Effects of inhaled low-concentration xenon gas on naltrexone-precipitated withdrawal symptoms in morphine-dependent mice

Abstract

Background: 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.

Methods: 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.

Results and conclusions: 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.

Keywords: Inhalation Therapy; Medications for opioid use disorder; Opioid withdrawal; Sympathetic nervous System; Xenon.

Figure 1

A: Procedures Before and After Gas Exposures – Naltrexone was administered before gas exposures. Gas concentrations over the 10-minute exposure periods are shown as means ± SEM of oxygen (O₂) and xenon (Xe) concentrations averaged for each 30 sec interval. Mouse transfer to individual behavioral observation chambers took at least 1 minute. Behavior then was videorecorded for 45 minutes. Figure 1B: Effects of Xenon on Jumping Counts – Shown are means ± SEM of jumping counts for controls (C) and Xe-treated (Xe) mice. Data from 26 male and 15 female mice were analyzed with Ns/group shown at each bar. *Xenon reduced jumping counts (F_1,37=7.3, P=0.0103). Figure 1C: Effects of Xenon on Jumping Counts Over Time – Shown are means ± SEM of jumping counts for 26 control and 15 Xe-treated mice in each observation period. We detected effects of treatment (F_1,156=11.2, P=0.001) and time (F_3,156=5.2, P=0.0019) on jumping counts. Post-hoc testing revealed an effect of xenon at reducing jumping counts in the first 10 minutes (*Tukey’s adjusted P=0.018 vs Control counts). These data suggest that xenon effects were rapid and that xenon accelerated the decline in naltrexone-precipitated jumping counts.