Noribogaine stimulates naloxone-sensitive [35S]GTPgammaS binding

Noribogaine is formed in vivo by the O-demethylation of the indole alkaloid ibogaine. We report here that noribogaine acts as a full agonist at the mu-opioid receptor. Noribogaine-stimulated guanylyl 5'gamma-[35S]thio]triphosphate ([35S]GTPgammaS) was studied in rat thalamic membranes to measure activation of guanine nucleotide binding proteins (G-proteins) in the presence of excess GDP. Noribogaine caused a 170% increase above basal [35S]GTPgammaS binding at sub-micromolar effective concentrations (EC50) in a naloxone-sensitive manner, confirming that this effect was an opioid receptor-mediated process. The level of intrinsic activity for noribogaine in these assays was comparable to the full agonists DAMGO and morphine. In contrast, ibogaine had no significant effect on [35S]GTPgammaS binding over a similar concentration range. The efficacy of noribogaine as a full mu-opioid agonist may explain ibogaine's ability to block the acute signs of opiate withdrawal and its suppressive effects on morphine self-administration.