Diabetic peripheral neuropathic pain (DPNP) is the most devastating complication of diabetes mellitus. Unfortunately, successful therapy for DPNP remains a challenge because its pathogenesis is still elusive. However, DPNP is believed to be due partly to abnormal hyperexcitability of dorsal root ganglion (DRG) neurons, but the relative contributions of specific functional subtypes remain largely unknown. Here, using the strepotozotocin (STZ) rat model of DPNP induced by a STZ injection (60 mg/kg, i.p), and intracellular recordings of action potentials (APs) from DRG neurons in anesthetized rats, we examined electrophysiological changes in C-and Aβ-nociceptive and Aβ-low threshold mechanoreceptive (LTM) neurons that may contribute to DPNP. Compared with control, we found in STZ-rats with established pain hypersensitivity (5 weeks post-STZ) several significant changes including: (a) A 23% increase in the incidence of spontaneous activity (SA) in Aβ-LTMs (but not C-mechanosensitive nociceptors) that may cause dysesthesias/paresthesia suffered by DPNP patients, (b) membrane hyperpolarization and a ∼85% reduction in SA rate in Aβ-LTMs by Kv7 channel activation with retigabine (6 mg/kg, i.v.) suggesting that Kv7/M channels may be involved in mechanisms of SA generation in Aβ-LTMs, (c) decreases in AP duration and in duration and amplitude of afterhyperpolarization (AHP) in C-and/or Aβ-nociceptors. These faster AP and AHP kinetics may lead to repetitive firing and an increase in afferent input to the CNS and thereby contribute to DPNP development, and (d) a decrease in the electrical thresholds of Aβ-nociceptors that may contribute to their sensitization, and thus to the resulting hypersensitivity associated with DPNP.

中文翻译：

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皮肤 Aβ-非伤害性，但不是 C-伤害性，背根神经节神经元在链脲佐菌素大鼠体内疼痛性糖尿病神经病变模型中表现出自发活动

糖尿病周围神经性疼痛 (DPNP) 是糖尿病最具破坏性的并发症。不幸的是，DPNP 的成功治疗仍然是一个挑战，因为它的发病机制仍然难以捉摸。然而，DPNP 被认为部分是由于背根神经节 (DRG) 神经元的异常过度兴奋，但特定功能亚型的相对贡献在很大程度上仍然未知。在这里，使用 STZ 注射（60 mg/kg，ip）诱导的 DPNP 链脲佐菌素（STZ）大鼠模型，以及麻醉大鼠 DRG 神经元的动作电位（AP）的细胞内记录，我们检查了 C-和可能导致 DPNP 的 Aβ 伤害性和 Aβ 低阈值机械感受 (LTM) 神经元。与对照相比，我们在具有确定的疼痛超敏反应（STZ 后 5 周）的 STZ 大鼠中发现了几个显着变化，包括：（a）Aβ-LTM（但不是 C-机械敏感伤害感受器）中自发活动（SA）的发生率增加了 23%可能导致 DPNP 患者的感觉迟钝/感觉异常，(b) 膜超极化和通过使用瑞替加滨 (6 mg/kg, iv) 激活 Kv7 通道使 Aβ-LTMs 中的 SA 率降低约 85%，表明 Kv7/M 通道可能参与 Aβ-LTM 中 SA 生成的机制，(c) 减少 AP 持续时间以及 C 和/或 Aβ-伤害性感受器中后超极化 (AHP) 的持续时间和幅度。这些更快的 AP 和 AHP 动力学可能导致重复发射和中枢神经系统传入输入的增加，从而促进 DPNP 的发展，