• Arturo Silva-Moreno, Claudia Gonzalez-Espinosa, Martha León-Olea, and Silvia L Cruz.
• Departamento de Farmacobiología, Cinvestav, Sede Sur. Calzada de Tenorios # 235, Col. Granjas Coapa, México DF, 14330, México.
• Eur. J. Pharmacol. 2012 Jan 15; 674 (2-3): 239-47.

AbstractIt 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.Copyright © 2011 Elsevier B.V. All rights reserved.

36 keywords...

hide…