G-protein–gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids
| Autor: | Gaspard Montandon, Hattie Liu, Jun Ren, Kevin Wickman, Richard L. Horner, Nicole C. Victoria, John J. Greer |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Enkephalin G protein Receptors Opioid mu Pharmacology Article Adenylyl cyclase Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine Animals Medicine Rats Wistar Receptor Mice Knockout Voltage-dependent calcium channel business.industry Inward-rectifier potassium ion channel Enkephalin Ala(2)-MePhe(4)-Gly(5) Potassium channel Rats Analgesics Opioid Bee Venoms 030104 developmental biology Anesthesiology and Pain Medicine Endocrinology G Protein-Coupled Inwardly-Rectifying Potassium Channels chemistry Opioid Female Respiratory Insufficiency business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Anesthesiology. 124:641-650 |
| ISSN: | 0003-3022 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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