title: Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin.
abstract: We have previously shown that stimulation of peripheral opioid receptors by exogenous opiates counteracts the thermal hyperalgesia elicited by a tibial osteosarcoma due to intraosteal inoculation of NCTC 2472 cells to mice. Aiming to study whether pheripheral endogenous enkephalins could also counteract this painful symptom, we assayed in this model the effects of PL37, an orally active dual inhibitor of enkephalin inactivating enzymes. Oral administration of PL37 (25 mg/kg) completely supressed osteosarcoma-induced thermal hyperalgesia through the activation of micro-opioid receptors, since the administration of cyprodime (1 mg/kg) inhibited its antihyperalgesic effect. Neither naltrindole (0.1 mg/kg) nor nor-binaltorphimine (10 mg/kg) modified this PL37-induced antihyperalgesic effect. Moreover, the inhibition of the antihyperalgesic effect induced by PL37 after the administration of naloxone-methiodide (2 mg/kg), a non selective opioid antagonist that does not cross the blood-brain barrier, demonstrates the involvement of peripheral opioid receptors. In contrast, centrally mediated effects may be detected when assaying a higher dose of PL37 (50 mg/kg). Besides, the administration of gabapentin (6.25-25 mg/kg, i.p.) dose-dependently inhibited osteosarcoma-induced thermal hyperalgesia. Interestingly, the combined administration of subeffective doses of PL37 and gabapentin completely prevented this type of thermal hyperalgesia. An isobolographic analysis of this interaction demonstrated a synergistic interaction between both drugs.
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, c/ Julián Clavería 6, Oviedo, Asturias, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Alvaro
authors.initials: A
authors.lastname: Meana
authors.forename: Hervé
authors.initials: H
authors.lastname: Poras
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000503:physiopathology*; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004220:Disulfides / Q000627:therapeutic use*; D004357:Drug Synergism; D000077206:Gabapentin; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012516:Osteosarcoma / Q000150:complications / Q000503:physiopathology*; D011437:Propylamines / Q000627:therapeutic use*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: C534222:1-(2-((1-ethoxycarbonyloxyethoxycarbonylmethyl)carbamoyl)-3-phenylpropyldisulfanylmethyl)-3-methylsulfanylpropylamine; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D004220:Disulfides; D011437:Propylamines; D000644:Quaternary Ammonium Compounds; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C041269:N-methylnaloxone; D015260:Neprilysin