Modulation of μ-opioid receptor activation by acidic pH is dependent on ligand structure and an ionizable amino acid residue.

Our investigations indicate that low pH selectively impairs μ-opioid receptor signalling modulated by ligands capable of forming hydrogen bonds with H2976.52 . We propose that protonation of H2976.52 at acidic pH reduces binding and subsequent signalling of such ligands. Novel agonists targeting opioid receptors in injured tissue might benefit from lack of hydrogen bond formation with H2976.52 .