Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice

Bedard, Madigan L.; Lord, Julia S.; Perez, Patric J.; Bravo, Isabel M.; Teklezghi, Adonay; Tarantino, Lisa M.; Diering, Graham H.; McElligott, Zoé A.

doi:10.1101/2022.04.06.487380

Cited by 6 publications

(14 citation statements)

References 74 publications

(165 reference statements)

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“…We found that female mice were less sensitive to the motor-suppressing effects of xylazine contrary to the recent findings in rats reported by Khatri et al (2023), potentially due to their use of repeated dosing of xylazine or species differences (25). Using a modified version of our 3-day precipitated withdrawal model (35)(36)(37), we show xylazine is indeed responsive to naloxone, contrary to common assumptions made by both medical professionals and in the media (7). Both males and females exhibited some level of somatic withdrawal behaviors to xylazine and naloxone, though females showed enhanced behavioral responding.…”

Section: Discussioncontrasting

confidence: 95%

“…Withdrawal from reinforcing substances is a critical component of the addiction cycle ( 45 – 47 ). Previously, we and others have used a 3-day repeated precipitated morphine withdrawal model to demonstrate that somatic symptoms exacerbate across withdrawal sessions ( 35–37, 48–51 ). Furthermore, we have shown that this model results in sleep disturbances and promotes long-lasting sex-dependent behavioral adaptations in both male and female mice over six weeks into forced abstinence ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

“…The following withdrawal behaviors were scored: escape jumps, paw tremors, jaw tremors, wet dog shakes, fecal boli count, grooming, and abnormal posture. Mice were returned to their home cages and precipitated withdrawal was repeated for 2 more days (35)(36)(37). Total counts for each behavior were recorded and a z-score was computed for each animal on each day of withdrawal (38).…”

Section: Precipitated Withdrawalmentioning

confidence: 99%

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Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration

Bedard,

Murray,

Huang

et al. 2023

Preprint

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Xylazine has been found in the unregulated drug supply at increasing rates, usually in combination with fentanyl. It has become critical to understand its basic pharmacology, how it impacts behavior, and how it interacts with fentanyl in rodent models of opioid administration. Despite commentary from scientists, politicians, and public health officials, it is not known if xylazine impacts the efficacy of naloxone, the opioid receptor antagonist used to reverse opioid induced respiratory depression. Furthermore, few studies have examined the effects of xylazine alone, without co-administration of ketamine. Here, we examine the impact of xylazine alone and in combination with fentanyl on several key behaviors in male and female mice. We demonstrate differential locomotor responses by dose and sex to xylazine. Surprisingly, our results further indicate that naloxone precipitates withdrawal from xylazine and a fentanyl/xylazine combination, in both sexes, with enhanced sensitivity in females. Further, we show that xylazine is a full agonist at the kappa opioid receptor, a potential mechanism for its naloxone sensitivity.One-Sentence SummaryWe present surprising new insights into xylazine and fentanyl pharmacology with immediate implications for clinical practice and frontline public health.

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Section: Discussioncontrasting

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Precipitated Withdrawalmentioning

confidence: 99%

See 1 more Smart Citation

Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration

Bedard,

Murray,

Huang

et al. 2023

Preprint

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“…Our recent study shows different effects of spontaneous and NPW on sleep in mice during and following a 3-day paradigm, indicating that the type of withdrawal can alter recovery from morphine exposure. 65 Other studies from the Rothwell lab showed that continuous morphine exposure resulted in tolerance to psychomotor effects while intermittent (daily injections, akin to spontaneous withdrawal) and interrupted (continuous minipump with NPW) resulted in sensitization to the psychomotor effects and that these effects were accompanied by downstream signaling changes. 76,77 Furthermore, more studies are needed to examine NPW following a single opioid exposure (sometimes called acute dependence 72 ) to shed light on the effects of fentanyl poisonings in those who are not opioid dependent.…”

Section: Modeling Opioid Withdrawalmentioning

confidence: 99%

“…continued proven to illuminate sex differences in withdrawal experiences. 65 Ultrasonic vocalizations have also been used to study withdrawal, particularly in neonates, and provide a useful measure of affective symptoms. 80 There are many other options available, and researchers should carefully determine the best ways to assess withdrawal.…”

Section: Withdrawal Behavior Scoringmentioning

confidence: 99%

All Hands on Deck: We Need Multiple Approaches To Uncover the Neuroscience behind the Opioid Overdose Crisis

Bedard,

Nowlan,

Martin del Campo

et al. 2023

ACS Chem. Neurosci.

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Opioid use disorder (OUD) affects millions of people throughout the United States, yet there are only three Food and Drug Administration-approved pharmacological treatments. Though these treatments have been shown to be effective, the number of overdose deaths continues to rise. The increase of fentanyl, fentanyl analogs, and adulterants in the illicit drug supply has further complicated treatment strategies. Preclinical researchers strive to model OUD to better understand this complicated disorder, and this research is a critical enabler for the development of novel treatments. As a result, there are many different preclinical models of OUD. Often, researchers form strong opinions on what they believe to be the "best" model to mimic the human condition. Here, we argue that researchers should be supportive of multiple models to promote new perspectives and discoveries and always consider the trends in human opioid use when designing preclinical studies. We describe the benefits of contingent and noncontingent models as well as models of opioid withdrawal and how each of these can help illuminate different components of OUD.

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Oral Fentanyl Consumption Alters Sleep Rhythms, Promotes Avoidance Behaviors, Impairs Fear Extinction Learning, and Alters Basolateral Amygdala Physiology in Male and Female Mice

Downs,

Kmiec,

McElligott

2023

Preprint

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The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the illicit drug supply. While many previous studies on fentanyl and other opioids have focused on intravenous administration, other routes of administration remain relatively understudied. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed enough fentanyl to precipitate withdrawal with naloxone, with males having more severe withdrawal symptoms. Fentanyl consumption disrupted normal sleep rhythms in both male and female mice. We also performed behavioral assays to measure approach/avoidance behavior and reward-seeking during fentanyl abstinence. Female mice showed more avoidance behaviors in the open field assay, whereas male mice showed evidence of these behaviors in the light/dark box assay. Female mice also showed increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning. Our experiments show that long-term oral fentanyl consumption disrupts sleep rhythms, promotes anxiety-like behavior, increases motivation for reward, and disrupts fear extinction learning. This model could be useful to further study fentanyl withdrawal syndrome and anxiety-like phenotypes associated with protracted fentanyl withdrawal.

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Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice

Cited by 6 publications

References 74 publications

Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration

Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to naloxone administration

All Hands on Deck: We Need Multiple Approaches To Uncover the Neuroscience behind the Opioid Overdose Crisis

Oral Fentanyl Consumption Alters Sleep Rhythms, Promotes Avoidance Behaviors, Impairs Fear Extinction Learning, and Alters Basolateral Amygdala Physiology in Male and Female Mice

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