The results of many recent pharmacological studies demonstrate that opiates can interact with their receptors in a number of different ways. In vivo and in situ experiments indicate that presence of at least four different agonist interactions, while in vitro binding studies indicate that interactions may differ between agonists and antagonists as well. The available evidence suggests that at least two topologically distinct receptors exist, one which binds alkaloids preferentially and the other peptides, while conformational changes of the same receptor probably account for agonist-antagonist heterogeneity. We propose that the topologically distinct receptors can be seen as simply receptors of differing affinities for the endogenous peptides, and thus may serve to regulate the latter's effects at a wide range heterogeneity even at nanomolar concentrations of ligand, suggesting that many binding molecules may not be pharmacologically relevant receptors.