Sodium ions are classically conceptualized as negative allosteric modulators for G protein coupled receptors (GPCRs), although there have been reports of either positive allosteric modulation or no effect of sodium on GPCR function. Here we identified opposing actions of sodium on the mu and kappa-opioid receptors. We utilized a variety of methods including radioligand binding, real-time conformational monitoring of transitions using bioluminescence resonance energy transfer and signaling assays using the TRUPATH resource. At the mu receptors, sodium behaved as a negative allosteric modulator of binding, conformational transitions and signaling. Intriguingly, bitopic mu agonists were unaffected by sodium concentrations. By contrast, at the kappa opioid receptor sodium negatively modulated agonist binding and positively modulated conformational transitions and signaling. Taken together, these findings support the notion that the differential sensitivities to sodium concentrations will result in opposing effects on cell surface and intracellular signaling.