To further investigate the roles of G-proteins in MOR inhibition, we modulated the regulator of G-protein signaling (RGS) and showed a limited role of RGS4 in modulating respiratory depression by activation of MORs, but an important role in the modulation of respiratory rhythm alone, suggesting that RGS4 proteins may regulate other G-protein-coupled receptors. This evidence concerns the gene OPRM1 and Respiratory insufficiency due to muscle weakness.