Phosphorylation of extracellular signal-regulated kinase 1/2 in subepidermal nerve fibers mediates hyperalgesia following diabetic peripheral neuropathy

Abstract

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.

Keywords: Extracellular signal-regulated kinase 1/2; Hypersensitivity; Neuropeptides; Streptozotocin; Subepidermal nerve fibers; Transient receptor potential vanilloid channels..