Opioid withdrawal: role in addiction and neural mechanisms

Monroe, Sean C; Radke, Anna K.

doi:10.1007/s00213-023-06370-2

Cited by 8 publications

(12 citation statements)

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“…Previous preclinical studies have shown that opioid withdrawal produces both acute physical/somatic symptoms and more delayed affective symptoms including anxiety-, depression-, and anhedonia-like behaviors (Monroe and Radke, 2023). The time course of withdrawal-induced anxiety differs in the literature based on the opioid regimen employed such that some studies have shown it at the 1-week post-withdrawal timepoint that we tested and others have shown a more delayed expression (Welsch et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Li,

McElroy,

Phillips

et al. 2024

J Psychopharmacol

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Background: The serotonin (5-hydroxytryptamine (5-HT))-mediated system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous studies showed that stress and drug exposure can modulate the dorsal raphe nucleus (DRN)-5-HT system via γ-aminobutyric acid (GABA)A receptors. Moreover, GABAA receptor-mediated inhibition of serotonergic DRN neurons is required for stress-induced reinstatement of opioid seeking. Aim/methods: To further test the role of GABAA receptors in the 5-HT system in stress and opioid-sensitive behaviors, our current study generated mice with conditional genetic deletions of the GABAA α1 subunit to manipulate GABAA receptors in either the DRN or the entire population of 5-HT neurons. The GABAA α1 subunit is a constituent of the most abundant GABAA subtype in the brain and the most highly expressed subunit in 5-HT DRN neurons. Results: Our results showed that mice with DRN-specific knockout of α1-GABAA receptors exhibited a normal phenotype in tests of anxiety- and depression-like behaviors as well as swim stress-induced reinstatement of morphine-conditioned place preference. By contrast, mice with 5-HT neuron-specific knockout of α1-GABAA receptors exhibited an anxiolytic phenotype at baseline and increased sensitivity to post-morphine withdrawal-induced anxiety. Conclusions: Our data suggest that GABAA receptors on 5-HT neurons contribute to anxiety-like behaviors and sensitivity of those behaviors to opioid withdrawal.

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Section: Discussionmentioning

confidence: 99%

Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Li,

McElroy,

Phillips

et al. 2024

J Psychopharmacol

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“…Another study found female mice spent decreased time in the center of the open field 6 weeks post-morphine withdrawal (47), suggesting the effects observed in the current study may persist even longer. Affective withdrawal symptoms have been suggested to be the main contributors to substance use disorder rather than somatic withdrawal signs (79, 80). Finding of increased mechanical pain sensitivity and increased anxiety-like behavior in the current study suggests a strong relevance of the IVSA of fentanyl model to studying FUD.…”

Section: Discussionmentioning

confidence: 99%

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Chen,

Xiao,

Kimbrough

2024

Preprint

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BackgroundThe rise in overdose deaths from synthetic opioids, especially fentanyl, necessitates the development of preclinical models to study fentanyl use disorder (FUD). While there has been progress with rodent models, additional translationally relevant models are needed to examine excessive fentanyl intake and withdrawal symptoms.MethodsThe study performed intravenous self-administration (IVSA) of fentanyl in male and female C57BL/6J mice for 14 days. Mechanical pain sensitivity during withdrawal was assessed using the von Frey test. Anxiety-like behavior was evaluated via the open field test one-week into abstinence and incubation of craving for fentanyl was assessed four weeks into abstinence.ResultsBoth male and female mice demonstrated a significant escalation in fentanyl intake over the 14 days of self-administration, with significant front-loading observed in the final days of self-administration. Increased mechanical pain sensitivity was present from 36- to 48-hour into withdrawal and increased anxiety-like behavior was found 1 week into abstinence. Four weeks into abstinence, mice showed significantly higher active lever pressing than the final self-administration session prior to abstinence.ConclusionsThe study establishes a translationally relevant mouse model of IVSA of fentanyl, effectively encapsulating critical aspects of FUD, including escalation of drug intake, front-loading behavior, withdrawal symptoms, and prolonged craving for drug into abstinence. This model offers a robust basis for further exploration into behavioral and neurobiological mechanisms involved in fentanyl dependence and potential therapeutic strategies.

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“…[50][51][52] Such effects are believed to be driven at least in part by reduced mesolimbic dopamine system function. 3,14 Although persistent motivational deficits have also been observed after more protracted periods of opioid withdrawal, [15][16][17]53 other findings suggest that motivational function recovers over time. 51,52 There have also been numerous reports of food-motivated behaviour becoming elevated during opioid withdrawal, particularly after long drug-free periods.…”

Section: Discussionmentioning

confidence: 99%

“…13,62,76,77 Importantly, acute morphine withdrawal triggers pronounced activation of the dynorphin-kappa opioid receptor (KOR) system, 3,14,78 which is notable given reports that KOR stimulation disrupts motivation 79 and cognition 78 but can promote hedonic reactivity to food stimuli. 77 However, chronic morphine exposure also leads to widespread changes in other neurochemical systems and neural circuits that are known to mediate food reward consumption and pursuit, 3,14 which may contribute to findings reported here.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Endogenous opioid systems are important regulators of feeding and food-motivated behaviour 13 and are persistently altered by chronic opioid exposure. 14 However, it remains unclear precisely how chronic opioid exposure and withdrawal impact the way food rewards are valued and pursued. For instance, animals with a history of opioid exposure display either diminished [15][16][17] or heightened [18][19][20][21][22] palatable food reward seeking and consumption, depending on study parameters such as withdrawal interval.…”

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confidence: 99%

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Differential effects of acute and prolonged morphine withdrawal on motivational and goal‐directed control over reward‐seeking behaviour

Halbout,

Hutson,

Agrawal

et al. 2024

Addiction Biology

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Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal‐directed control over reward seeking. Specifically, morphine‐withdrawn rats were impaired in using current reward value to select actions both when relying on prior action‐outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal‐directed action selection. However, brief re‐exposure to morphine was sufficient to impair motivation and disrupt goal‐directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine‐paired context cues and in the absence of response‐contingent feedback. We suggest that these opioid‐withdrawal induced deficits in motivation and goal‐directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

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Opioid withdrawal: role in addiction and neural mechanisms

Cited by 8 publications

References 252 publications

Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Differential effects of acute and prolonged morphine withdrawal on motivational and goal‐directed control over reward‐seeking behaviour

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Opioid withdrawal: role in addiction and neural mechanisms

Cited by 8 publications

References 252 publications

Role of α1-GABAA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Role of α1-GABAA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Differential effects of acute and prolonged morphine withdrawal on motivational and goal‐directed control over reward‐seeking behaviour

Contact Info

Product

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Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression

Role of α1-GABA_A receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression