Introduction to the Special Issue: “Making orexin-based therapies for addiction a reality: What are the steps from here?”

James, Morgan H.; Aston‐Jones, Gary

doi:10.1016/j.brainres.2020.146665

Cited by 17 publications

(10 citation statements)

References 45 publications

(48 reference statements)

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“…For example, systemic administration of the OxR2 antagonist NBI-80713 reduces heroin self-administration in rats with a history of extended (12h/d) heroin self-administration [20], indicating that signaling at OxR2 might become important under conditions of heightened motivation for opioid. Taken together, these data indicate that compounds that block signaling at both OxR1 and OxR2 (dual orexin receptor antagonists; DORAs) might have stronger antiaddiction properties compared to single orexin receptor antagonists (SORAs), particularly in highly addicted individuals [21,22].…”

Section: Introductionmentioning

confidence: 93%

“…When administered immediately prior to bedtime, suvorexant decreases latency to sleep onset and increases time spent sleeping [23], presumably due to its actions at OxR2. However, its actions at both OxR1 and OxR2 raise the possibility that it could be repurposed for use in populations with substance use disorders, including OUD [21,22]. To date, only a small number of studies has tested the efficacy of suvorexant on drug-seeking behaviors, with each focusing on psychostimulants.…”

Section: Introductionmentioning

confidence: 99%

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The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

O’Connor¹,

Fragale²,

James³

et al. 2020

Preprint

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The orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD).Suvorexant (Belsomra TM ) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

O’Connor¹,

Fragale²,

James³

et al. 2020

Preprint

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“…One important first step to address this might be to test the effects of orexin receptor antagonism on responding for CE. Although we acknowledge that as a field, we are far from understanding the role of the orexin system in the context of individual drugs of abuse, we suggest that if orexin-based therapeutics are to be effective in the clinic, as we and others have suggested (Campbell et al, 2020a;James and Aston-Jones, 2020;James et al, 2020;Yeoh et al, 2014), it is imperative that investigations going forward begin to examine their efficacy in preclinical models that take polydrug use into account.…”

Section: Orexin As a Mediator Of Cocaine And Alcohol Behaviorsmentioning

confidence: 95%

“…One strong candidate system is the hypothalamic orexin (hypocretin) system, given its common role in mediating reward seeking, including both cocaine and alcohol seeking (Campbell et al, 2020a;James et al, 2017b;Mahler et al, 2014). Indeed, an extensive literature of preclinical studies now indicate that orexin receptor antagonists are highly effective at protecting against cocaine and alcohol use and a series of ongoing clinical studies are seeking to extend these observations to human patients (Campbell et al, 2020a;James and Aston-Jones, 2020;Suchting et al, 2019). Critically with respect to cocaine + alcohol coabuse, orexin receptor antagonists also protect against the negative aspects of drug reward, including stress and anxiety behaviors during withdrawal (Georgescu et al, 2003;Li et al, 2010;Li et al, 2011;Yeoh et al, 2014), which appear to be a major driving factor for alcohol use in CUD populations (Higgins et al, 1993;McCance et al, 1995;McCance-Katz et al, 1993).…”

Section: Introduction: Coabuse Of Alcohol In Cocaine Use Disordermentioning

confidence: 99%

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

et al. 2021

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An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report co-abusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol-and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use.

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“…An interesting area that is emerging is that of addiction, with reports suggesting that DORAs may help in treatment of opioid and cocaine addiction, and alcohol abuse [25,26] . The premise for these is that orexin Ox1R signalling triggers psychostimulant-seeking behaviour, and that selective orexin blockade may inhibit the exaggerated craving, while the rest of physiological drives remaining unaffected.…”

mentioning

confidence: 99%

Dual orexin receptor antagonist in treatment of insomnia

Trajanović¹

2020

Engrami

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A novel group of medications, dual orexin receptor antagonists, emerged as a competent group that challenges current first-line hypnotics. They have relatively infrequent and mostly well-tolerated side effects, primarily in the form of residual somnolence, fatigue and nightmares/disturbing dreams. The advantage over conventional hypnotics stems from the specifics of their target receptors, which translates into lack of tolerance after long term use and good safety profile. They are particularly favoured in some specific populations, including the elderly. Ongoing and future studies are set to explore their effect on selected conditions, such as addiction and psychiatric disorders, dementias, perimenopausal condition and circadian rhythm disorders, to name a few.

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Introduction to the Special Issue: “Making orexin-based therapies for addiction a reality: What are the steps from here?”

Cited by 17 publications

References 45 publications

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

Dual orexin receptor antagonist in treatment of insomnia

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