Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders

Chavkin, Charles

doi:10.1038/s41386-018-0046-4

Cited by 6 publications

(7 citation statements)

References 6 publications

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“…In this study, stress did not drive dopamine release in the nucleus accumbens or caudate nucleus (Miller et al, 1984). Other studies using selective KOR antagonists also found evidence that endogenous opioid peptides contribute to the encoding of aversive experiences (McLaughlin et al, 2006;Land et al, 2008;Chavkin, 2018;Robble et al, 2020).…”

Section: Function Of Opioid Peptidessupporting

confidence: 51%

Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

et al. 2020

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In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, .20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors, proenkephalin, prodynorphin, and proopiomelanocortin, by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides binds to all three of the opioid receptor types (m, d, or k), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in the brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been used to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e., to excised tissue) or in vivo (in animals), using antagonists of opioid receptors to infer endogenous peptide activity, and genetic knockout of opioid peptide precursors. Collectively, these studies add to our current understanding of the function of endogenous opioids, especially when similar results are found using different approaches. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENTActivation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects, including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.

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Section: Function Of Opioid Peptidessupporting

confidence: 51%

Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

et al. 2020

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“…Antagonism of KOPr by buprenorphine also likely plays a role in its clinical use for OUD. There is now substantial evidence that KOPr antagonists inhibit stress-induced, but not drug primeinduced, reinstatement of drug-seeking behavior (Bailey and Husbands, 2014) and attenuate a diverse range of stress-induced behaviors, suggesting a role for KOPr antagonists as stressresilience medications (Chavkin, 2018). KOPr antagonists also have anxiolytic-like and antidepressant-like effects in various behavioral paradigms (for a review, see Van't Veer and Carlezon, 2013).…”

Section: Introductionmentioning

confidence: 99%

OREX-1019: A Novel Treatment of Opioid Use Disorder and Relapse Prevention

Maguire

Gerak

Cami‐Kobeci

et al. 2019

J Pharmacol Exp Ther

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There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the m opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue-plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue-plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at m opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-ago go related gene) K 1 channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue-plus heroinprimed reinstatement of, responding previously maintained by remifentanil.

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“…The interaction of stress and EtOH drinking is complex, but the Pdyn/KOR system is a definite molecular mediator engaged within cycles of bingeing, withdrawal, and relapse. These data point to KOR antagonists as potential stress resilience medications for alcohol use disorder (Chavkin 2018).…”

Section: Discussionmentioning

confidence: 88%

The Kappa Opioid Receptor is required for some intermittent alcohol drinking induced changes in stress and threat responding in male C57BL/6J mice

Hwa

Bowling

Calloway

et al. 2020

Preprint

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The dynorphin/kappa opioid receptor (KOR) system in the brain regulates both stressful experiences and negative, aversive states during withdrawal from drugs of abuse. We explored the role of this system during acute withdrawal from long-term alcohol drinking, focusing on the bed nucleus of the stria terminalis (BNST), a region strongly implicated in alcohol-withdrawal induced alterations of behavior. Male C57BL/6J mice were subjected to repeated forced swim tests, home cage exposure to a predator odor, and a visual threat after eight weeks intermittent access to alcohol or water. Systemic injection of KOR antagonist norBNI reversed alcohol-related differences in immobility time during the second swim test and reduced burying behavior in response to predator odor, but did not affect behavioral response to visual threat. In dynorphin-GFP reporter mice, c-Fos immunoreactivity was increased in dynorphin-containing neurons after repeated swim stress and alcohol drinking. Using dynorphin-GFP mice, there was enhanced spontaneous excitatory synaptic drive onto dynorphin neurons in the BNST after alcohol-drinking mice underwent forced swim stress. Finally, knockdown of dynorphin in the BNST using a viral shRNA affected swim stress behavior and responses to TMT in alcohol drinkers and controls, but did not affect alcohol drinking. These studies confirm BNST dynorphin recruitment during acute withdrawal as playing a key role in altered behavioral responses to stressful stimuli.HighlightsIntermittent alcohol drinking changed stress reactions in mice.KOR antagonist norBNI altered stress responses in alcohol drinkers.Alcohol and swim stress increased c-Fos immunoreactivity in BNST dynorphin neurons.Swim stress enhanced excitatory drive onto BNST dynorphin cells in alcohol mice.BNST dynorphin knockdown affected some stress behavior, but not alcohol drinking.

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Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders

Cited by 6 publications

References 6 publications

Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

Five Decades of Research on Opioid Peptides: Current Knowledge and Unanswered Questions

OREX-1019: A Novel Treatment of Opioid Use Disorder and Relapse Prevention

The Kappa Opioid Receptor is required for some intermittent alcohol drinking induced changes in stress and threat responding in male C57BL/6J mice

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