Investigation of the persistent opioid receptor binding of hydrazine-containing opiate ligands to brain membranes has revealed that it is related to conversion of these ligands to fatty acylhydrazone or fatty acylhydrazide derivatives. The fatty acyl group was found to be derived from membrane phosphatides. Persistent binding does not occur when this pool of phosphatides is removed by extensive washing, and it is restored upon addition of phosphatide to the membranes. In washed membranes, synthetically derived fatty acylhydrazones exhibited persistent binding similar to that found when naltrexonazine was incubated with brain membranes. It is suggested that the persistent binding is a consequence of the localization of fatty acylnaltrexazone derived from naltrexonazine in a membrane lipid bilayer that interfaces with the opioid receptor system rather than the persistence of naltrexonazine itself.