title: Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  E-52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat.
  
  
  
  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.
authors.affiliation: Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada CSIC-IQM, Alcorcón, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Paniagua
authors.affiliation: Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada CSIC-IQM, Alcorcón, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Girón
authors.affiliation: Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada CSIC-IQM, Alcorcón, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Goicoechea
authors.affiliation: Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada CSIC-IQM, Alcorcón, Spain.
authors.forename: V
authors.initials: V
authors.lastname: López-Miranda
authors.affiliation: Drug Discovery & Preclinical Research, Esteve, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Vela
authors.affiliation: Drug Discovery & Preclinical Research, Esteve, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Merlos
authors.affiliation: Farmacología y Nutrición, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Unidad Asociada CSIC-IQM, Alcorcón, Spain.
authors.forename: M I
authors.initials: MI
authors.lastname: Martín Fontelles
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003929:Diabetic Neuropathies / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009437:Neuralgia / Q000209:etiology / Q000517:prevention & control*; D017288:Pain Threshold / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D009025:Morpholines; D011720:Pyrazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine