title: Synergistic antinociceptive interaction between palmitoylethanolamide and tramadol in the mouse formalin test.
abstract: Pharmacological synergism has been used to obtain a higher efficacy using drug concentrations at which side effects are minimal. In this study, the pharmacological antinociceptive interaction between N-palmitoylethanolamide (PEA) and tramadol was investigated. The individual concentration-response curves for PEA (0.1-56.2 μg/paw) and tramadol (1-56.2 μg/paw) were evaluated in mice in which nociception was induced by an intraplantar injection of 2% formalin. Isobolographic analysis was used to evaluate the pharmacological interaction between PEA (EC50=23.7±1.6 μg/paw) and tramadol (EC50=26.02±2.96 μg/paw) using the EC50 and a fixed 1:1 ratio combination. The isobologram demonstrated that the combinations investigated in this study produced a synergistic interaction; the experimental values (Zexp=9.5±0.2 μg/paw) were significantly smaller than those calculated theoretically (Zadd=24.8±0.2 μg/paw). The antinociceptive mechanisms of the PEA and tramadol combination involved the opioid receptor, transient receptor potential cation channel subfamily V member 1 (TRPV1), and peroxisome proliferator-activated receptor alpha (PPAR-α). The sedative effect of the combination of PEA and tramadol was less than that generated by individual treatments. These findings suggest that the PEA and tramadol combination produced enhanced antinociceptive efficacy at concentrations at which side effects are minimal.
authors: Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, D.F.11340, Mexico.
authors: Myrna
authors: M
authors: Déciga-Campos
authors: Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México, D.F.11340, Mexico.
authors: Pamela Moncerrat
authors: PM
authors: Ramírez-Marín
authors: Departamento de Farmacobiología, Cinvestav-Sede Sur, México, D.F.14330, Mexico. Electronic address: flopez@cinvestav.mx.
authors: Francisco Javier
authors: FJ
authors: López-Muñoz
mesh_terms: D000577:Amides; D000700:Analgesics / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004357:Drug Synergism; D004983:Ethanolamines / Q000008:administration & dosage* / Q000378:metabolism; D005260:Female; D054539:Medication Therapy Management; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010169:Palmitic Acids / Q000008:administration & dosage* / Q000378:metabolism; D014147:Tramadol / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000577:Amides; D000700:Analgesics; D004983:Ethanolamines; D010169:Palmitic Acids; D014147:Tramadol; C005958:palmidrol
keywords: Antinociception; Isobolographic; N-palmitoylethanolamide; Synergism; Tramadol