The ability of Ibutropin to blunt fentanyl-induced respiratory depression is independent of its activation of carotid body chemoafferents

This study examined the effects of intravenous injection of isobutyric tropine ester (Ibutropin) on ventilation in freely-moving sham-operated (SHAM) male Sprague Dawley rats and those with bilateral carotid sinus nerve transection (CSNX). This study also examined the effects of a subsequent injection of fentanyl on ventilatory parameters in both groups of rats. Ibutropin (200 μmol/kg, i.v.) elicited rapid and pronounced increases in breathing frequency, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives in SHAM rats, but substantially smaller responses in CSNX rats. The subsequent injection of fentanyl (75 μg/kg, i.v.) elicited similar ventilatory responses in Ibutropin-treated SHAM and CSNX rats with markedly different changes in end-inspiratory and end-expiratory pauses, expiratory delay, and apneic pause. Moreover, the fentanyl-induced responses in Ibutropin-treated SHAM and CSNX rats were substantially smaller than in rats that were pre-injected with vehicle (saline) rather than Ibutropin. These novel findings suggest that Ibutropin acts at the carotid body-chemoafferent complex to drive ventilation by mechanisms that may involve the rapid entry of this cell-permeant tropine ester into chemoafferent nerve terminals and/or primary glomus cells. A key finding was that the ability of Ibutropin to blunt the adverse effects of fentanyl on breathing does not require functional carotid body chemoreceptor afferent input to brainstem structures controlling breathing. As such, the ability of Ibutropin to greatly diminish the adverse effects of fentanyl on breathing may involve the actions of Ibutropin within central respiratory control centers and/or peripheral structures other than the carotid bodies. SIGNIFICANCE STATEMENT: This study revealed that the ability of Ibutropin to blunt the respiratory depressant effects of fentanyl may involve mechanisms present in central respiratory control centers and/or peripheral structures other than the carotid bodies.