Park Gwi H, Smith Eric M, Obert David P, Vincent Kathleen F, Solt Ken
From the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Department of Anesthesiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Anesth Analg. 2025 Jun 12. doi: 10.1213/ANE.0000000000007589.
Xylazine is an alpha-2 adrenergic agonist approved for veterinary use as a sedative and analgesic for animals. Unfortunately, xylazine has recently become a common adulterant of street drugs in the United States with xylazine-related overdoses and deaths increasing each year. Although the alpha-2 adrenergic antagonist, atipamezole, is an efficacious reversal agent for xylazine that is approved for use in animals, it is not approved for humans. In this study, we aimed to test alternative reversal agents for xylazine, and compare them with atipamezole in a rat model of xylazine-induced unconsciousness.
In adult Sprague-Dawley rats, we induced loss of righting reflex (LORR, a surrogate end point for loss of consciousness) with xylazine (5 mg/kg, intravenous [IV]) and attempted to restore consciousness by administering agents with distinct molecular mechanisms of action: atipamezole (alpha-2 adrenergic antagonist, 200 µg/kg IV); d-amphetamine (norepinephrine and dopamine reuptake inhibitor and releasing agent, 1 mg/kg); chloro-APB (dopamine D1 receptor agonist, 3 mg/kg IV); and atomoxetine (norepinephrine reuptake inhibitor, 3 mg/kg IV). Pulse oximetry and heart rate were monitored continuously. After administration of the reversal agents, time to return of righting reflex (RORR) was recorded (n = 12) and animals were assessed with a novel object recognition test (n = 17). One subset of animals underwent surgery to have electroencephalogram (EEG) leads implanted (n = 4). EEG data were recorded after xylazine injection and ensuing administration of a reversal agent and spectral analysis was performed.
After xylazine-induced unconsciousness, the median time to RORR in atipamezole-, d-amphetamine-, and chloro-APB-treated rats was 1.5 minutes (Interquartile Range [1.0-2.0]), 2 minutes (interquartile range [IQR] [1.0-3.0]), and 2 minutes (IQR [1.0-2.0]) post drug injection, respectively, compared to 56 minutes (IQR [39.5-70.5]) after saline control (F[4,40] = 41.62, P < .0001). Atomoxetine did not significantly accelerate time to RORR. During the novel object recognition test, all animals spent the same amount of time with the familiar and novel object (range 0-143.5 sec), indicating that no reversal agents restored recognition memory. Xylazine induced an EEG pattern dominated by slow-delta oscillations. Atipamezole, d-amphetamine, and chloro-APB restored EEG oscillations similar to the awake state.
Atipamezole, d-amphetamine, and chloro-APB accelerate emergence from xylazine-induced unconsciousness and restore EEG oscillation patterns consistent with wakefulness. However, none of these reversal agents restore recognition memory.
赛拉嗪是一种α-2肾上腺素能激动剂，被批准用于兽医领域，作为动物的镇静剂和镇痛药。不幸的是，赛拉嗪最近在美国已成为街头毒品的常见掺杂物，与赛拉嗪相关的过量用药和死亡人数每年都在增加。虽然α-2肾上腺素能拮抗剂阿替美唑是一种用于赛拉嗪的有效逆转剂，已被批准用于动物，但未被批准用于人类。在本研究中，我们旨在测试赛拉嗪的替代逆转剂，并在赛拉嗪诱导昏迷的大鼠模型中，将它们与阿替美唑进行比较。
在成年Sprague-Dawley大鼠中，我们用赛拉嗪（5mg/kg，静脉注射[IV]）诱导翻正反射消失（LORR，意识丧失的替代终点），并试图通过给予具有不同分子作用机制的药物来恢复意识：阿替美唑（α-2肾上腺素能拮抗剂，200μg/kg静脉注射）；右旋苯丙胺（去甲肾上腺素和多巴胺再摄取抑制剂及释放剂，1mg/kg）；氯-APB（多巴胺D1受体激动剂，3mg/kg静脉注射）；和托莫西汀（去甲肾上腺素再摄取抑制剂，3mg/kg静脉注射）。连续监测脉搏血氧饱和度和心率。在给予逆转剂后，记录恢复翻正反射（RORR）的时间（n = 12），并用新颖物体识别测试对动物进行评估（n = 17）。一组动物接受手术植入脑电图（EEG）电极（n = 4）。在注射赛拉嗪并随后给予逆转剂后记录EEG数据，并进行频谱分析。
赛拉嗪诱导昏迷后，阿替美唑、右旋苯丙胺和氯-APB治疗的大鼠恢复翻正反射的中位时间分别为注射药物后1.5分钟（四分位间距[1.0 - 2.0]）、2分钟（四分位间距[IQR][1.0 - 3.0]）和2分钟（IQR[1.0 - 2.0]），而生理盐水对照组为56分钟（IQR[39.5 - 70.5]）（F[4,40] = 41.62，P <.0001）。托莫西汀没有显著加快恢复翻正反射的时间。在新颖物体识别测试中，所有动物与熟悉物体和新颖物体相处的时间相同（范围为0 - 143.5秒），这表明没有逆转剂能恢复识别记忆。赛拉嗪诱导的EEG模式以慢δ振荡为主。阿替美唑、右旋苯丙胺和氯-APB恢复了类似于清醒状态的EEG振荡。
阿替美唑、右旋苯丙胺和氯-APB可加速赛拉嗪诱导昏迷后的苏醒，并恢复与清醒状态一致的EEG振荡模式。然而，这些逆转剂均不能恢复识别记忆。
