Delta-opioid receptor antagonist naltrindole reduces oxycodone addiction and constipation in mice

Eur J Pharmacol. 2019 Jun 5;852:265-273. doi: 10.1016/j.ejphar.2019.04.009. Epub 2019 Apr 6.


Oxycodone, a widely prescribed and very potent oral opioid analgesic agent, is highly addictive and has many side effects, including troublesome constipation. Our studies in mice indicated that pretreatment of naltrindole did not significantly affect the analgesic efficacy of oxycodone but attenuated the tolerance and withdrawal induced by chronic oxycodone administration. Naltrindole also attenuated the oxycodone-induced rewarding and re-instatement behaviors, as shown by the conditioned place preference test. Further, oxycodone-induced decrease in intestinal transit (i.e., constipation) was reduced by naltrindole. However, naltrindole did not block the respiratory depression produced by oxycodone. Taken together, these data suggest that naltrindole can attenuate some major side effects while retaining the analgesic efficacy of oxycodone in mice. Naltrindole and oxycodone may have the potential to be a potent analgesic combination with much lower levels of oxycodone's side effects of addictive liability and constipation.

Keywords: Conditioned place preference; Delta-opioid receptor; Dependence; Naltrindole; Oxycodone; Tolerance.

MeSH terms

  • Analgesics / adverse effects
  • Animals
  • Constipation / chemically induced
  • Constipation / drug therapy*
  • Drug Tolerance
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Naltrexone / analogs & derivatives*
  • Naltrexone / pharmacology
  • Naltrexone / therapeutic use
  • Narcotic Antagonists / pharmacology*
  • Narcotic Antagonists / therapeutic use
  • Opioid-Related Disorders / complications
  • Opioid-Related Disorders / drug therapy*
  • Opioid-Related Disorders / etiology
  • Oxycodone / adverse effects*
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Respiratory Insufficiency / complications


  • Analgesics
  • Narcotic Antagonists
  • Receptors, Opioid, delta
  • Naltrexone
  • Oxycodone
  • naltrindole