DORSAL ROOT GANGLION AS SOURCE OF NEUROPATHIC PAIN

糖尿病导致广泛的外周感觉和自主神经病变，特别是在血糖水平控制不佳的情况下。糖尿病感觉神经病变与阴性和阳性神经症状有关。阴性(功能丧失)症状包括振动知觉降低、光触觉和位置觉受损、肌腱反射无力和压抑、对热刺激和有害刺激失去敏感性。阴性的神经症状是感觉神经纤维受损的结果。阳性的神经系统症状包括神经病理性疼痛和感觉异常。疼痛是糖尿病最常见的衰弱并发症之一，但这一领域的研究在很大程度上没有引起研究人员的注意。拟议的研究将开始解决这一知识差距。众所周知，血糖水平控制不佳的链脲佐菌素或四氧嘧啶糖尿病大鼠会出现痛觉过敏。先前对自发性糖尿病(BB)大鼠的神经生理学研究发现，自发性动作电位放电起源于背根神经节(DRG)神经元的细胞体，发生率异常高。本探索性/发育性(R21)研究方案的目的是将自发性糖尿病BB大鼠痛觉过敏的出现与伤害性DRG神经元胞体自发动作电位放电的出现联系起来。此外，我们还将研究河豚毒素敏感钠电流和河豚毒素抗性电压门控钠电流对自发动作电位放电的依赖性。同样的问题也将被问到电压门控钠电流，它可能导致因神经损伤而进行手术治疗(通过神经节切除术)的人类患者获得的DRG神经元的自发动作电位放电。总之，拟议的研究有望提供有关背根节作为神经病理性疼痛的外周来源的新信息。这些结果将构成计划中的RO1研究提案的基础。

Diabetes causes widespread peripheral sensory and autonomic neuropathy, particularly when blood glucose levels are poorly controlled. Diabetic sensory neuropathy is associated with both negative and positive neurological symptoms. Negative (loss of function) symptoms include reduced vibration perception, compromised light touch and position sense, weakness and depressed tendon reflexes, loss of sensitivity to thermal and noxious stimuli. Negative neurological symptoms are the result of damage to sensory fibers. Positive neurological symptoms comprise neuropathic pain and paresthesias. Pain ranks among the most common debilitating complications of diabetes, yet research in this area has, to a large extent, escaped the attention of investigators. The proposed study will begin to address this gap in knowledge. Streptozotocin- or alloxan-diabetic rats with poorly controlled blood sugar levels are known to be hyperalgesic. A previous neurophysiological study in spontaneously diabetic (BB) rats found an abnormally high incidence of spontaneous action potential discharge originating in the cell bodies of dorsal root ganglion (DRG) neurons. The goal of the present exploratory/developmental (R21) research proposal is to correlate the appearance of hyperalgesia in the spontaneously diabetic BB rat with the emergence of spontaneous action potential discharge in the cell bodies of nociceptive DRG neurons. Furthermore, we will examine the dependence of spontaneous action potential discharge on the contribution of tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium currents. The same question will be asked about voltage- gated sodium currents which may contribute to spontaneous action potential discharge in DRG neurons obtained from human patients treated surgically (by ganglionectomy) for intractable neuropathic pain due to nerve injury. Together, the proposed studies are expected to provide new information about the DRG as a peripheral source of neuropathic pain. The results will form the basis of a planned RO1 research proposal.