Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota

Ren, Michelle; Lotfipour, Shahrdad

doi:10.3390/microorganisms10061127

Cited by 12 publications

(4 citation statements)

References 48 publications

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“…However, these responses were similar in males and females, indicating that both sexes are responsive to the rewarding and reinforcing effects of heroin self-administration. This was consistent with a lack of sex differences in opioid intake at fixed and progressive ratios reported by Ren and Lotfipour in a fentanyl self-administration model (63). While sex effects were not observed in heroin intake, our results show that the gut microbiome was significantly altered after the selfadministration and extinction/reinstatement phases of contingent heroin intake by comparison to saline-yoked controls.…”

Section: Discussionsupporting

confidence: 92%

Long access heroin self-administration significantly alters gut microbiome composition and structure

Greenberg,

Winters,

Zagorac

et al. 2024

Front. Psychiatry

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IntroductionIt is well known that chronic opioid use disorder is associated with alterations in gastrointestinal (GI) function that include constipation, reduced motility, and increased bacterial translocation due to compromised gut barrier function. These signs of disrupted GI function can be associated with alterations in the gut microbiome. However, it is not known if long-access opioid self-administration has effects on the gut microbiome.MethodsWe used 16S rRNA gene sequencing to investigate the gut microbiome in three independent cohorts (N=40 for each) of NIH heterogeneous stock rats before onset of long-access heroin self-administration (i.e., naïve status), at the end of a 15-day period of self-administration, and after post-extinction reinstatement. Measures of microbial α- and β-diversity were evaluated for all phases. High-dimensional class comparisons were carried out with MaAsLin2. PICRUSt2 was used for predicting functional pathways impacted by heroin based on marker gene sequences.ResultsCommunity α-diversity was not altered by heroin at any of the three phases by comparison to saline-yoked controls. Analyses of β-diversity showed that the heroin and saline-yoked groups clustered significantly apart from each other using the Bray-Curtis (community structure) index. Heroin caused significant alterations at the ASV level at the self-administration and extinction phases. At the phylum level, the relative abundance of Firmicutes was increased at the self-administration phase. Deferribacteres was decreased in heroin whereas Patescibacteria was increased in heroin at the extinction phase. Potential biomarkers for heroin emerged from the MaAsLin2 analysis. Bacterial metabolomic pathways relating to degradation of carboxylic acids, nucleotides, nucleosides, carbohydrates, and glycogen were increased by heroin while pathways relating to biosynthesis of vitamins, propionic acid, fatty acids, and lipids were decreased.DiscussionThese findings support the view that long access heroin self-administration significantly alters the structure of the gut microbiome by comparison to saline-yoked controls. Inferred metabolic pathway alterations suggest the development of a microbial imbalance favoring gut inflammation and energy expenditure. Potential microbial biomarkers and related functional pathways likely invoked by heroin self-administration could be targets for therapeutic intervention.

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Section: Discussionsupporting

confidence: 92%

Long access heroin self-administration significantly alters gut microbiome composition and structure

Greenberg,

Winters,

Zagorac

et al. 2024

Front. Psychiatry

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“…The current study builds upon previous findings and demonstrates that 2 hours of access to 2.5 µg/kg/infusion of fentanyl over 14 days is sufficient to establish escalation of fentanyl intake and result in withdrawal symptoms in mice. Previous literature has investigated rodent models of opioid dependence, including morphine (47)(48)(49), oxycodone (10,12,50,51), heroin (6,(52)(53)(54), remifentanil (34,(55)(56)(57)(58), and fentanyl (24,33,36,38,(59)(60)(61)(62)(63)(64)(65)(66), using various routes of administration, with the majority of studies done in rats. IVSA of fentanyl has been widely studied in rats (24,25,(59)(60)(61)(62)(67)(68)(69)(70)(71), with findings demonstrating mixed results on the development of dependence and withdrawal signs.…”

Section: Discussionmentioning

confidence: 99%

“…Previous literature has investigated rodent models of opioid dependence, including morphine (47)(48)(49), oxycodone (10,12,50,51), heroin (6,(52)(53)(54), remifentanil (34,(55)(56)(57)(58), and fentanyl (24,33,36,38,(59)(60)(61)(62)(63)(64)(65)(66), using various routes of administration, with the majority of studies done in rats. IVSA of fentanyl has been widely studied in rats (24,25,(59)(60)(61)(62)(67)(68)(69)(70)(71), with findings demonstrating mixed results on the development of dependence and withdrawal signs. One previous study reported that rats undergoing 14 days IVSA of fentanyl for 6 hours per day maintained a consistent rate of self-administration (62).…”

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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“…Alpha diversity includes richness, referring to the number of overall microbial species present in a sample, as well as evenness, referring to the distribution of abundance of all species in the sample. Previous studies on the influence of opioids on alpha diversity report conflicting results (Lee et al, 2018;Ren and Lotfipour, 2022;Zhang et al, 2021), likely due to differences in the type of opioid administered, timing and length of dosing schedule, as well as timepoints sampled after opioid exposure; however, the majority report a decrease in alpha diversity with chronic opioid use (Cruz-Lebrón et al, 2021;Gicquelais et al, 2020;Ren and Lotfipour, 2022;Sharma et al, 2020;Wang et al, 2018).…”

Section: Introductionmentioning

confidence: 98%

Perinatal Morphine Exposure Induces Long-Term Changes in the Intestinal Microbiota of Male and Female Rats

Harder,

Dauriat,

Chassaing

et al. 2023

Preprint

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The increased use of opioids by women of reproductive age has resulted in a dramatic rise in number of infants exposed to opioids in utero. Although perinatal opioid exposure (POE) has been associated with an elevated risk of infection and hospitalization later in life, the mechanism(s) by which opioids influence immune development and maturation is not fully elucidated. Alterations in the intestinal microbiota composition, which leads to changes in immune training and maturation, could be at play. Chronic opioid use in adults is associated with a proinflammatory and pathogenic microbiota composition; therefore, we hypothesized here that in utero morphine exposure could negatively affect intestinal microbiota composition, leading to alterations in immune system function. We report that a clinically-relevant model of perinatal opioid exposure, in rats, induces profound intestinal microbiota dysbiosis that is maintained into adulthood. Furthermore, microbial maturity was reduced in morphine-exposed offspring. This suggests that increased risk of infection observed in children exposed to opioids during gestation may be a consequence of microbiota alterations with downstream impact on immune system development. Further investigation of how perinatal morphine induces dysbiosis will be critical to the development of early life interventions designed to ameliorate the increased risk of infection observed in these children.

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Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota

Cited by 12 publications

References 48 publications

Long access heroin self-administration significantly alters gut microbiome composition and structure

Long access heroin self-administration significantly alters gut microbiome composition and structure

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

Perinatal Morphine Exposure Induces Long-Term Changes in the Intestinal Microbiota of Male and Female Rats

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