High affinity ibogaine binding to a mu opioid agonist site.

Ibogaine, a naturally occurring alkaloid, may reduce drug-seeking behavior and opioid withdrawal symptoms. Previous research found weak binding to opioid receptors, but this study examined ibogaine's interaction with the mu opioid receptor in mouse forebrain using a radiolabeled tracer. Analysis revealed ibogaine binds to two different affinity states of the receptor, with a high-affinity binding constant (Ki) of about 130 nM and a lower one of 4 µM. Adding sodium chloride, which shifts receptors to a low-affinity state, reduced ibogaine's binding, indicating it acts as an agonist at the mu opioid receptor. This suggests ibogaine's effects on pain, withdrawal, and drug seeking may be mediated through mu opioid receptor activation.

Study at a glance

Abstract

The naturally occurring indole alkaloid ibogaine is of interest because of its reported ability to block drug seeking behavior for extended periods. The compound also potentiates morphine-induced analgesia in mice and reduces certain naltrexone-precipitated withdrawal signs in morphine-dependent rats. Although these results might suggest ibogaine interaction with opioid receptors, previous receptor binding studies (Brain Res. 571:242-247, 1980) found that ibogaine had a Ki value of only 2 microM for the kappa opioid receptor and was virtually inactive in blocking mu and delta receptor binding (Ki > 100 microM). The present investigation of ibogaine interaction with the mu opioid receptor from mouse forebrain labeled with [3H]-naloxone, however, yielded significantly more potent mu opioid Ki values. LIGAND analysis indicated that the data were best fit by a two site binding model, with Ki values of about 130 nM and 4 microM, reflecting ibogaine recognition of different agonist affinity states of the receptor. Inclusion of 100 mM NaCl in the assay to induce the agonist low affinity state of the receptor, reduced ibogaine's inhibition of [3H]-naloxone binding. These results suggest that ibogaine is an agonist at the mu opioid receptor with a Ki value of about 130 nM, potentially explaining ibogaine's antinociceptive effects as well as its reported reduction of opioid withdrawal symptoms and attenuation of drug seeking behavior.