Intravenous bolus injection of fentanyl triggers an immediate central and upper airway obstructive apnea via activating vagal sensory afferents

Intravenous bolus (IVb) injection of fentanyl induces an immediate apnea, but the characteristics of the apnea and relevant mechanism remain unclear. Here, we tested whether IVb injection of fentanyl induced an immediate central and upper airway obstructive apnea associated with chest wall rigidity via activating vagal C-fibers (VCFs) and vagal afferent opioid receptors (ORs). Cardiorespiratory and electromyography of external and internal intercostal, thyroarytenoid, and superior pharyngeal constrictor muscles (EMG_EI, EMG_II, EMG_TA, and EMG_SPC) responses to IVb injection of fentanyl were recorded in anesthetized and spontaneously breathing rats with or without bilateral perivagal capsaicin treatment or intravagal microinjection of naloxone. An immunohistochemical approach was employed to define the presence of opioid mu-receptor (MOR) expression in vagal C-neurons, and a patch clamp technique was utilized to determine the evoked current responses of vagal C-neurons to fentanyl in vitro. Fentanyl induced an immediate apnea and subsequent respiratory depression. The apnea was characterized by cessation of EMG_EI activity and augmentation of tonic discharges of EMG_II, EMG_TA, and EMG_SPC, i.e., central expiratory apnea, laryngeal closure, and pharyngeal constriction/collapse accompanied with chest wall rigidity. The apneic response was abolished by blockade of VCF signal conduction and largely attenuated by antagonism of vagal afferent ORs. The latter significantly alleviated the initial (within 5-min postinjection), but not the latter, respiratory depression. Vagal C-neurons expressed MORs and were activated by fentanyl. We conclude that IVb injection of fentanyl causes a VCF- and vagal afferent OR-mediated immediate central apnea, upper airway obstruction, and chest wall rigidity.<b>NEW & NOTEWORTHY</b> Intravenous bolus injection of fentanyl triggers an immediate apnea, but the nature of apnea and relevant mechanisms remain unknown. Results in this study reveal that this fentanyl injection concurrently triggers an immediate central and upper airway obstructive apnea associated with chest wall rigidity via activating vagal sensory C-fibers.