Effects of intracerebroventricular administration of β-funaltrexamine on DAMGO-stimulated [35S]GTP-γ-S binding in rat brain sections

Abstract

Intracerebroventricular administration of β-funaltrexamine (β-FNA) reduces the density of μ opioid receptors as measured by in situ autoradiography by 40-50% throughout the brain, with little regional variation [Martin et el. (1993) J. Pharmacol. Exp. Ther. 267:506-514] Recently an assay has been developed to study opioid stimulation of [35S]GTP-γ-S binding autoradiographically in situ using slide-mounted brain sections [Sim et al. (1995) Proc. Natl. Aced. Sci. U.S.A. 92:7242- 7246]. The present study was undertaken to determine the effect of μ opioid receptor alkylation on G protein activation by the μ opioid agonist DAMGO. Animals were injected intracerebroventricularly with 40 nmol of β-FNA or saline and sacrificed 24 hours later. DAMGO stimulated [35S]GTP-γ-S binding with an anatomical specificity consistent with the localization of μ opioid receptors. The percent stimulation by DAMGO ranged from ~50 to 100% in the regions studied. β-FNA significantly decreased G protein activation by DAMGO in regions that are consistent with its reported long-lasting and insurmountable antagonism of the antinociceptive (medial thalamus, central gray) and reinforcing (nucleus accumbens) effects of γ opioid agonists [Adams et el. (1990) J. Pharmacol. Exp. Ther. 255:1027-1032; Martin et el. (1995) J. Pharmacol. Exp. Ther. 272:1135-1140]. However, the effects of β- FNA were not equal in all brain regions. This may indicate regional differences in the coupling efficiency of μ opioid receptors with G proteins, or in the effects of β-FNA on μ opioid receptor binding or on μ opioid receptor-stimulated G protein activity.