Neurons in the medullary reticular formation (MRF) contained within the nuclei reticularis gigantocellularis and reticularis paragigantocellularis were evaluated for their responses to morphine administered in the periaqueductal gray (PAG) and iontophoresed at the recording site. Morphine had a predominant excitatory effect on neurons in the MRF whether microinjected in the PAG or iontophoresed at the recording locus. Although morphine generally excited neurons in the MRF when administered at either site, examination of individual neurons for their responses to both modes of administration of morphine indicated that the effect produced by morphine administered in the PAG was rarely mimicked by morphine iontophoresed at the recording locus. Moreover, morphine administered in the PAG markedly attenuated the noxious evoked excitatory response of MRF neurons, an effect not reliably produced by morphine iontophoresed in the MRF when microinjected in the PAG is not mediated by an enkephalinergic interneurons. The implications of these results on the role of the MRF in opiate-induced antinociception are discussed.