title: Synergistic antinociceptive actions and tolerance development produced by morphine-fentanyl coadministration: correlation with μ-opioid receptor internalization.
abstract: It has been described that coadministration of opioids with low doses of other analgesics can reduce adverse effects and increase antinociception, but combinations of two μ-opioid receptor agonists have been poorly explored. The objective of this work was threefold: 1) to evaluate the antinociceptive combination of i.c.v. morphine and fentanyl at different doses; 2) to compare the antinociception produced by acute or repeated administration of an effective morphine dose (1 μg) alone, or combined with a low fentanyl dose (1 ng); and 3) to correlate these effects with μ-opioid receptor internalization in periaqueductal gray matter and locus coeruleus. Antinociception was evaluated by the tail-flick test and receptor internalization was analyzed by confocal microscopy in Wistar rats. Drug interactions were examined by administering combinations of opioids in 1:3, 1:1 and 3:1 ratios of their respective ED(50) fractions. For tolerance and internalization studies, animals were i.c.v. injected only once (acute treatment) or twice a day until five administrations were completed. Our results show that morphine and fentanyl have synergistic effects. The combination of 1 ng fentanyl with 1 μg morphine increases the magnitude and duration of antinociception not only after a single injection, but also after five administrations when tolerance develops to morphine alone. Increased and long-lasting antinociception correlates positively with increased β-arrestin 2 activity and μ-opioid receptor internalization in periaqueductal gray matter and locus coeruleus. These results suggest that combined administration of morphine and fentanyl increases long-lasting antinociception and β-arrestin 2 signaling contributes to the combination effects.
authors.affiliation: Departamento de Farmacobiología, Cinvestav, Sede Sur. Calzada de Tenorios # 235, Col. Granjas Coapa, México DF, 14330, México.
authors.forename: Arturo
authors.initials: A
authors.lastname: Silva-Moreno
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzalez-Espinosa
authors.forename: Martha
authors.initials: M
authors.lastname: León-Olea
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Cruz
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D004705:Endocytosis / Q000187:drug effects*; D005283:Fentanyl / Q000008:administration & dosage* / Q000494:pharmacology*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; C000605257:Arrb2 protein, rat; D019390:Arrestins; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D009020:Morphine; D005283:Fentanyl