Synergistic antinociceptive actions and tolerance development produced by morphine-fentanyl coadministration: correlation with μ-opioid receptor internalization

Eur J Pharmacol. 2012 Jan 15;674(2-3):239-47. doi: 10.1016/j.ejphar.2011.10.034. Epub 2011 Oct 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology
  • Animals
  • Arrestins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Drug Tolerance*
  • Endocytosis / drug effects*
  • Fentanyl / administration & dosage*
  • Fentanyl / pharmacology*
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism
  • Male
  • Morphine / administration & dosage*
  • Morphine / pharmacology*
  • Nociception / drug effects
  • Periaqueductal Gray / drug effects
  • Periaqueductal Gray / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism*
  • beta-Arrestin 2
  • beta-Arrestins


  • Analgesics, Opioid
  • Arrb2 protein, rat
  • Arrestins
  • Receptors, Opioid, mu
  • beta-Arrestin 2
  • beta-Arrestins
  • Morphine
  • Fentanyl