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

Abstract

BackgroundE‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl]‐morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.MethodsMechanical 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.ResultsZucker 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.ConclusionsE‐52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat.SignificanceBlockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients.What does this study add? This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats.The methodology includes behavioural evidences, electrophysiological data and vascular‐isolated models.

May a sigma‐1 antagonist improve neuropathic signs induced by cisplatin and vincristine in rats?

“…There are few studies showing the vascular effects of the σ1R modulation (Hosszu et al., ; Tagashira et al., ), although some recent studies showed σ1R expression in vascular tissue (Amer et al., ; Bhuiyan, Tagashira, Shioda, & Fukunaga, ). The repeated administration of MR‐309 was able to correct both the increase in coronary perfusion pressure and endothelial dysfunction in the aorta, which agree with our previous recordings in diabetic rats, demonstrating that MR‐309 treatment can improve vascular parameters (Paniagua et al., ).…”

“…It shows efficacy in nociceptive as well as neuropathic pain models. MR-309 demonstrated the antinociceptive effect of the σ1R blockade mainly develop for peripheral sensitization pain models, such as in capsaicin sensitization (Entrena et al, 2009), partial sciatic nerve ligation (Romero et al, 2012) and diabetic neuropathy (Paniagua et al, 2017).…”

Investigational sigma-1 receptor antagonists for the treatment of pain

“…E-52862 has demonstrated efficacy in translationally driven neuropathic pain models, that is, chemotherapy-induced neuropathy [37] and diabetes-induced neuropathy [108]. E-52862 reduced dose-dependently both the development and the expression of cold and mechanical allodynia in paclitaxel-treated mice, in accordance with the results obtained in s 1 R KO mice, which did not develop paclitaxel-induced neuropathy [37].…”

“…Similarly, single or repeated-dose administration of E-52862 reduced both mechanical allodynia and thermal hyperalgesia developed in Zucker Diabetic Fatty rats. At the electrophysiology level, diabetic rats treated with E-52862 showed a lower response to ramp or supra-threshold step mechanical stimulation compared to rats receiving vehicle in the skin-saphenous nerve preparation [108]. In an operant self-administration model, mice with partial sciatic nerve ligation, but not sham-operated animals, self-administered E-52862 to relieve pain.…”

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…administration of 101 demonstrated its dose‐dependent antinociceptive effect, without inducing motor impairment at these doses. Further studies emphasize the analgesic activity of 101 in neuropathic pain of different etiology, in rats …”