Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

Background: E-52862 (S1RA, 4-[2-[[5-methyl-1-(2-naphthalenyl)-1Hpyrazol- 3-yl] oxy] ethyl]-morpholine), a novel selective sigma 1 receptor (sigma 1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if sigma 1R blockade with E-52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model. Methods: Mechanical and thermal response thresholds were tested on 7-, 13-, 14-and 15-week-old ZDF rats treated with saline or with E-52862 acutely administered on week 13, followed by sub-chronic administration (14 days). Axonal peripheral activity (skin-saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15-week-old ZDF rats treated with saline or E-52862 and in LEAN rats. Results: Zucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single-dose and sub-chronic E-52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E-52862 treatment increased the mean mechanical threshold (77.3 +/- 21 mN vs. 19.6 +/- 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 +/- 36.5 vs. 352.8 +/- 41.4 spikes) or by repeated mechanical supra-threshold steps (39.4 +/- 1.4 vs. 83.5 +/- 0.9). E-52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed. Conclusions: E-52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat. Significance: Blockade of sigma 1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients.