Delta Opioid Pharmacology in Relation to Alcohol Behaviors

Alongkronrusmee, Doungkamol; Chiang, Terrance; Rijn, Richard M. van

doi:10.1007/164_2016_30

Cited by 15 publications

(6 citation statements)

References 191 publications

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“…Several studies have shown that activation of δOPs can modulate alcohol intake (Alongkronrusmee, Chiang, & van Rijn, 2016) and thus, a synthetic opioid that preferentially activates δOP could minimize the impact of μOP-mediated reward and κOP-mediated aversion on the behavioural effects in the alcohol assays. Indeed, our characterization revealed that MP102 had the desired in vitro pharmacological profile of a G protein-biased, δOP-preferring agonist.…”

Section: Discussionmentioning

confidence: 99%

G protein‐biased kratom‐alkaloids and synthetic carfentanil‐amide opioids as potential treatments for alcohol use disorder

Gutridge

Robins

Cassell

et al. 2020

British J Pharmacology

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Background and Purpose Mitragyna speciosa, more commonly known as kratom, is a plant that contains opioidergic alkaloids but is unregulated in most countries. Kratom is used in the self‐medication of chronic pain and to reduce illicit and prescription opioid dependence. Kratom may be less dangerous than typical opioids because of the stronger preference of kratom alkaloids to induce receptor interaction with G proteins over β‐arrestin proteins. We hypothesized that kratom (alkaloids) can also reduce alcohol intake. Experimental Approach We pharmacologically characterized kratom extracts, kratom alkaloids (mitragynine, 7‐hydroxymitragynine, paynantheine, and speciogynine) and synthetic carfentanil‐amide opioids for their ability to interact with G proteins and β‐arrestin at μ, δ, and κ opioid receptors in vitro. We used C57BL/6 mice to assess to which degree these opioids could reduce alcohol intake and whether they had rewarding properties. Key Results Kratom alkaloids were strongly G protein‐biased at all three opioid receptors and reduced alcohol intake, but kratom and 7‐hydroxymitragynine were rewarding. Several results indicated a key role for δ opioid receptors, including that the synthetic carfentanil‐amide opioid MP102—a G protein‐biased agonist with modest selectivity for δ opioid receptors—reduced alcohol intake, whereas the G protein‐biased μ opioid agonist TRV130 did not. Conclusion and Implications Our results suggest that kratom extracts can decrease alcohol intake but still carry significant risk upon prolonged use. Development of more δ opioid‐selective synthetic opioids may provide a safer option than kratom to treat alcohol use disorder with fewer side effects.

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Section: Discussionmentioning

confidence: 99%

G protein‐biased kratom‐alkaloids and synthetic carfentanil‐amide opioids as potential treatments for alcohol use disorder

Gutridge

Robins

Cassell

et al. 2020

British J Pharmacology

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“…Opioid receptors are expressed in multiple CNS regions, including reward and emotion-related brain structures [ 122 ]. In addition to their well-known antinociceptive effects, opioid receptors are known to play a role in the mechanisms of drug abuse [ 123 ] and alcohol addiction [ 124 ]. There is also some evidence on involvement of opioid receptors in the mechanisms of antidepressant drug action [ 125 ].…”

Section: Palmitoylation Of G Protein-coupled Receptors (Gpcrs)mentioning

confidence: 99%

Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

Науменко

Ponimaskin

2018

Neural Plasticity

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The majority of neuronal proteins involved in cellular signaling undergo different posttranslational modifications significantly affecting their functions. One of these modifications is a covalent attachment of a 16-C palmitic acid to one or more cysteine residues (S-palmitoylation) within the target protein. Palmitoylation is a reversible modification, and repeated cycles of palmitoylation/depalmitoylation might be critically involved in the regulation of multiple signaling processes. Palmitoylation also represents a common posttranslational modification of the neurotransmitter receptors, including G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LICs). From the functional point of view, palmitoylation affects a wide span of neurotransmitter receptors activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, recycling, and synaptic clustering. This review summarizes the current knowledge on the palmitoylation of neurotransmitter receptors and its role in the regulation of receptors functions as well as in the control of different kinds of physiological and pathological behavior.

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“…Considering that DORs play a role in mood disorders such as depression and anxiety [113,134] and that depression-like and anxiety-like behaviors are comorbid with AUD [135], the role of DORs in alcohol addiction has been investigated as a potential target for treatment of AUD. It has been suggested that acute and chronic alcohol exposure can affect the expression, pharmacology, and function of DORs [136,137]. For instance, prolonged alcohol exposure using two-bottle limited access [138] or alcohol-induced conditioned place preference (CPP) procedures increased expression of DORs [139].…”

Section: Dorsmentioning

confidence: 99%

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

et al. 2020

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G protein-coupled receptors (GPCRs) constitute the largest class of cell surface signaling receptors and regulate major neurobiological processes. Accordingly, GPCRs represent primary targets for the treatment of brain disorders. Several human genetic polymorphisms affecting GPCRs have been associated to different components of alcohol use disorder (AUD). Moreover, GPCRs have been reported to contribute to several features of alcohol-related behaviors in animal models. Besides traditional pharmacological tools, genetic-based approaches mostly aimed at deleting GPCR genes provided substantial information on how key GPCRs drive alcohol-related behaviors. In this review, we summarize the alcohol phenotypes that ensue from genetic manipulation, in particular gene deletion, of key GPCRs in rodents. We focused on GPCRs that belong to fundamental neuronal systems that have been shown as potential targets for the development of AUD treatment. Data are reviewed with particular emphasis on alcohol reward, seeking, and consumption which are behaviors that capture essential aspects of AUD. Literature survey indicates that in most cases, there is still a gap in defining the intracellular transducers and the functional crosstalk of GPCRs as well as the neuronal populations in which their signaling regulates alcohol actions. Further, the implication of only a few orphan GPCRs has been so far investigated in animal models. Combining advanced pharmacological technologies with more specific genetically modified animals and behavioral preclinical models is likely necessary to deepen our understanding in how GPCR signaling contributes to AUD and for drug discovery.

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Delta Opioid Pharmacology in Relation to Alcohol Behaviors

Cited by 15 publications

References 191 publications

G protein‐biased kratom‐alkaloids and synthetic carfentanil‐amide opioids as potential treatments for alcohol use disorder

G protein‐biased kratom‐alkaloids and synthetic carfentanil‐amide opioids as potential treatments for alcohol use disorder

Palmitoylation as a Functional Regulator of Neurotransmitter Receptors

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

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