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Título: | Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats |
Autor: | Paniagua, N.; Girón, Rocío CSIC ORCID; Goicoechea, C.; López-Miranda, V.; Vela, J. M.; Merlos, M.; Martín, M. Isabel CSIC | Fecha de publicación: | 2017 | Editor: | John Wiley & Sons | Citación: | European Journal of Pain (United Kingdom) 21: 61-72 (2017) | Resumen: | Background: E-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. 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 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. | Versión del editor: | http://dx.doi.org/10.1002/ejp.897 | URI: | http://hdl.handle.net/10261/162688 | DOI: | 10.1002/ejp.897 | Identificadores: | doi: 10.1002/ejp.897 issn: 1090-3801 e-issn: 1532-2149 |
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