title: G-protein-gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids.
abstract: BACKGROUND
  Drugs acting on μ-opioid receptors (MORs) are widely used as analgesics but present side effects including life-threatening respiratory depression. MORs are G-protein-coupled receptors inhibiting neuronal activity through calcium channels, adenylyl cyclase, and/or G-protein-gated inwardly rectifying potassium (GIRK) channels. The pathways underlying MOR-dependent inhibition of rhythmic breathing are unknown.
  
  
  METHODS
  By using a combination of genetic, pharmacological, and physiological tools in rodents in vivo, the authors aimed to identify the role of GIRK channels in MOR-mediated inhibition of respiratory circuits.
  
  
  RESULTS
  GIRK channels were expressed in the ventrolateral medulla, a neuronal population regulating rhythmic breathing, and GIRK channel activation with flupirtine reduced respiratory rate in rats (percentage of baseline rate in mean ± SD: 79.4 ± 7.4%, n = 7), wild-type mice (82.6 ± 3.8%, n = 3), but not in mice lacking the GIRK2 subunit, an integral subunit of neuronal GIRK channels (GIRK2, 101.0 ± 1.9%, n = 3). Application of the MOR agonist [D-Ala, N-MePhe, Gly-ol]-enkephalin (DAMGO) to the ventrolateral medulla depressed respiratory rate, an effect partially reversed by the GIRK channel blocker Tertiapin-Q (baseline: 42.1 ± 7.4 breath/min, DAMGO: 26.1 ± 13.4 breath/min, Tertiapin-Q + DAMGO: 33.9 ± 9.8 breath/min, n = 4). Importantly, DAMGO applied to the ventrolateral medulla failed to reduce rhythmic breathing in GIRK2 mice (percentage of baseline rate: 103.2 ± 12.1%, n = 4), whereas it considerably reduced rate in wild-type mice (62.5 ± 17.7% of baseline, n = 4). Respiratory rate depression by systemic injection of the opioid analgesic fentanyl was markedly reduced in GIRK2 (percentage of baseline: 12.8 ± 15.8%, n = 5) compared with wild-type mice (72.9 ± 27.3%).
  
  
  CONCLUSIONS
  Overall, these results identify that GIRK channels contribute to respiratory inhibition by MOR, an essential step toward understanding respiratory depression by opioids.
authors.affiliation: From the Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada (G.M., H.L., R.L.H.); Department of Physiology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada (J.R., J.J.G.); and Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota (N.C.V., K.W.).
authors.forename: Gaspard
authors.initials: G
authors.lastname: Montandon
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Victoria
authors.forename: Hattie
authors.initials: H
authors.lastname: Liu
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
authors.forename: Richard L
authors.initials: RL
authors.lastname: Horner
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000633:toxicity; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C029738:tertiapin