Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation
This in vitro study investigated the molecular mechanism of action of iboga alkaloids, using recombinant mu-opioid receptor-expressing cells, rat thalamic membranes, and rat brain slices. There was no supporting evidence for the hypothesis that opioid withdrawal is mediated by the activation of the mu-opioid receptor.
Authors
- Antonio, T.
- Childers, S. R.
- Rothman, R. B.
Published
Abstract
Objective
The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.
Methods
Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.
Results
In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [35S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not stimulate [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]GTPγS binding in brain slices using autoradiography.
Discussion
An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.
Research Summary of 'Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation'
Introduction
Antonio and colleagues introduce the iboga alkaloids as a family of approximately 80 natural and synthetic monoterpene indole compounds built on an ibogamine core. Prior preclinical and clinical observations show that some iboga alkaloids, most notably ibogaine and its metabolite noribogaine, reduce opioid withdrawal signs and alter drug self-administration; these effects have motivated interest in their use as probes for neurobiology and as potential addiction pharmacotherapies. Although ibogaine binds the µ-opioid receptor (MOR) with low micromolar affinity, its pharmacology is puzzling: it does not produce classical MOR-mediated analgesia but can potentiate morphine analgesia and reduce morphine tolerance, and clinical detoxification after a single ibogaine dose appears to persist beyond the compound's elimination half-life. These observations raise the question of whether iboga alkaloid effects are mediated by direct MOR agonism, or by alternative mechanisms. The present study set out to replicate and extend prior functional reports regarding MOR activation by iboga alkaloids. Specifically, the investigators tested ibogaine, noribogaine and the synthetic congener 18-methoxycoronaridine (18-MC) for their ability to stimulate MOR-coupled G protein activation using agonist-stimulated [35S]GTPγS binding. Experiments were performed across multiple laboratories and preparations, including cells overexpressing human, rat or mouse MORs, rat thalamic membranes, and autoradiography of rat brain slices, with the aim of clarifying whether an MOR agonist action can account for the effects of these compounds on opioid withdrawal.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Antonio, T., Childers, S. R., Rothman, R. B., Dersch, C. M., King, C., Kuehne, M., Bornmann, W. G., Eshleman, A. J., Janowsky, A., Simon, E. R., Reith, M. E. A., & Alper, K. (2013). Effect of Iboga Alkaloids on µ-Opioid Receptor-Coupled G Protein Activation. PLoS ONE, 8(10), e77262. https://doi.org/10.1371/journal.pone.0077262
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Papers cited by this study that are also in Blossom
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Alper, K. R., Lotsof, H. S., Frenken, G. M. N. et al. · The American Journal on Addictions (2010)
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Wasko, M. J., Witt-Enderby, P. A., Surratt, C. K. · ACS Chemical Neuroscience (2018)
Malcolm, B., Polanco, M., Barsuglia, J. P. · Journal of Psychoactive Drugs (2018)
Barsuglia, J. P., Polanco, M., Palmer, R. et al. · Progress in Brain Research (2018)
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