Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

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Abstract

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.

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Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.

John M. Christie (2008)

A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the mu-opioid receptor itself, cellular tolerance and withdrawal in opioid-sensitive neurons, systems tolerance and withdrawal in opioid-sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks. Receptor tolerance appears to involve enhancement of mechanisms of receptor regulation, including desensitization and internalization. Adaptations causing cellular tolerance are more complex but several important processes have been identified including upregulation of cAMP/PKA and cAMP response element-binding signalling and perhaps the mitogen activated PK cascades in opioid sensitive neurons that might not only influence tolerance and withdrawal but also synaptic plasticity during cycles of intoxication and withdrawal. The potential complexity of network, or systems adaptations that interact with opioid-sensitive neurons is great but some candidate neuropeptide systems that interact with mu-opioid sensitive neurons may play a role in tolerance and withdrawal, as might activation of glial signalling. Implication of synaptic forms of learning such as long term potentiation and long term depression in opioid addiction is still in its infancy but this ultimately has the potential to identify specific synapses that contribute to compulsive use and relapse.

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Capturing adenylyl cyclases as potential drug targets.

Gerd Geisslinger, Thomas Eschenhagen, Sandra Pierre … (2009)

Cyclic AMP (cAMP) is an important intracellular signalling mediator. It is generated in mammals by nine membrane-bound and one soluble adenylyl cyclases (ACs), each with distinct regulation and expression patterns. Although many drugs inhibit or stimulate AC activity through the respective upstream G-protein coupled receptors (for example, opioid or beta-adrenergic receptors), ACs themselves have not been major drug targets. Over the past decade studies on the physiological functions of the different mammalian AC isoforms as well as advances in the development of isoform-selective AC inhibitors and activators suggest that ACs could be useful drug targets. Here we discuss the therapeutic potential of isoform-selective compounds in various clinical settings, including neuropathic pain, neurodegenerative disorders, congestive heart failure, asthma and male contraception.

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Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter.

Gary Rudnick, Howard Jacobs, Yuan Zhang … (2007)

Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) noncompetitively by decreasing V(max) with little change in the K(m) for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog 2beta-2-carbomethoxy-3-(4-[(125)I]iodophenyl)tropane. However, inhibition of binding was competitive, increasing the apparent K(D) without much change in B(max). Ibogaine increased the reactivity of cysteine residues positioned in the proposed cytoplasmic permeation pathway of SERT but not at nearby positions out of that pathway. In contrast, cysteines placed at positions in the extracellular permeation pathway reacted at slower rates in the presence of ibogaine. These results are consistent with the proposal that ibogaine binds to and stabilizes the state of SERT from which 5-HT dissociates to the cytoplasm, in contrast with cocaine, which stabilizes the state that binds extracellular 5-HT.

Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

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Most cited references 104

Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.

Capturing adenylyl cyclases as potential drug targets.

Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter.

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