Manuel Merlos

Publications (106) View all

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

  L. Romero, D. Zamanillo, X. Nadal, R. Sanchez-Arroyos, I. Rivera-Arconada, A. Dordal, A. Montero, A. Muro, A. Bura, C. Segales, [......], X. Codony, G. Encina, J. Burgueno, M. Merlos, J.M. Baeyens, J. Giraldo, J.A. Lopez-Garcia, R. Maldonado, C.R. Plata-Salaman, J.M. Vela
  [show abstract] [hide abstract]
  ABSTRACT: BACKGROUND AND PURPOSE: The sigma-1 (sigma(1) ) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of sigma(1) receptor ligands used as pharmacological tools are unclear and the demonstration that sigma(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing. EXPERIMENTAL APPROACH: The pharmacological properties of a novel sigma(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of sigma(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for sigma(1) receptor occupancy were measured to substantiate behavioural data. KEY RESULTS: Formalin-induced nociception (both phases), ca
  Br.J Pharmacol. 08/2012; 166(8):2289-2306.
• Article: Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.

  L Romero, D Zamanillo, X Nadal, R Sánchez-Arroyos, I Rivera-Arconada, A Dordal, A Montero, A Muro, A Bura, C Segalés, [......], X Codony, G Encina, J Burgueño, M Merlos, J M Baeyens, J Giraldo, J A López-García, R Maldonado, C R Plata-Salamán, J M Vela
  [show abstract] [hide abstract]
  ABSTRACT: The sigma-1 (σ(1) ) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ(1) receptor ligands used as pharmacological tools are unclear and the demonstration that σ(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing. The pharmacological properties of a novel σ(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ(1) receptor occupancy were measured to substantiate behavioural data. Formalin-induced nociception (both phases), capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity were dose-dependently inhibited by systemic administration of S1RA. Occupancy of σ(1) receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve-injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ(1) receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation. 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.
  British Journal of Pharmacology 03/2012; 166(8):2289-306. · 4.41 Impact Factor
• Article: The intestinal anti-inflammatory effect of dersalazine sodium is related to a down-regulation in IL-17 production in experimental models of rodent colitis.

  D Camuesco, M E Rodríguez-Cabezas, N Garrido-Mesa, M Cueto-Sola, E Bailón, M Comalada, B Arribas, M Merlos, D Balsa, A Zarzuelo, G Janer, J Xaus, J Román, J Gálvez
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  ABSTRACT: Dersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR-12715) with 5-aminosalicylic acid (5-ASA). DS has been demonstrated to have anti-inflammatory effects on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to further characterize the anti-inflammatory effects of DS. Effect of DS (10 or 30 mg·kg(-1) b.i.d.) on TNBS-induced colitis in rats was studied after 2 and 7 days with special focus on inflammatory mediators. Additionally, its anti-inflammatory properties were analysed in two different models of dextran sodium sulphate (DSS)-induced colitis, BALB/c and C57BL/6 mice, the latter being dependent on IL-17. DS, when administered for 7 days, showed intestinal anti-inflammatory effects in TNBS-induced colitis; these effects were observed both macroscopically and through the profile of inflammatory mediators (TNF, IL-1β, IL-6 and IL-17). Although the 2 day treatment with DS did not induce intestinal anti-inflammatory effects, it was sufficient to reduce the enhanced IL-17 expression. DS showed beneficial effects on DSS-induced colitis in C57BL/6 mice and reduced colonic pro-inflammatory cytokines IL-1β, IL-6 and IL-17. In contrast, it did not exert intestinal anti-inflammatory effects on DSS-induced colitis in BALB/c mice. DS exerts intestinal anti-inflammatory activity in different rodent models of colitis through down-regulation of IL-17 expression.
  British Journal of Pharmacology 07/2011; 165(3):729-40. · 4.41 Impact Factor
• Source

  Available from: Caridad Pontes

  Conference Proceeding: Biomarker-guided design to test clinical Proof of Concept in allergic respiratory diseases of UR-63325, a new H4R antagonist

  R Vives, J Peña, J Alfón, C Salcedo, J Rios, C Pontes, M Merlos
  European Respiratory Society (ESR) annual congress, Barcelona, Spain; 09/2010
• Conference Proceeding: First into Man administration of UR-63325, a new H4R antagonist for the treatment of allergic respiratory diseases.

  R Vives, J Cebrecos, J Huguet, J Peña, J Alfón, A Fernández, C Salcedo, J Rios, C Pontes, M Merlos
  29th European Academy of Allergy and Clinical Immunology (EAACI) Congress; 06/2010