Roles of Peripheral and Central µ₁-Opioid Receptors in the Fentanyl-Induced Cardiorespiratory Responses

Background: Intravenous bolus (IVb) injection of fentanyl triggers a vagal-mediated immediate apnea and subsequent respiratory depression in anesthetized rats. This study compared the gender-dependence of these responses in conscious rats and roles of peripheral and central opioid receptors (ORs), especially μ- and μ1-ORs in the genesis of these responses. Methods: Cardiorespiratory responses to IVb injection of fentanyl (50 μg kg -1 ) were recorded in male and female conscious rats ( Study I). The same protocols were performed after: naloxone (NLX) and naloxone methiodide (NLM) to systemically and peripherally antagonize ORs respectively ( Study II); CTAP and methylnaltrexone (MNTX) to systemically and peripherally block μ-ORs ( Study III); and naloxonazine (NLZ) to systemically block μ 1 -ORs ( Study IV). Results: IVb injection of fentanyl induced an immediate life-threatening apnea (~1.5 min) and severe bradycardia, which was followed by cardiorespiratory depression lasting for ~55 min with little difference between genders. NLX fully eliminated and CTAP substantially blunted all cardiorespiratory responses to fentanyl, while NLM and MNTX substantially minimized the immediate apnea and reduced bradycardia by ~50% with limited impact on the subsequent cardiorespiratory depression. NLZ nearly abolished the fentanyl-evoked responses. Conclusion: Our results indicate that peripherally restricted OR (particularly μ 1 -OR) antagonism prevents the fentanyl-induced immediate apnea, but fails to change the subsequent respiratory depression.