Peripheral neuropathy, a chronic complication of diabetes mellitus (DM), is often accompanied by the onset of severe pain symptoms that affect quality of life. However, the underlying mechanisms remain elusive. In the present study, we used Sprague-Dawley rats to establish a rodent model of the human type 1 DM by a single intraperitoneal (i.p.) injection with streptozotocin (STZ) (60 mg/kg). Hypersensitivity, including hyperalgesia and allodynia, developed in the STZ-induced diabetic rats. Cutaneous innervation exhibited STZ-induced reductions of protein gene product 9.5-, peripherin-, and neurofilament 200-immunoreactivity (IR) subepidermal nerve fibers (SENFs). Moreover, the decreases of substance P (SP)- and calcitonin gene-related peptide (CGRP)-IR SENFs were distinct gathered from the results of extracellular signal-regulated kinase 1 and 2 (ERK1/2)- and phosphorylated ERK1/2 (pERK1/2)-IR SENFs in STZ-induced diabetic rats. Double immunofluorescence studies demonstrated that STZ-induced pERK1/2-IR was largely increased in SENFs where only a small portion was colocalized with SP- or CGRP-IR. By an intraplantar (i. pl.) injection with a MEK inhibitor, U0126 (1,4-Diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), hyperalgesia was attenuated in a dose-responsive manner. Botulinum toxin serotype A had dose-dependent analgesic effects on STZ-induced hyperalgesia and allodynia, which exhibited equivalent results as the efficacy of transient receptor potential vanilloid (TRPV) channel antagonists. Morphological evidence further confirmed that STZ-induced SP-, CGRP- and pERK1/2-IR were reduced in SENFs after pharmacological interventions. From the results obtained in this study, it is suggested that increases of pERK1/2 in SENFs may participate in the modulation of TRPV channel-mediated neurogenic inflammation that triggers hyperalgesia in STZ-induced diabetic rats. Therefore, ERK1/2 provides a potential therapeutic target and efficient pharmacological strategies to address hyperglycemia-induced neurotoxicity.

中文翻译：

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糖尿病周围神经病变后，表皮下神经纤维中细胞外信号调节激酶1/2的磷酸化介导痛觉过敏。

周围神经病变是糖尿病（DM）的慢性并发症，通常伴有影响生活质量的严重疼痛症状的发作。但是，基本机制仍然难以捉摸。在本研究中，我们使用Sprague-Dawley大鼠通过单次腹膜内（ip）注射链脲佐菌素（STZ）（60 mg / kg）建立人1型DM的啮齿动物模型。在STZ诱导的糖尿病大鼠中出现了超敏反应，包括痛觉过敏和异常性疼痛。皮肤神经支配表现出STZ诱导的蛋白基因产物9.5-，外周蛋白-和神经丝200-免疫反应性（IR）表皮下神经纤维（SENFs）减少。而且，物质P（SP）和降钙素基因相关肽（CGRP）-IR SENF的减少与细胞外信号调节激酶1和2（ERK1 / 2）-和磷酸化ERK1 / 2（pERK1 / 2）-STZ诱导的糖尿病大鼠中的IR SENFs。双重免疫荧光研究表明，在SENF中，STZ诱导的pERK1 / 2-IR大大增加，其中只有一小部分与SP-或CGRP-IR共定位。通过足底内（i。pl。）注射MEK抑制剂U0126（1,4-二氨基-2,3-二氰基-1,4-双[2-氨基苯硫基]丁二烯），痛觉过敏在剂量反应性中减弱。方式。肉毒杆菌毒素血清型A对STZ诱导的痛觉过敏和异常性疼痛具有剂量依赖性镇痛作用，其表现与瞬态受体电位类香草酸（TRPV）通道拮抗剂的功效相当。形态学证据进一步证实，通过药物干预后，STZ诱导的SP-，CGRP-和pERK1 / 2-IR在SENF中降低。从这项研究中获得的结果，表明SENF中pERK1 / 2的增加可能参与了TRPV通道介导的神经源性炎症的调节，该炎症触发了STZ诱导的糖尿病大鼠的痛觉过敏。因此，ERK1 / 2提供了潜在的治疗目标和有效的药理策略，以解决高血糖引起的神经毒性。提示SENF中pERK1 / 2的增加可能参与了TRPV通道介导的神经源性炎症的调节，该炎症触发了STZ诱导的糖尿病大鼠的痛觉过敏。因此，ERK1 / 2提供了潜在的治疗目标和有效的药理策略，以解决高血糖引起的神经毒性。提示SENF中pERK1 / 2的增加可能参与了TRPV通道介导的神经源性炎症的调节，该炎症触发了STZ诱导的糖尿病大鼠的痛觉过敏。因此，ERK1 / 2提供了潜在的治疗目标和有效的药理策略，以解决高血糖引起的神经毒性。