Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED₅₀ values for hypoventilation showed a rank order of potency as follows: fentanyl (ED₅₀ = 0.96 mg/kg) > 3-furanylfentanyl (ED₅₀ = 2.60 mg/kg) > crotonylfentanyl (ED₅₀ = 2.72 mg/kg) > para-methoxyfentanyl (ED₅₀ = 3.31 mg/kg) > buprenorphine (ED₅₀ = 10.8 mg/kg) > isobutyrylfentanyl (ED₅₀ = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED₅₀ = 16.1 mg/kg) > thiophenefentanyl (ED₅₀ = 18.0 mg/kg) > morphine (ED₅₀ = 55.3 mg/kg) > benzodioxolefentanyl (ED₅₀ = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.