Noribogaine stimulates naloxone-sensitive [³⁵S]GTPγS 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 μ-opioid receptor. Noribogaine-stimulated guanylyl 5'γ-[³⁵S]thio]- triphosphate ([³⁵S]GTPγS) 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]GTPγS 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]GTPγS binding over a similar concentration range. The efficacy of noribogaine as a full μ-opioid agonist may explain ibogaine's ability to block the acute signs of opiate withdrawal and its suppressive effects on morphine self-administration.