title: Antinociceptive effects of a new sigma-1 receptor antagonist (N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamide) in two types of nociception.
abstract: Pain has become an active clinical challenge due its etiological heterogeneity, symptoms and mechanisms of action. In the search for new pharmacological therapeutic alternatives, sigma receptors have been proposed as drug targets. This family consists of sigma-1 and sigma-2 receptors. The sigma-1 system is involved in nociception through its chaperone activity. Additionally, it has been shown that agonist to these receptors promote related sensitisation and pain hypersensitisation, suggesting the possible use of antagonists for sigma-1 receptors as an alternative therapy. The aim of this study was to evaluate the antinociceptive effect of a new sigma-1 receptor antagonist N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamida (NMIN) in two types of pain (arthritic and neuropathic) and to compare its efficacy and potency with reference drugs. The antinociceptive effects of NMIN were quantitatively evaluated using the pain-induced functional impairment model in the rat and the acetone test in a rat model of neuropathic pain. NMIN (sigma-1 receptor affinity of 324nM) did not show any antinociceptive activity in the arthritic pain model but showed a dose-dependent anti-allodynic effect in neuropathic pain. NMIN showed a similar efficacy compared to the effects obtained with morphine and the sigma-1 antagonist BD-1063. However, these reference drugs showed increased potency compared with NMIN. Our results suggest that sigma-1 receptors may play an important direct role in neuropathic pain but not in arthritic pain, supporting the hypothesis that NMIN may be useful for the treatment of neuropathic pain.
authors.affiliation: Maestría en Cs. Farmacéuticas, Div. de CBS, Universidad Autónoma Metropolitana, Unidad Xochimilco, C.P. 04960 Delegación Coyoacán, México D.F., Mexico. Electronic address: qfbetzy@hotmail.com.
authors.forename: Betzabeth Anali
authors.initials: BA
authors.lastname: García-Martínez
authors.affiliation: Departamento de Farmacobiología, Cinvestav-Sede Sur, México, D.F. 14330, Mexico. Electronic address: oajmorales@gmail.com.
authors.forename: Osmar Antonio
authors.initials: OA
authors.lastname: Jaramillo-Morales
authors.affiliation: Departamento de Farmacobiología, Cinvestav-Sede Sur, México, D.F. 14330, Mexico. Electronic address: jvidalespinosa@gmail.com.
authors.forename: Josué Vidal
authors.initials: JV
authors.lastname: Espinosa-Juárez
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209 Mexico. Electronic address: gabriel_navarrete@uaem.mx.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos 62209 Mexico. Electronic address: mhla_ff@uaem.mx.
authors.forename: Luis Alberto
authors.initials: LA
authors.lastname: Melo-Hernández
authors.affiliation: Departamento Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, México, D.F. 04960, Mexico. Electronic address: rmlopez@correo.xoc.uam.mx.
authors.forename: José Raúl
authors.initials: JR
authors.lastname: Medina-López
authors.affiliation: Departamento Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, México, D.F. 04960, Mexico. Electronic address: adoming@correo.xoc.uam.mx.
authors.forename: Adriana Miriam
authors.initials: AM
authors.lastname: Domínguez-Ramírez
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Germany. Electronic address: dirk.schepmann@uni-muenster.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Departamento de Farmacobiología, Cinvestav-Sede Sur, México, D.F. 14330, Mexico. Electronic address: flopez@cinvestav.mx.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: López-Muñoz
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000096:Acetone / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001168:Arthritis / Q000150:complications; D003251:Constriction, Pathologic / Q000150:complications; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology*; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy; D059225:Nociception / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D000081:Acetamides; D000096:Acetone; D000700:Analgesics; D000701:Analgesics, Opioid; D009020:Morphine; D009281:Naphthalenes; D010879:Piperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C000611677:N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamide
keywords: Antagonist sigma-1 receptor; Antinociceptive; Arthritic pain; BD-1063; Morphine; Neuropathic pain