DORSAL ROOT GANGLION AS SOURCE OF NEUROPATHIC PAIN

糖尿病引起广泛的外周感觉和自主神经病变，特别是当血糖水平控制不佳时。 糖尿病感觉神经病变与阴性和阳性神经症状相关。 阴性（功能丧失）症状包括振动感知降低、轻触和位置感受损、腱反射无力和抑制、对热和伤害性刺激的敏感性丧失。 阴性神经症状是感觉纤维受损的结果。 阳性神经症状包括神经性疼痛和感觉异常。 疼痛是糖尿病最常见的衰弱并发症之一，但这方面的研究在很大程度上没有引起研究人员的注意。 拟议的研究将开始填补这一知识空白。 已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具有痛觉过敏。 先前在自发性糖尿病（BB）大鼠中的神经生理学研究发现，起源于背根神经节（DRG）神经元胞体的自发动作电位放电的发生率异常高。 本探索性/发展性（R21）研究提案的目标是将自发性糖尿病BB大鼠中痛觉过敏的出现与伤害性DRG神经元细胞体中自发性动作电位放电的出现相关联。 此外，我们将研究依赖于河豚毒素敏感和河豚毒素抵抗的电压门控钠电流的贡献的自发动作电位放电。 关于电压门控钠电流将提出相同的问题，电压门控钠电流可能有助于DRG神经元中的自发动作电位放电，DRG神经元得自因神经损伤引起的顽固性神经性疼痛而手术治疗（通过神经节切除术）的人类患者。 总之，拟议的研究有望提供有关DRG作为神经性疼痛外周来源的新信息。 这些结果将构成计划的RO 1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.