Alteration of orexin-A and PKCα in the postmortem brain of pure-opioid and multi-drug abusers

Sadat‐Shirazi, Mitra‐Sadat; Soltani, Haniyeh; Nikpour, Neda; Haghshenas, Masoud; Khalifeh, Solmaz; Mokri, Azarakhsh; Zarrindast, Mohammad‐Reza

doi:10.1016/j.npep.2020.102074

Cited by 6 publications

(4 citation statements)

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“…OX cell bodies are found in the hypothalamus only, but OX neurons project throughout the brain and to regions that are pivotal in the regulation of motivation and responses to drug-related stimuli ( Peyron et al, 1998 ; Fadel and Deutch, 2002 ; Baldo et al, 2003 ; Sakurai and Mieda, 2011 ). Suvorexant may reduce drug intake and drug seeking by acutely attenuating the effects of drug-induced neuroadaptations of the OX system (see Georgescu et al, 2003 ; Thannickal et al, 2018 ; Fragale et al, 2020 ; Sadat-Shirazi et al, 2020 ) and/or downstream circuits. For example, chronic SUV treatment with higher doses than those utilized in the current studies were shown to block morphine-induced enhancement of whole brain CREB and p-ERK protein expression ( Esmaili-Shahzade-Ali-Akbari et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The orexin (OX) system, also known as the hypocretin system, is involved in various physiological processes, such as sleep/wake regulation ( Chemelli et al, 1999 ; Hoyer and Jacobson, 2013 ; Inutsuka and Yamanaka, 2013 ; Krystal et al, 2013 ), stress ( Berridge et al, 2010 ; Sargin, 2019 ), feeding ( Sakurai et al, 1998 ), and reward processing ( Harris et al, 2005 ; Martin-Fardon & Weiss, 2012 ; Matzeu and Martin-Fardon, 2020 ). The OX system is strongly recruited by drug use and was shown to incur neuroadaptations with repeated drug use, including cocaine ( Zhang et al, 2007 ; James et al, 2019 ; Matzeu and Martin-Fardon, 2021 ), alcohol ( Amodeo et al, 2020 ), nicotine ( Kane et al, 2000 ), and opioids ( Georgescu et al, 2003 ; Thannickal et al, 2018 ; Fragale et al, 2020 ; Sadat-Shirazi et al, 2020 ). Additionally, pharmacological manipulations of OX transmission have been shown to influence drug intake and seeking of alcohol ( Moorman and Aston-Jones, 2009 ; Shoblock et al, 2011 ; Martin-Fardon & Weiss, 2012), cocaine ( Borgland et al, 2006 ; Martin-Fardon and Weiss, 2014a ), and opioids ( Smith and Aston-Jones, 2012 ; Matzeu and Martin-Fardon, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

et al. 2023

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Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse.Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i. v., 8 h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0–20 mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20 mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD.Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20 mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females.Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

et al. 2023

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“…For example, among OUD patients undergoing a buprenorphine taper, the Food and Drug Administration-approved dual orexin-receptor antagonist suvorexant improved total sleep time and decreased subjective opioid withdrawal on the SOWS for patients relative to placebo (Huhn et al, 2022). These results may be related to the increase in orexin signaling implicated in opioid withdrawal for which a dual orexin-receptor antagonist may be efficacious (Huhn et al, 2022; Sadat-Shirazi et al, 2020) and have prompted several additional ongoing inquiries into the role of the orexin system in OUD. Cognitive-behavioral therapy for insomnia has also shown promise in reducing insomnia symptoms (Mitchell et al, 2012); however, it has not been systematically tested in individuals with OUD.…”

Section: Discussionmentioning

confidence: 99%

Pain and withdrawal are common among patients receiving medications for opioid use disorder and associated with pain catastrophizing, negative affect, and poor sleep.

Berry,

Dunn

2024

Experimental and Clinical Psychopharmacology

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Substantial percentages of persons receiving medications for opioid use disorder (MOUD) continue to experience clinically significant levels of pain and opioid withdrawal, which may pose barriers to reducing opioid use. Continued pain, in particular, may increase the risk for psychiatric problems and poorer treatment retention, especially with a lack of adequate care for pain. The goals of these analyses were to characterize the prevalence of, and patient-level variables associated with, pain and opioid withdrawal, as well as utilization of related coping strategies and treatments. Participants were 18 years of age or older and received methadone or buprenorphine for opioid use disorder (n = 179). Participants completed this survey in person, within their MOUD clinic. Participants completed patient-level and demographic questions as well as measures of pain, withdrawal, utilization of related coping strategies, and pain treatment. Numerous participants endorsed chronic pain (41.9%) or opioid withdrawal (89.4%) and indicated reliance upon over-the-counter medications and prayer for pain management. Multiple linear regression models showed greater pain catastrophizing and negative affect accounted for variability in pain severity and pain interference, as well as opioid withdrawal. Persons who slept less and endorsed chronic pain also reported greater pain severity and interference, and pain interference was higher with increased age. These and previous findings combine to further highlight the detrimental role that pain catastrophizing and negative affect can play in pain perception and withdrawal, but also represent promising treatment targets to facilitate pain and withdrawal management and improved quality of life.

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“…Dual-orexin receptor antagonists (DORAs) improve sleep continuity and duration in humans (7), and orexin receptor antagonists decrease opioid withdrawal symptoms, opioid tolerance, and motivation to seek opioids in rodent models of OUD (8)(9)(10)(11)(12)(13)(14). Suvorexant is a Food and Drug Administration (FDA)-approved DORA used to treat both sleep initiating and maintenance insomnia (15,16) and could be particularly efficacious in persons with OUD who may experience sleep disturbance as a result of increased orexin signaling (17,18). Suvorexant is a schedule IV compound that is distinct from benzodiazepines and "z" drugs; for example, suvorexant promotes sleep by inhibiting wakefulness rather than promoting sedation and has lower ratings of "drug high" and "euphoric mood" when compared with zolpidem (19).…”

Section: Introductionmentioning

confidence: 99%

Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper

et al. 2022

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Increased orexin/hypocretin signaling is implicated in opioid withdrawal, sleep disturbances, and drug-seeking behaviors. This study examined whether a dual-orexin receptor antagonist would improve sleep and withdrawal outcomes when compared with placebo during a buprenorphine/naloxone taper. Thirty-eight participants with opioid use disorder were recruited to a clinical research unit and maintained on 8/2 to 16/4 mg of buprenorphine/naloxone treatment for 3 days before being randomized to 20 mg of suvorexant ( n = 14), 40 mg of suvorexant ( n = 12), or placebo ( n = 12); 26 individuals completed the study. After randomization, participants underwent a 4-day buprenorphine/naloxone taper and 4-day post-taper observation period. Total sleep time (TST) was collected nightly with a wireless electroencephalography device and wrist-worn actigraphy; opioid withdrawal symptoms were assessed via the Subjective Opiate Withdrawal Scale (SOWS); and abuse potential was assessed on a 0- to 100-point visual analog scale of “High” every morning. A priori outcomes included two-group (collapsing suvorexant doses versus placebo) and three-group comparisons of area-under-the-curve (AUC) scores for TST, SOWS, and High. In two-group comparisons, participants receiving suvorexant displayed increased TST during the buprenorphine/naloxone taper and decreased SOWS during the post-taper period. In three-group comparisons, participants receiving 20 mg of suvorexant versus placebo displayed increased AUC for TST during the buprenorphine/naloxone taper, but there was no difference in SOWS among groups. There was no evidence of abuse potential in two- or three-group analyses. The results suggest that suvorexant might be a promising treatment for sleep and opioid withdrawal in individuals undergoing a buprenorphine/naloxone taper.

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Alteration of orexin-A and PKCα in the postmortem brain of pure-opioid and multi-drug abusers

Cited by 6 publications

References 58 publications

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

Pain and withdrawal are common among patients receiving medications for opioid use disorder and associated with pain catastrophizing, negative affect, and poor sleep.

Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper

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