Roles of peripheral and central µ ₁ -opioid receptors in the fentanyl-induced cardiorespiratory responses

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 mu1 opioid receptor (µ₁-ORs) in the genesis of these responses. Cardiorespiratory responses to ivb injection of fentanyl (50 µg·kg^-1) were recorded in male and female conscious rats (<i>study I</i>). The same protocols were performed after: naloxone (NLX) and naloxone methiodide (NLM) to systemically and peripherally antagonize ORs, respectively (<i>study II</i>); D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and methylnaltrexone (MNTX) to systemically and peripherally block opioid mu-receptors (<i>study III</i>); and naloxonazine (NLZ) to systemically block µ₁-ORs (<i>study IV</i>). 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, whereas 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. Our results indicate that peripherally restricted OR (particularly µ₁-OR) antagonism prevents the fentanyl-induced immediate apnea, but fails to change the subsequent respiratory depression.<b>NEW & NOTEWORTHY</b> The cardiorespiratory responses to rapid intravenous injection of fentanyl have not been fully investigated. We demonstrate in this study that intravenous bolus injection of fentanyl triggers an immediate sustained apnea and subsequent respiratory depression without remarkable gender-difference in conscious rats. The immediate apnea is triggered by activating peripheral opioid receptors and the subsequent respiratory depression is mediated by activating central opioid receptors, in which µ1-opioid receptors play a key role.