Opioid peptides act as
growth factors in neural and non-neural cells and tissues, in addition to serving for neurotransmission/neuromodulation in the nervous system. The native
opioid growth factor (OGF), [Met(5)]-
enkephalin, is a tonic inhibitory
peptide that plays a role in cell proliferation and tissue organization during development,
cancer, cellular renewal, wound healing, and angiogenesis. OGF action is mediated by a receptor mechanism. Assays with radiolabeled OGF have detected specific and saturable binding, with a one-site model of kinetics. Subcellular fractionation studies show that the receptor for OGF (OGFr) is an
integral membrane protein associated with the nucleus. Using
antibodies generated to a binding fragment of OGFr, this receptor has been cloned and sequenced in human, rat, and mouse. OGFr is distinguished by containing a series of imperfect repeats. The molecular and
protein structure of OGFr have no resemblance to that of classical
opioid receptors, and have no significant homologies to known domains or functional motifs with the exception of a bipartite
nuclear localization signal. Immunoelectron microscopy and immunocytochemistry investigations, including co-localization studies, have detected OGFr on the outer nuclear envelope where it interfaces with OGF. The
peptide-receptor complex associates with
karyopherin, translocates through the nuclear pore, and can be observed in the inner nuclear matrix and at the periphery of
heterochromatin of the nucleus. Signal transduction for modulation of
DNA activity is dependent on the presence of an appropriate confirmation of
peptide and receptor. This report reviews the history of OGF-OGFr, examines emerging insights into the mechanisms of action of
opioid peptide-receptor interfacing, and discusses the clinical significance of these observations.