Pharmacological activation of Sig-1R ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the Akt/GSK-3β/NF-κB pathway

Abstract

Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus (DM) and is characterized by spontaneous pain and neuroinflammation. The Sigma-1 receptor (Sig-1R) has been proposed as a target for analgesic development. It has anti-inflammatory properties and has been found to regulate DNP. However, it is not known whether Sig-1R can ameliorate pathological neuroinflammation in DNP. The present study used a rat model of DNP and a highly selective agonist of Sig-1R to assess the effects of the protein on neuropathic pain in rats with type 2 diabetes mellitus. The rats were divided into Control, Model, PRE-084 (0.3 mg/kg), PRE-084 (0.6 mg/kg), PRE-084 (1 mg/kg), and metformin (Met, 20 mg/kg) groups, with seven rats per group, and their body weight, fasting blood glucose, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were tested weekly for two weeks. After treatment with PRE-084, the pain thresholds in the DNP rats were significantly improved, together with pathological changes in the dorsal root ganglion, reductions in the serum levels of TNF-α, IL-1β, IL-6, MOD, and prostaglandin E2, and the activity of superoxide dismutase was increased. The mRNA levels of TNF-α, IL-1β, and cyclooxygenase 2 were reduced. Pharmacological inhibition of Sig-1R with BD1047 (10 µM) abolished Sig-1R-mediated activation of lipopolysaccharide-treated BV-2 microglial cells. It was also found that PRE-084 increased phosphorylation of serine/threonine protein kinase B (Akt) and glycogen synthase kinase 3β (GSK3β) at Ser9, inhibiting nuclear factor kappa B(NF-κB)-mediated neuroinflammation in the dorsal root ganglion, thus reducing DNP. The findings suggest that the effect of Sig-1R agonist PRE-084 on DNP may be to reduce the level of inflammation by downregulating Akt/GSK-3β/NF-κB signaling, thereby contributing to the treatment of the disease.