兴奋作用的机制，重点是12-肾上腺素受体亚型和激活的G蛋白种类。 下行抑制的解剖和回路的这些变化提示了治疗神经病理性疼痛的新方法。我们提供的初步数据表明，这一途径可以被加巴喷丁激活。由于去甲肾上腺素在神经损伤后也能刺激脊髓乙酰胆碱的释放用于镇痛，去甲肾上腺素转运体和胆碱酯酶抑制剂可以增强这一途径。在人类身上令人兴奋的新的初步数据表明，胆碱酯酶抑制剂多奈哌齐(Aricept.)为慢性神经性疼痛患者提供止痛和改善认知功能。具体目标3将使用临床上可用的口服药物，在动物和患者身上测试去甲肾上腺素能发芽的治疗后果。这些研究将提高我们的认识，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，即使用麻醉剂也很难治疗。这些在老鼠和慢性疼痛患者身上的研究将探索使用药物的新方法，以帮助身体自身的止痛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.