Xylazine effects on opioid-induced brain hypoxia

Abstract

Rationale: Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression.

Objectives: In this study, we examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats.

Results: In the temperature experiment, we found that intravenous xylazine at low, human-relevant doses (0.33, 1.0, 3.0 mg/kg) dose-dependently decreases locomotor activity and induces modest but prolonged brain and body hypothermia. In the electrochemical experiment, we found that xylazine at the same doses dose-dependently decreases nucleus accumbens oxygenation. In contrast to relatively weak and prolonged decreases induced by xylazine, intravenous fentanyl (20 μg/kg) and heroin (600 μg/kg) induce stronger biphasic brain oxygen responses, with the initial rapid and strong decrease, resulting from respiratory depression, followed by a slower, more prolonged increase reflecting a post-hypoxic compensatory phase, with fentanyl acting much quicker than heroin. The xylazine-fentanyl mixture eliminated the hyperoxic phase of oxygen response and prolonged brain hypoxia, suggesting xylazine-induced attenuation of the brain's compensatory mechanisms to counteract brain hypoxia. The xylazine-heroin mixture strongly potentiated the initial oxygen decrease, and the pattern lacked the hyperoxic portion of the biphasic oxygen response, suggesting more robust and prolonged brain hypoxia.

Conclusions: These findings suggest that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths.

Keywords: Brain hyperoxia; Brain hypoxia; Cerebral vasoconstriction; Fentanyl; Heroin; Hypothermia; Peripheral vasodilation.

Figure 1.

Changes in temperature induced by iv xylazine at different doses (0.33, 1.0 and 3.0 mg/kg in awake, freely moving rats. A = Absolute temperature changes. B = relative temperature changes; C = Brain-muscle and skin-muscle differentials. D = Locomotor activity. Filled symbols show values significantly different from pre-injection baseline.

Figure 2.

Relative changes in NAc oxygen levels induced by xylazine at different doses (0.3, 1.0 and 3.0) in freely moving rats. A = mean (±SEM) changes assessed with slow (1-min) time resolution. B = mean (±SEM) changes assessed with rapid (10-s) time resolution. Filled symbols show values significantly different from pre-injection baseline. n = numbers of averaged responses

Figure 3.

Mean (±SEM) changes in NAc oxygen levels induced by fentanyl (20 ug/kg) and its mixture with xylazine (20 ug/kg + 1 mg/kg) in freely moving rats. A = mean (±SEM) changes assessed with slow (1-min) time resolution. B = mean (±SEM) changes assessed with rapid (10-s) time resolution. Filled symbols show values significantly different from pre-injection baseline. n = numbers of averaged responses. Bold horizontal lines with asterisk show time intervals, during which between-group values were significant.

Figure 4.

Primary data examples of changes in electrochemical currents (nA) induced by fentanyl and fentanyl-xylazine mixture in freely moving rats. A = fentanyl alone (20 ug/kg), B = fentanyl (20 ug/kg)+xylazine (1 mg/kg), typical example; C and D = unusual changes induced by fentanyl-xylazine mixture with convulsions. Values of reduction current are shown with original (1-s) time resolution, and they were inverted. Since basal reduction currents widely varied between sensors, data were analyzed as the change relative to basal value=100%. Convulsions were never seen after fentanyl alone, but they occurred in 3 cases (in 2 rats) after injections of fentanyl-xylazine mixture.

Figure 5.

Mean (±SEM) changes in NAc oxygen levels induced by heroin (600 ug/kg) and its mixture with xylazine (600 ug/kg + 1 mg/kg) in freely moving rats. A = mean (±SEM) changes assessed with slow (1-min) time resolution. B = mean (±SEM) changes assessed with rapid (10-s) time resolution. Filled symbols show values significantly different from pre-injection baseline. n = numbers of averaged responses. Bold horizontal lines with asterisk show time intervals, during which between-group values were significant.