Kaufman Marc J, Meloni Edward G, Qrareya Alaa N, Paronis Carol A, Bogin Vlad
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Drug Alcohol Depend. 2024 Feb 1;255:110967. doi: 10.1016/j.drugalcdep.2023.110967. Epub 2023 Sep 19.
Opioid withdrawal symptoms (OWS) are highly aversive and prompt unprescribed opioid use, which increases morbidity, mortality, and, among individuals being treated for opioid use disorder (OUD), recurrence. OWS are driven by sympathetic nervous system (SNS) hyperactivity that occurs when blood opioid levels wane. We tested whether brief inhalation of xenon gas, which inhibits SNS activity and is used clinically for anesthesia and diagnostic imaging, attenuates naltrexone-precipitated withdrawal-like signs in morphine-dependent mice.
Adult CD-1 mice were implanted with morphine sulfate-loaded (60 mg/ml) minipumps and maintained for 6 days to establish morphine dependence. On day 7, mice were given subcutaneous naltrexone (0.3 mg/kg) and placed in a sealed exposure chamber containing either 21% oxygen/balance nitrogen (controls) or 21% oxygen/added xenon peaking at 30%/balance nitrogen. After 10 minutes, mice were transferred to observation chambers and videorecorded for 45 minutes. Videos were scored in a blind manner for morphine withdrawal behaviors. Data were analyzed using 2-way ANOVAs testing for treatment and sex effects.
Xenon-exposed mice exhibited fewer jumps (P = 0.010) and jumping suppression was detectible within the first 10-minute video segment, but no sex differences were detected. Brief inhalation of low concentration xenon rapidly and substantially attenuated naltrexone-precipitated jumping in morphine-dependent mice, suggesting that it can inhibit OWS. If xenon effects translate to humans with OUD, xenon inhalation may be effective for reducing OWS, unprescribed opioid use, and for easing OUD treatment initiation, which could help lower excess morbidity and mortality associated with OUD.
阿片类药物戒断症状（OWS）极具不适感，并促使人们非处方使用阿片类药物，这会增加发病率、死亡率，在接受阿片类药物使用障碍（OUD）治疗的个体中还会导致复发。OWS是由血液中阿片类药物水平下降时发生的交感神经系统（SNS）亢进所驱动的。我们测试了短暂吸入氙气是否能减轻纳曲酮诱发的吗啡依赖小鼠的戒断样体征，氙气可抑制SNS活动，临床上用于麻醉和诊断成像。
成年CD-1小鼠植入加载硫酸吗啡（60mg/ml）的微型泵，并维持6天以建立吗啡依赖。在第7天，给小鼠皮下注射纳曲酮（0.3mg/kg），并将其置于一个密封的暴露室中，该暴露室含有21%氧气/其余为氮气（对照组）或21%氧气/添加氙气，氙气峰值为30%/其余为氮气。10分钟后，将小鼠转移到观察室并进行45分钟的视频记录。对视频进行盲法评分以评估吗啡戒断行为。使用双向方差分析对数据进行分析，以测试治疗和性别效应。
暴露于氙气的小鼠跳跃次数较少（P = 0.010），并且在第一个10分钟的视频片段内就可检测到跳跃抑制，但未检测到性别差异。短暂吸入低浓度氙气可迅速且显著减轻纳曲酮诱发的吗啡依赖小鼠的跳跃，表明它可以抑制OWS。如果氙气的作用能转化到患有OUD的人类身上，吸入氙气可能对减少OWS、非处方阿片类药物使用以及缓解OUD治疗起始有效，这有助于降低与OUD相关的过高发病率和死亡率。
