Dermorphin Blocks Apneic Response to Intravenous Bolus Injection of Fentanyl

Background: Sudden death induced by intravenous bolus (IVb) injection of overdose fentanyl is the major cause of opioid-induced deaths; however, the relevant countermeasure without the antagonistic impact on the fentanyl-induced analgesia is lacking. IVb injection of fentanyl in rats triggers a vagal-mediated immediate sustained apnea via acting on mu1 opioid receptor (µ1-OR), which becomes lethal if overdosed. Because dermorphin is a potent analgesic and can promote rapid desensitization of µ-ORs, we tested whether dermorphin affected cardiorespiratory activities and more importantly, whether dermorphin pretreatment would prevent/blunt the fentanyl-induced apnea.Methods: We made three comparisons in anesthetized and spontaneously breathing rats: (1) the cardiorespiratory responses to IVb injection of dermorphin without and with naloxonazine (a µ1-OR antagonist) pretreatment; (2) the reproducibility of the responses to IVb injection of dermorphin and fentanyl (each repeated three times within a 2-hour period); and (3) the effects of dermorphin pretreatment on the fentanyl-induced apnea and fentanyl pretreatment on dermorphin-induced response. Results: Dermorphin administered through IVb injection triggered an immediate apnea followed by a brief bradypnea, which was antagonized by naloxonazine pretreatment. Although both dermorphin and fentanyl elicited a nearly similar immediate apnea, the recovery of respiratory response was much faster in the former than the latter (0.5 min vs. 30 min). Interestingly, the apneic response was triggered only by the first dermorphin injection, but evoked similarly by all three trials of fentanyl injections. While dermorphin pretreatment blocked the fentanyl-induced apnea, fentanyl pretreatment failed to affect the dermorphin-induced apnea. Conclusion: Our results suggest that dermorphin pretreatment is able to block fentanyl-induced apneic response presumably through desensitization of µ1-ORs in vagal afferents and/or their pathways. Supported by HL163512 and DA059063. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.