The Role of Orexin-1 Receptor Signaling in Demand for the Opioid Fentanyl

Fragale, Jennifer E.; Pantazis, Caroline B.; James, Morgan H.; Aston‐Jones, Gary

doi:10.1101/533059

Cited by 8 publications

(20 citation statements)

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“…4B ; ␤ ϭ 0.438, p ϭ 0.118). Baseline demand has also been shown to predict the antimotivational effects of systemic SB treatment (James et al, 2019;Fragale et al, 2019). Consistent with such previous findings, baseline ␣ was negatively correlated with intra-VP SB efficacy (1.0 mM; Fig.…”

Section: Baseline Demand For Remifentanil Predicts Cue-induced Reinstsupporting

confidence: 88%

“…We also reported that systemic blockade of OxR1s attenuated cue-induced reinstatement of heroin, fentanyl, and remifentanil seeking (Smith and Aston-Jones, 2012;Porter-Stransky et al, 2017;Fragale et al, 2019). Using within-session behavioral economics (BE) procedures, we recently found that systemic OxR1 antagonism decreased demand for fentanyl and remifentanil (Porter-Stransky et al, 2017;Fragale et al, 2019). Together, these results support a role for OxR1 signaling in opioid addiction.…”

Section: Introductionmentioning

confidence: 63%

“…Remifentanil was dissolved in 0.9% sterile saline for intravenous selfadministration. For systemic administration, SB was prepared as de-scribed previously and injected intraperitoneally at a volume of 4.0 ml/kg (Bentzley and Aston-Jones, 2015;Porter-Stransky et al, 2017;James et al, 2018bFragale et al, 2019). For intra-VP microinjections, SB was dissolved in sterile artificial CSF (aCSF) to a concentration of 0.1, 0.5, and 1 mM, as described previously (Mahler et al, 2013).…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported that baseline demand for cocaine and fentanyl predicted other addiction behaviors including cueinduced reinstatement (Bentzley et al, 2014;James et al, 2019;Fragale et al, 2019). Thus, we sought to determine whether baseline demand for remifentanil also predicted reinstatement of remifentanil seeking (as measured by active lever responding).…”

Section: Baseline Demand For Remifentanil Predicts Cue-induced Reinstmentioning

confidence: 99%

“…We found that stimulation of lateral hypothalamus (LH) orexin neurons reinstated extinguished morphine seeking and that systemic pretreatment with the selective orexin-1 receptor (OxR1) antagonist SB-334867 (SB) blocked this effect (Harris et al, 2005). We also reported that systemic blockade of OxR1s attenuated cue-induced reinstatement of heroin, fentanyl, and remifentanil seeking (Smith and Aston-Jones, 2012;Porter-Stransky et al, 2017;Fragale et al, 2019). Using within-session behavioral economics (BE) procedures, we recently found that systemic OxR1 antagonism decreased demand for fentanyl and remifentanil (Porter-Stransky et al, 2017;Fragale et al, 2019).…”

Section: Introductionmentioning

confidence: 98%

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Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil

et al. 2019

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Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; ␣) for remifentanil without affecting remifentanil consumption at low effort. Baseline ␣ values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline ␣ values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists.

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Section: Baseline Demand For Remifentanil Predicts Cue-induced Reinstsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Section: Baseline Demand For Remifentanil Predicts Cue-induced Reinstmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil

et al. 2019

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The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

2020

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There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition-the ability to cancel ongoing behavior-is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop-signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards, consistent with other recent findings. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug-seeking behavior are not related to effects on response inhibition.

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Changes in fentanyl demand following naltrexone, morphine, and buprenorphine in male rats

Hammerslag

Hofford

Kang

et al. 2020

Drug and Alcohol Dependence

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Background-Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at μ opioid receptors, they may alter the relationship between price and opioid intake.Methods-This study examined demand for a commonly abused synthetic prescription opioid, fentanyl, in male rats following s.c. pre-treatment with naltrexone (0.1 -1.0 mg/kg), morphine (0.3 -3.0 mg/kg) or buprenorphine (0.3 -3.0 mg/kg). We normalized demand curves to intake at the lowest price and estimated effects on elasticity (sensitivity to changes in price). Rats were first trained to earn fentanyl (5 μg/kg/infusion) on a fixed ratio schedule, then they underwent daily training under a threshold procedure designed to produce within-session demand curve estimates. Rats received 14 threshold sessions before undergoing a series of tests encompassing each drug, at each dose.Results-Elasticity was increased by pretreatment with naltrexone, morphine or buprenorphine. Morphine also decreased initial intake, when the price for fentanyl was lowest. In contrast, initial intake was increased by naltrexone (according to an inverted-U shaped curve). The effects of naltrexone did not persist after the test session, but morphine and buprenorphine continued affecting demand elasticity 24 h or 48 h after the test, respectively.

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The Role of Orexin-1 Receptor Signaling in Demand for the Opioid Fentanyl

Cited by 8 publications

References 50 publications

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task

Changes in fentanyl demand following naltrexone, morphine, and buprenorphine in male rats

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