Evaluation of receptor mechanism mediating fentanyl analgesia and toxicity

In the present study the antagonism of fentanyl pharmacodynamics was studied in the mouse and the receptor populations mediating the analgesic and lethal effects of fentanyl were examined. Both 1 and 8 days following implantation (s.c.) of a 15 mg naltrexone pellet there was a significant shift to the right of the fentanyl dose-response curves for analgesia and lethality. The analgesia dose-response curves were shifted significantly more (80- to 264-fold) than the lethality curves (13- to 16-fold) in the presence of naltrexone. In addition, acute naloxone (0.1 mg/kg s.c.), antagonized fentanyl analgesia more than lethality. Consequently, the relative safety ratio of fentanyl (LD50/ED50) was decreased in the presence of opioid antagonists. Pretreatment with naloxonazine (35 mg/kg s.c.) 24 h prior to testing effectively inhibited fentanyl-induced analgesia, but not fentanyl-induced lethality. However, pretreatment with beta-funaltrexamine (beta-FNA) (20 mg/kg, s.c.) 24 h prior to testing inhibited both fentanyl-induced analgesia and lethality. Implantation (s.c.) of a 75 mg morphine pellet for 72 h resulted in cross-tolerance to both fentanyl analgesia and lethality. However, the degree of the cross-tolerance was 1.8-fold for analgesia and 4.5-fold for lethality. Displacement studies of [3H]naltrexone by fentanyl in mouse brain homogenate indicated two populations of binding sites. Taken together, the pharmacodynamic studies and the binding studies suggest that fentanyl exerts its analgesic and lethal effects through different receptor populations.