Isobutyric tropine ester (Ibutropin) overcomes fentanyl-induced respiratory depression in unanesthetized rats without compromising analgesia

We are examining the pharmacological profile of tropine and tropine analogues on opioid-induced respiratory depression (OIRD). We report here the effects of Ibutropin (isobutyric tropine ester, tropine isobutyrate) on changes in ventilatory parameters, Alveolar-arterial (A-a) gradient (index of alveolar gas-exchange), arterial blood-gas (ABG) chemistry (pH, pCO₂, pO₂, sO₂), sedation (righting reflex), and antinociception (tail-flick latency) in freely-moving male Sprague Dawley rats elicited by prior injection of fentanyl. The injection of fentanyl (75 μg/kg, IV) produced (a) substantial decreases in frequency of breathing, tidal volume and minute ventilation, and changes in other ventilatory parameters, and (b) increases in A-a gradient (i.e., mismatch in alveolar ventilation-perfusion) that were accompanied by decreases in arterial blood pH, pO₂ and sO₂, and increases in pCO₂, responses consistent with reduced ventilatory drive. An injection of Ibutropin (200 μmol/kg, IV) given 5 min after fentanyl (75 μg/kg, IV) elicited an immediate and sustained reversal of the adverse effects of fentanyl on recorded ventilatory parameters, A-a gradient and ABG chemistry. Additionally, Ibutropin reduced the sedative, but not analgesic, actions of fentanyl. These findings show that Ibutropin has the profile to be advantageous for development as an agent to reverse OIRD. Since previous research has shown that tropine itself contrarily worsens the deleterious actions of fentanyl, we conclude that the positive actions of Ibutropin arise from its ability as an ester to readily enter cells and interrupt the events elicited by fentanyl in ventilatory control pathways, but not those driving the analgesic actions of fentanyl. Therefore, these findings reveal that Ibutropin has the profile to be advantageous for development as an agent to reverse OIRD.