Dermorphin blocks apneic response to intravenous bolus injection of fentanyl

Sudden death induced by intravenous bolus (IVb) injection of overdose fentanyl is the major cause of overdose opioid-induced deaths; however, the relevant countermeasure is lacking. IVb injection of overdose 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 if dermorphin pretreatment would prevent/blunt the fentanyl-induced apnea.

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-h period) and (3) the effects of dermorphin pretreatment on the fentanyl-induced apnea and fentanyl pretreatment on dermorphin-induced response.

IVb injection of dermorphin triggered an immediate apnea followed by a brief bradypnea, depending on activating μ₁-ORs. Although dermorphin and fentanyl both elicited a similar immediate apnea, the recovery of respiratory response was much faster in the former than the latter (0.5 min vs. 30 min). Importantly, the apneic response was triggered only by the first dermorphin injection, but always evoked by the three trials of fentanyl injections. Dermorphin pretreatment blocked fentanyl-induced apnea, while fentanyl pretreatment failed to affect the dermorphin-induced apnea.

Our results suggest that dermorphin pretreatment is able to block fentanyl-induced apnea likely via desensitization of μ₁-ORs in vagal afferents and/or their pathways. This pretreatment may be a potential therapeutic intervention in fentanyl abusers to prevent and minimize the fentanyl-induced apnea.