Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats.
Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats.
复制标题
Xylazine 在自我给药过程中抑制芬太尼的消耗，并诱导大鼠体内纳洛酮不会改变的独特的性别特异性戒断综合征。
DOI：
10.1037/pha0000670
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发表时间：
2024
影响因子：
2.3
通讯作者：
Gipson,CassandraD
中科院分区：
文献类型：
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作者：
Khatri,ShaileshN;Sadek,Safiyah;Kendrick,PercellT;Bondy,EmmaO;Hong,Mei;Pauss,Sally;Luo,Dan;Prisinzano,ThomasE;Dunn,KellyE;Marusich,JulieA;Beckmann,JoshuaS;Hinds,TerryD;Gipson,CassandraD
处方和非法阿片类药物的使用是一场公共卫生危机，随着形势转向芬太尼的使用。由于芬太尼的效力是吗啡的100倍，因此其使用与致命过量的更高风险相关，可以通过纳洛酮（Narcan）给药进行补救。然而，最近的报告表明，甲苯噻嗪，麻醉剂，越来越多地检测到意外芬太尼过量死亡。传闻报告表明，甲苯噻嗪可能延长芬太尼的“高”，改变芬太尼戒断的发作，并增加对纳洛酮诱导的过量逆转的抵抗力。迄今为止，据我们所知，尚未有临床前研究评价赛拉嗪对芬太尼自我给药（SA; 2.5 μg/kg/输注）或停药的影响。我们建立了甲苯噻嗪/芬太尼共SA和戒断的大鼠模型，并评估了生物性别的功能结果。当单独给药时，慢性甲苯噻嗪（2.5 mg/kg，腹膜内）诱导了独特的性别特异性戒断症状，雌性动物表现出体征延迟发作，并可能增强了对甲苯噻嗪运动抑制作用的敏感性。与单独使用芬太尼SA相比，无论是实验者给药还是添加到静脉芬太尼产品中（0.05、0.10和0.5 mg/kg/输注），甲苯噻嗪均降低了雄性和雌性大鼠的芬太尼消耗量。有趣的是，当自我静脉给药时，这种作用具有剂量依赖性。纳洛酮（0.1 mg/kg，皮下注射）未增加芬太尼戒断的躯体体征，无论两种性别的芬太尼输注中是否包含甲苯噻嗪;然而，与芬太尼SA单独给药后的雌性动物相比，甲苯噻嗪/芬太尼联合SA给药后各时间点的戒断躯体体征更高，无论纳洛酮暴露如何。总之，这些结果表明，甲苯噻嗪/芬太尼co-SA剂量依赖性地抑制两种性别的芬太尼摄入量，并在雌性动物中诱导了一种独特的戒断综合征，急性纳洛酮治疗未改变该症状。
Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl “high,” alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date, no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 μg/kg/infusion) or withdrawal to our knowledge. We established a rat model of xylazine/fentanyl co-SA and withdrawal and evaluated outcomes as a function of biological sex. When administered alone, chronic xylazine (2.5 mg/kg, intraperitoneal) induced unique sex-specific withdrawal symptomatology, whereby females showed delayed onset of signs and a possible enhancement of sensitivity to the motor-suppressing effects of xylazine. Xylazine reduced fentanyl consumption in both male and female rats regardless of whether it was experimenter-administered or added to the intravenous fentanyl product (0.05, 0.10, and 0.5 mg/kg/infusion) when compared to fentanyl SA alone. Interestingly, this effect was dose-dependent when self-administered intravenously. Naloxone (0.1 mg/kg, subcutaneous injection) did not increase somatic signs of fentanyl withdrawal, regardless of the inclusion of xylazine in the fentanyl infusion in either sex; however, somatic signs of withdrawal were higher across time points in females after xylazine/fentanyl co-SA regardless of naloxone exposure as compared to females following fentanyl SA alone. Together, these results indicate that xylazine/fentanyl co-SA dose-dependently suppressed fentanyl intake in both sexes and induced a unique withdrawal syndrome in females that was not altered by acute naloxone treatment.