title: μ opioid receptor activation hyperpolarizes respiratory-controlling Kölliker-Fuse neurons and suppresses post-inspiratory drive.
abstract: CONCLUSIONS
  In addition to reductions in respiratory rate, opioids also cause aspiration and difficulty swallowing, indicating impairment of the upper airways. The Kölliker-Fuse (KF) maintains upper airway patency and a normal respiratory pattern. In this study, activation of μ opioid receptors in the KF reduced respiratory frequency and tidal volume in anaesthetized rats. Nerve recordings in an in situ preparation showed that activation of μ opioid receptors in the KF eliminated the post-inspiration phase of the respiratory cycle. In brain slices, μ opioid agonists hyperpolarized a distinct population (61%) of KF neurons by activation of an inwardly rectifying potassium conductance. These results suggest that KF neurons that are hyperpolarized by opioids could contribute to opioid-induced respiratory disturbances, particularly the impairment of upper airways.
  Opioid-induced respiratory effects include aspiration and difficulty swallowing, suggesting impairment of the upper airways. The pontine Kölliker-Fuse nucleus (KF) controls upper airway patency and regulates respiration, in particular the inspiratory/expiratory phase transition. Given the importance of the KF in coordinating respiratory pattern, the mechanisms of μ opioid receptor activation in this nucleus were investigated at the systems and cellular level. In anaesthetized, vagi-intact rats, injection of opioid agonists DAMGO or [Met(5) ]enkephalin (ME) into the KF reduced respiratory frequency and amplitude. The μ opioid agonist DAMGO applied directly into the KF of the in situ arterially perfused working heart-brainstem preparation of rat resulted in robust apneusis (lengthened low amplitude inspiration due to loss of post-inspiratory drive) that was rapidly reversed by the opioid antagonist naloxone. In brain slice preparations, activation of μ opioid receptors on KF neurons hyperpolarized a distinct population (61%) of neurons. As expected, the opioid-induced hyperpolarization reduced the excitability of the neuron in response to either current injection or local application of glutamate. In voltage-clamp recordings the outward current produced by the opioid agonist ME was concentration dependent, reversed at the potassium equilibrium potential and was blocked by BaCl2 , characteristics of a G protein-coupled inwardly rectifying potassium (GIRK) conductance. The clinically used drug morphine produced an outward current in KF neurons with similar potency to morphine-mediated currents in locus coeruleus brain slice preparations. Thus, the population of KF neurons that are hyperpolarized by μ opioid agonists are likely mediators of the opioid-induced loss of post-inspiration and induction of apneusis.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR, 97239, USA.
authors.forename: Erica S
authors.initials: ES
authors.lastname: Levitt
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Abdala
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Julian F R
authors.initials: JF
authors.lastname: Paton
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, 97239, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Bissonnette
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, OR, 97239, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Williams
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D065836:Kolliker-Fuse Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000502:physiology*; D012119:Respiration / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D018698:Glutamic Acid; D004744:Enkephalin, Methionine; D009020:Morphine