Pharmacological properties of S1RA, a new sigma‐1 receptor antagonist that inhibits neuropathic pain and activity‐induced spinal sensitization

Romero, Luz; Zamanillo, Daniel; Nadal, Xavier; Sánchez-Arroyos, R.; Rivera-Arconada, Iván; Dordal, Alberto; Montero, Ana; Muro, Anna; Bura, Alessandra; Segalés, C.; Laloya, M.; Hernández, Enrique; Portillo‐Salido, Enrique; Escriche, Marisol; Codony, Xavier; Encina, Gregorio; Burgueño, Javier; Merlos, Manuel; Baeyens, José M.; Giraldo, Jesús; López-García, J.A.; Maldonado, Rafaël; Plata-Salamán, CR; Vela, José Miguel

doi:10.1111/j.1476-5381.2012.01942.x

Cited by 161 publications

(229 citation statements)

References 37 publications

(65 reference statements)

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“…These antinociceptive effects are in good agreement with previous data related to the effect of σ1R antagonists in different animal models such as the sciatic nerve ligation (de la Puente et al., 2009; Romero et al., 2012) or the paclitaxel‐induced neuropathy (Nieto et al., 2012). …”

Section: Discussionmentioning

confidence: 99%

“…To disregard acute effects of the last dose, behavioural tests were carried out 12 h after the last administration (week 15) because E‐52862 maximum plasma concentration is achieved shortly after its administration to rodents ( t max = 15 min after i.p. administration to rats) and it is quickly metabolized, having a short half‐life in rats ( t 1/2 = 1.4 h) (Romero et al., 2012; Vidal‐Torres et al., 2014). …”

Section: Methodsmentioning

confidence: 99%

“…The therapeutic potential of σR ligands includes several diseases (Maurice and Su, 2009; Tsai et al., 2009) and it is known that blocking σ1R induces antinociception (Zamanillo et al., 2013). Moreover, recent studies using σ1R knock‐out mice and pharmacological interventions with selective σ1R antagonists (Romero et al., 2012) showed an antinociceptive effect of σ1R modulation independent of the opioid system. σ1R knock‐out mice showed attenuated nociceptive responses in the formalin test (Cendán et al., 2005), in sciatic nerve injury (de la Puente et al., 2009), in capsaicin sensitization (Entrena et al., 2009) and in antitumoral‐induced cold and mechanical allodynia (Nieto et al., 2012).…”

Section: Introductionmentioning

confidence: 98%

“…Recently, a new drug, E‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl] morpholine), has been characterized as a novel σ1R selective antagonist that shows efficacy in nociceptive as well as in neuropathic pain models (Romero et al., 2012). As σ1R antagonists are effective in several peripheral neuropathy models, including sciatic nerve ligation (de la Puente et al., 2009; Romero et al., 2012) and paclitaxel‐induced neuropathy (Nieto et al., 2012), our aim was to test if the blockade of the σ1R with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a widely accepted model of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…As σ1R antagonists are effective in several peripheral neuropathy models, including sciatic nerve ligation (de la Puente et al., 2009; Romero et al., 2012) and paclitaxel‐induced neuropathy (Nieto et al., 2012), our aim was to test if the blockade of the σ1R with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a widely accepted model of type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

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

Paniagua

Girón

Goicoechea

et al. 2016

European Journal of Pain

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Paniagua

Girón

Goicoechea

et al. 2016

European Journal of Pain

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The 3Ns of Preclinical Animal Models in Biomedical Research

Vela

Maldonado

Hamon

2014

In Vivo Models for Drug Discovery

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Sigma‐1 Receptor Expression in DRG Neurons During a Carrageenan‐Provoked Inflammation

Jerčić

Kostić

Uljević

et al. 2019

The Anatomical Record

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Sigma 1 receptor (σ1R) is a non-opioid receptor that modulates pain perception and is strongly expressed in dorsal root ganglion (DRG) neurons. We studied the changes in the expression of σ1R in different subpopulations of DRG neurons during the first 48 hr in a carrageenaninduced inflammation rat model, with σ1R being a possible base for the development of neuropathic pain after inflammation. Twenty Sprague Dawley rats were divided into five groups (N = 4 in each group): the control (C) group was sacrificed immediately; all other animals received an intraplantar injection of 0.1 mL 2% carrageenan and were sacrificed in 6, 12, 24 or 48 hr after the injection and DRGs were collected and processed for immunohistochemistry. σ1R fluorescence intensity decreased slightly but significantly in up to 24 hr post-carrageenan injection in all subpopulations of DRG neurons (ib4+; ib4− medium, ib4− large and ib4− in total; P < 0.05 -P < 0.001), with the exception of the ib4− small neurons (<25 μm; P > 0.05). This decrement was followed by a subsequent increase in σ1R fluorescence intensity 48 hr after the plantar carrageenan injection (P < 0.05 -P < 0.0001). The same trend was also observed in the CGRP+ population of the DRG neurons, in the total population as well as in the CGRP+ small (<25 μm) and larger CGRP (>25 μm) sub-populations (P < 0.05 -P < 0.001). The presented results may contribute to further understanding of role of σ1R in the development of peripheral sensitization during inflammation. They may also be valuable for the therapeutic application of σ1R antagonists, particularly in the adjustment of the ABBREVIATIONS: CCI = chronic constriction injury; CFA = complete Freund adjuvant; CGRP = calcitonin gene-related peptide; DRG = dorsal root ganglion; ER = endoplasmic reticulum; ib4 = isolectin B4; IP3 = inositol 1,4,5-triphosphate; KO = knockout; PBS = phosphate-buffered saline; SNL = spinal nerve ligation; σ1R = sigma 1 receptor Grant sponsor: Ministarstvo Znanosti, Obrazovanja i Sporta.

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Pharmacological properties of S1RA, a new sigma‐1 receptor antagonist that inhibits neuropathic pain and activity‐induced spinal sensitization

Abstract: These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Cited by 161 publications

References 37 publications

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

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

The 3Ns of Preclinical Animal Models in Biomedical Research

Sigma‐1 Receptor Expression in DRG Neurons During a Carrageenan‐Provoked Inflammation

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