Pharmacological characterization of the new selective sigma-1 receptor (σ 1 R) antagonist S1RA for the treatment of neuropathic pain

M Merlos1, R Sanchez-Arroyos1, E Portillo-Salido1, L Romero1, A Muro1, J Burgueño1, R Maldonado2, JM Baeyens3, D Zamanillo1, JM Vela1. 1ESTEVE, Department of Pharmacology, 08041 Barcelona, Spain, 2Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Laboratory of Neuropharmacology, 08003 Barcelona, Spain, 3Faculty of Medicine, University of Granada, Department of Pharmacology and Institute of Neurosciences, 18012 Granada, Spain

We have previously reported a reduction of neuropathic pain behaviours and activity-induced spinal sensitization in the sigma-1 receptor (σ1R) knockout mice. These findings identify σ1R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to σ1R as a new target for alleviating neuropathic pain. We have developed a selective σ1R antagonist (S1RA) that mimics in wild-type mice the phenotype reported in σ1R knockout mice. We describe here the main pharmacological in vitro and in vivo properties of S1RA. S1RA (4-[2-[[5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl]oxy]ethyl] morpholine) is a high affinity (Ki = 17 nM), selective σ1R antagonist that reduced pain behaviour when administered systemically to wild-type male CD-1 mice exposed to chemical sensitization of pain pathways (intraplantar injection of 2.5% formalin in 20 µL saline or 1 µg capsaicin in 20 µL 1% DMSO, according to Cendan et al., 2005 and Entrena et al., 2009). ED50 values were 44, 40, and 26 mg/kg i.p. for phase I and II of formalin (licking/biting time) and capsaicin (mechanical allodynia), respectively. S1RA administered on days 11-13 post-surgery dose-dependently inhibited neuropathic pain induced by partial sciatic nerve ligation (PSNL), measured as mechanical allodynia or thermal hyperalgesia in the ipsilateral paw (De la Puente et al., 2009). ED50 values were 23 and 19 mg/kg i.p., respectively. No tolerance to the antiallodynic and antihyperalgesic effects was developed following repeated S1RA administration. In addition, ex vivo binding of σ1R occupancy in the CNS was measured as inhibition of [3H](+)-pentazocine binding in brain sections (Romero et al., 2012). Male CD-1 mice received S1RA or vehicle and the ex vivo binding was determined at the same time point (30 min after S1RA administration), route of administration and doses (16, 32, and 64 mg/kg i.p.) used to determine efficacy in the PSNL neuropathic pain model. We found a dose-dependent occupation of σ1Rs in the brain. Sigmoidal dose-response curves obtained from binding and functional assays were submitted to nonlinear regression analysis. Significant correlations (Spearman, p<0.001) were found between the percentages of σ1R occupancy in several brain areas and the antinociceptive effect in the PSNL model. All these results support the use of the new analgesic S1RA for the treatment of neuropathic pain.

Cendán CM, et al. (2005). Formalin-induced pain is reduced in sigma(1) receptor knockout mice. Eur J Pharmacol 511: 73–74.

De la Puente B, et al. (2009). Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain 145: 294–303.

Entrena JM, et al. (2009). Sigma-1 receptors are essential for capsaicin-induced mechanical hyper-sensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice. Pain 143: 252–261.

Romero, L et al. (2012). Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization. Br. J. Pharmacol. Accepted.