title: Involvement of enkephalins in the inhibition of osteosarcoma-induced thermal hyperalgesia evoked by the blockade of peripheral P2X3 receptors.
abstract: Although previous studies describe the up-regulation of purinergic P2X(3) receptors expressed at peripheral nociceptive fibers in experimental painful neoplastic processes, the analgesic efficacy of P2X(3) receptor antagonists has not been tested in these settings. We study here the effect of the P2X(3) receptor antagonist, A-317491, on thermal hyperalgesia produced by the intratibial inoculation of NCTC 2472 fibrosarcoma cells to C3H/HeJ mice. The peritumoral administration of A-317491 (10-100 microg) dose-dependently attenuated osteosarcoma-induced thermal hyperalgesia without modifying thermal latencies measured in the contralateral paws. This antihyperalgesic effect was inhibited by the coadministration of naloxone-methiodide (0.1-1 microg) or the systemic injection of the selective mu-opioid receptor antagonist cyprodime (1 mg/kg), demonstrating the involvement of peripheral mu-opioid receptors. Furthermore, the antihyperalgesic effect induced by A-317491, was antagonised by the coadministration of an anti-enkephalin antibody supporting the participation of endogenous enkephalins. Consistent with this result, the antihyperalgesic effect induced by A-317491 was dramatically enhanced by the administration of an enkephalin-degrading inhibitor, Debio 0827, as demonstrated by isobolographic analysis. This synergism opens the theoretical possibility that the combination of both types of drugs could be useful to counteract some nociceptive symptoms derived from tumor development.
authors.affiliation: Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, C/Julián Clavería 6, 33006 Oviedo, Asturias, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: González-Rodríguez
authors.forename: Marta
authors.initials: M
authors.lastname: Pevida
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fournié-Zaluski
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004745:Enkephalins / Q000378:metabolism*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000150:complications* / Q000378:metabolism*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058477:Receptors, Purinergic P2X3
chemical_list: D004745:Enkephalins; C546409:P2rx3 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3