Figure 4.
Nitazenes are potent analgesics but produce potent respiratory depression that is longer-lasting than fentanyl
(A) Tail-flick analgesia assay dose-response relationships, measured as the mean percentage of the maximum possible effect per dose, are shown for isotonitazene (black), N-desethyl isotonitazene (green), fentanyl (blue), and metonitazene (brown). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001, significant difference vs. vehicle control. Dunnett’s T3 test was used for all compounds except fentanyl, which used Dunn’s test.
(B) The dose response relationship between drug concentration and mean respiratory rate as measured by the phrenic nerve activity assay are shown for N-desethyl isotonitazene (red, n = 6) and fentanyl (blue, n = 4). Error bars represent ±SEM for each compound.
(C) Respiratory depression measured as respiratory rate (bpm, breaths per minute) in percent of baseline respiratory rate after a single dose (1 μg/kg) of either fentanyl (blue, n = 3) or N-desethyl isotonitazene (red, n = 6). Error bars are ±SEM.
(D) The time to recovery of baseline respiratory rate after an apnea inducing dosage of either fentanyl (blue, 9.0 ± 0.5 μg/kg, n = 4) or N-desethyl isotonitazene (red, 3.5 ± 0.3 μg/kg, n = 6) is shown. Error bars are ±SEM.
(E) Example of the respiratory rate response to a 3 μg/kg bolus of N-desethyl isotonitazene. Pictured is the respiratory rate at each respiratory cycle. The “apneic dose” had been determined for the animal with titration earlier in the experiment (see B), and complete recovery of respiratory rate was accomplished (see D). After bolus injection, respiratory rate decreased over ∼3 min until complete apnea. After confirming apnea for 5 min, IV naloxone (20 μg/kg) was administered. Thirty seconds after IV injection, phrenic nerve activity restarted, and respiratory rate reached steady-state recovery after ∼3 min. Naloxone frequently increases respiratory rate above pre-opioid baseline, which likely indicates reversal of endogenous opioid activity in our preparation as previously described.35
(F) Pooled data for the recovery of respiratory rate from N-desethyl isotonitazene-induced apnea after IV naloxone injection (20 μg/kg, n = 6). Error bars are ±SEM.
Relates to Figure S4.