Potentiation of morphine-induced mechanical antinociception by s1 receptor inhibition: Role of peripheral s1 receptors Sánchez-Fernández, Cristina Nieto López, Francisco Rafael González Cano, Rafael Artacho Cordón, Antonia Romero, Lucía Montilla-García, Ángeles Zamanillo, Daniel Baeyens Cabrera, José Manuel Entrena Fernández, José Manuel Cobos del Moral, Enrique José Supported by FPU grants from the Spanish Ministerio de Educación y Ciencia (MEC), and E. J. Cobos by the Research Program of the University of Granada. This research was done in partial fulfillment of the requirements for the doctoral thesis of C. Sánchez-Fernández. his study was partially supported by the Spanish Ministry of Education and Science (MEC) [grant SAF2006-06122], Junta de Andalucía [grant CTS 109], Laboratorios Esteve, and The Centre for Industrial Technological Development (Spanish Government) [Genius Pharma project]. We studied the modulation of morphine-induced mechanical antinociception and side effects by σ1 receptor inhibition. Both wild-type (WT) and σ1 receptor knockout (σ1-KO) mice showed similar responses to paw pressure (100–600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ1 antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, σ1-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1–16 mg/kg). Similarly, systemic treatment of WT mice with σ1 antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective σ1 agonist PRE-084. Although the local administration of morphine (50–200 μg) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in σ1-KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with σ1 antagonists and the opioid. None of the σ1 antagonists tested enhanced morphine-antinociception in σ1-KO mice, confirming a σ1-mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in σ1-KO mice. These results cannot be explained by a direct interaction of σ1 ligands with μ-opioid receptors or adaptive changes of μ-receptors in σ1-KO mice, given that [3H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the σ1 drugs tested bound to μ-opioid receptors. These results show that σ1 receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level. 2025-01-29T13:25:17Z 2025-01-29T13:25:17Z 2013-07 journal article C. Sánchez-Fernández et al. / Neuropharmacology 70 (2013) 348e358. https://doi.org/10.1016/j.neuropharm.2013.03.002 https://hdl.handle.net/10481/101001 10.1016/j.neuropharm.2013.03.002 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Elsevier