Role of delta opioid efficacy as a determinant of mu/delta opioid interactions in rhesus monkeys

Eur J Pharmacol. 2009 Jan 5;602(1):92-100. doi: 10.1016/j.ejphar.2008.11.004. Epub 2008 Nov 11.


Delta opioid agonists can selectively enhance the antinociceptive effects of mu opioid agonists without enhancing some other, potentially undesirable mu agonist effects. However, the degree of delta receptor efficacy required to produce this profile of interactions is unknown. To address this issue, the present study examined interactions produced by the mu agonist fentanyl and the intermediate-efficacy delta opioid MSF61 in rhesus monkeys. For comparison, interactions were also examined between fentanyl and the relatively high-efficacy delta agonist SNC243A and the delta antagonist naltrindole, which has negligible efficacy at delta receptors. Two different behavioral procedures were used: (a) a warm-water tail-withdrawal assay of thermal nociception, and (b) an assay of schedule-controlled responding for food reinforcement. Drug interactions within each procedure were evaluated using dose-addition analysis to compare experimental results with expected additivity. Drug interactions across procedures were evaluated using dose-ratio analysis to assess relative potencies to produce antinociception vs. response-rate suppression. As expected, dose-addition analysis found that fentanyl/SNC243A interactions were superadditive in the assay of antinociception but additive in the assay of schedule-controlled responding. Conversely, fentanyl/MSF61 interactions were generally additive in both procedures, and fentanyl/naltrindole interactions were additive or subadditive in both procedures. Dose-ratio analysis found that fentanyl alone produced antinociception and rate suppression with similar potencies. Some fentanyl/SNC243A mixtures produced antinociception with up to 4-fold greater potency than rate-suppression. However, fentanyl/MSF61 and fentanyl/naltrindole mixtures produced antinociception with lower potency than rate suppression. These results suggest that relatively high delta receptor efficacy is required for mu/delta antinociceptive synergy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Fentanyl / pharmacology
  • Hot Temperature
  • Ligands
  • Macaca mulatta / metabolism*
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Pain / drug therapy
  • Pain / metabolism
  • Pain Measurement
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / metabolism*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism*


  • Analgesics, Opioid
  • Ligands
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Naltrexone
  • naltrindole
  • Fentanyl