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-Ala2, N-MePhe4, 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 641-650 |
| Number of pages | 10 |
| Journal | Anesthesiology |
| Volume | 124 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2016 |
Bibliographical note
Funding Information:The authors thank Laura Vechio, M.Sc., and Ali Salahpour, Ph.D. (both from Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada), and Beverly Orser, M.D., Ph.D. (Department of Physiology, University of Toronto), for technical support with genotyping. This study was supported by a Parker B. Francis Fellowship (950-229813; to Dr. Montandon), Tier 1 Canada Research Chair (to Dr. Horner), National Institute on Drug Abuse Training Grant (T32 DA07234; to Dr. Victoria), the Canadian Institutes for Health Research (grant no. MOP-15563 to Dr. Horner, and grant no. MOP-141725 to Dr. Greer), the National Sanitarium Association Innovative Research Program (00144051; to Dr. Horner), and the National Institutes for Health (MH061933 and DA034696; to Dr. Wickman).
Publisher Copyright:
© 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc.