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

Bedard, Madigan L.; Huang, Xi-Ping; Murray, Jackson G.; Nowlan, Alexandra C.; Conley, Sara Y.; Mott, Sarah E.; Loyack, Samuel J.; Cline, Calista A.; Clodfelter, Caroline G.; Dasgupta, Nabarun; Krumm, Brian; Roth, Bryan L.; McElligott, Zoe A.

doi:10.1016/j.addicn.2024.100155

Cited by 8 publications

(2 citation statements)

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“…Our findings agree with recent work from our laboratory that found that males experienced more severe withdrawal from fentanyl, albeit in a model of non-contingent fentanyl administration. Interestingly, this same study demonstrated that the kappa-opioid system may play a larger role in somatic withdrawal in females vs. males 35 . While clinical studies generally report that women experience worse withdrawal symptoms than men, it is important to note that these studies are typically limited to heroin or illicit use of prescription opioids rather than fentanyl 57,58 .…”

Section: Discussionmentioning

confidence: 75%

“…The withdrawal behaviors evaluated included: escape jumps, paw tremors, jaw tremors, abnormal postures, wet dog shakes, grooming behaviors, and fecal boli number. Data were converted to a z-score for each behavior and a mean z-score of all behaviors together was calculated to generate a global withdrawal score for each mouse 34,35 .…”

Section: Opioid Withdrawal Behaviorsmentioning

confidence: 99%

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Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance 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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Section: Discussionmentioning

confidence: 75%

Section: Opioid Withdrawal Behaviorsmentioning

confidence: 99%