Endomorphin-stimulated [35S]GTPγS binding in rat brain:: Evidence for partial agonist activity at μ-opioid receptors

Endomorphin-1 is a peptide whose binding selectivity suggests a role as an endogenous ligand at mu-opioid receptors. In the present study, the effect of endomorphin-1 on mu receptor-coupled G proteins was compared with that of the mu agonist DAMGO by using agonist-stimulated [S-35]GTP gamma S binding in rat brain. [S-35]GTP gamma S autoradiography revealed a similar localization of endomorphin-1- and DAMGO-stimulated [S-35]-GTP gamma S binding in areas including thalamus, caudate-putamen, amygdala, periaqueductal gray, parabrachial nucleus, and nucleus tractus solitarius. Naloxone blocked endomorphin-1-stimulated labeling in all regions examined. Although the distribution of endomorphin-1-stimulated [S-35]GTP gamma S binding resembled that of DAMGO, the magnitude of endomorphin-1-stimulated binding was significantly lower than that produced by DAMGO. Concentration-effect curves of endomorphin-1 and DAMGO in thalamic membranes confirmed that endomorphin-1 produced only 70% of DAMGO-stimulated [S-35]GTP gamma S binding. Differences in maximal stimulation of [S-35]GTP gamma S binding between DAMGO and endomorphin-1 were magnified by increasing GDP concentrations, and saturation analysis of net endomorphin-1-stimulated [S-35]GTP gamma S binding revealed a lower apparent B-max value than that obtained with DAMGO. Endomorphin-1 also partially antagonized DAMGO stimulation of [S-35]GTP gamma S binding. These results demonstrate that endomorphin-1 is a partial agonist for G protein activation at the mu-opioid receptor in brain.