Impact of Efficacy at the m-Opioid Receptor on Antinociceptive Effects of Combinations of m-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

Cannabinoid receptor agonists, such as D-tetrahydrocannabinol (D-THC), enhance the antinociceptive effects of m-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associatedwith large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of m-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n 5 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, D-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of D-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4and 19.6-fold, respectively. D-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4and 7.9-fold, respectively, and the buprenorphine curve only 5.4and 4.1-fold, respectively. Neither D-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.