Morphine-Induced Acetylcholine Release at the Hypoglossal Motor Nucleus: Implications for Opiate-Induced Respiratory Suppression

Study Objectives: The medullary hypoglossal nucleus (XII) innervates the genioglossal muscles of the tongue, and opioid-induced alterations in tongue muscle tone contribute to airway obstruction. Previous studies have shown that morphine causes a significant decrease in acetylcholine (ACh) release in some brain regions, but the effects of morphine on ACh release in XII have not been quantified. Design: A within-subjects design was used to test the hypothesis that morphine alters ACh release in XII of anesthetized Wistar rat. ACh release during microdialysis with Ringer's solution (control) was compared to ACh release during dialysis delivery of opioids. Setting: University of Michigan Patients or Participants: N/A Interventions: Microdialysis delivery of opioids to XII. Measurements and Results: Morphine caused a statistically significant, concentration-dependent increase in XII ACh release. The increase in XII ACh release caused by 10 μM morphine was blocked by the mu opioid antagonist naloxone and not blocked by the kappa opioid antagonist norbinaltorphimine. Conclusions: The data comprise the first direct measures of ACh release in XII and support the conclusion that morphine depresses hypoglossal nerve activity, in part, by increasing ACh release in XII. Activation of mu opioid receptors on inhibitory neurons within XII likely disinhibits cholinergic terminals, causing increased ACh release. The results are consistent with previous studies showing that blocking the enzymatic degradation of ACh in XII significantly inhibited tongue muscle activity.