Atividade da metformina em modelos experimentais de dor neuropática e possíveis mecanismos de ação.

Abstract

Neuropathic pain is due to nervous system injury or dysfunction and, more broadly, a consequence of somesthetic system injury or disease. Neuropathic pain is a debilitating chronic pain modality that has a significant impact on the patient's quality of life. The limitations of currently available analgesic pharmacotherapy have stimulated research aimed at repositioning drugs from different therapeutic classes. In this context, metformin, an oral hypoglycemic agent, has shown promising results in a previous study by our research group, exhibiting activity in nociceptive and inflammatory pain models. In the same study, it was shown that the antinociceptive activity of metformin is related to the activation of opioidergic and serotoninergic pathways, activation of ATP-dependent potassium channels and inhibition of the proinflammatory cytokines production. Thus, in the present study, we investigated the activity of metformin, at doses of 250, 500 or 1000 mg/kg, per os (p.o.) in models of neuropathic pain induced by intraperitoneal (i.p.) administration of paclitaxel (2 mg/kg, four administrations every other day) or by medial plantar nerve ligation (MPNL). Metformin significantly reduced mechanical allodynia when administered twice, at an interval of 2 h, on the seventh day after the first paclitaxel injection or MPNL. To investigate potential mechanisms mediating metformin's antinociceptive activity, opioidergic (naltrexone 5 or 10 mg/kg, i.p.) and ATP-dependent potassium channel (glibenclamide 20 or 40 mg/kg, p.o.) antagonists were used. The effect induced by metformin on the concentration of inflammatory cytokines in dorsal root ganglia (DRG) and thalamus was also evaluated. Analysis of the expression of mir-500, miR-7a and miR-125b-5p in the thalamus was also performed. The antinociceptive effect induced by metformin was only attenuated by naltrexone in the model of neuropathic pain induced by paclitaxel. Metformin administration reduced tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and CXCL-1 concentrations in DRGs in paclitaxel- or MPNL-induced neuropathic pain models. Additionally, metformin reduced concentrations of TNF-α (MPNL model) and IL-6 (MPNL and paclitaxel models) in the thalamus. Metformin was not able to reverse the expression of any miRNA in the thalamus in both models. The results demonstrate that the antinociceptive activity of metformin seems to be mediated by the activation of opioidergic receptors in paclitaxel-induced neuropathic pain model and may be related to reduced production of inflammatory cytokines in the DRG and thalamus in both models. Thus, metformin may represent an important alternative in the pharmacotherapy of patients with neuropathic pain and the results may stimulate further preclinical and clinical trials to investigate the potential use of this drug as an analgesic.