G-protein-gated inwardly rectifying potassium channels modulate respiratory depression by opioids

Abstract

Background

Drugs acting on μ-opioid receptors (MOR) are widely used as analgesics, but present side-effects including life-threatening respiratory depression. MOR 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

Using a combination of genetic, pharmacological and physiological tools in rodents in vivo, we 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 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, TertiapinQ+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 to wild-type mice (72.9±27.3%).

Conclusion

Overall, these results identify that GIRK channels contribute to respiratory inhibition by MOR, an essential step toward understanding respiratory depression by opioids.