Mechanisms of heat stress potentiation of fentanyl lethality in rats

Introduction. As a rule, preclinical safety assessment of narcotic analgesic agents is conducted at ambient temperatures of 20–24 °C. However, their clinical use may occur under different thermal conditions. Previous studies have demonstrated the ability of heat stress to potentiate the lethal and narcotic effects of fentanyl in rats, yet the mechanisms underlying this phenomenon remain unknown.

Objective. Testing hypotheses on the mechanisms of fentanyl toxicity potentiation in rats under heat stress conditions.

Materials and methods. The study was conducted on outbred male albino rats weighing 191–210 g. We investigated the effects of intravenous fentanyl administration at a dose of 200 μg/kg and/or a 40-min exposure to an ambient temperature of 40 °C on body temperature and mass, brain moisture content and mass, glutamine concentration in brain tissue, biochemical parameters of blood collected from the a. carotis communis and v. jugularis interna, and oxygen consumption by brain homogenates. Statistical analysis was performed using the OriginPro software.

Results. Fentanyl administration induced opisthotonus, coma, bradypnea, and fundal cyanosis. The 40-min lethality following fentanyl injection was 0–9% at an ambient temperature of 22 °C and 68–71% at an ambient temperature of 40 °C. In surviving rats removed from the thermal chamber, rectal temperature was elevated to 42.9 °C. The relative mass of the freshly isolated brain and the brain dried to a constant weight increased by 7.4% and 7.2%, respectively. Glutamine content in brain tissue increased by 46%. Plasma concentrations of ammonia, creatinine, and lactate were elevated by 2.0–2.2, 2.1–2.3, and 1.5–1.6 times, respectively. In the absence of fentanyl administration, no lethality was observed in rats placed in the thermal chamber. Rectal temperature increased to 42.7 °C. The relative mass of the freshly isolated brain and the dried brain increased by 6.1% and 8.9%, respectively. Brain glutamine content increased by 43%. Plasma creatinine levels rose by 2.2–2.4 times, and lactate levels increased by 25–45%. In the absence of heat stress, fentanyl increased plasma creatinine concentration only by 1.6–1.8 times. The arteriovenous gradient of plasma ammonia concentration was positive in all animals. Oxygen consumption by brain homogenates decreased by 10% under isolated heat stress and increased by 7% under a combined action of heat stress and fentanyl administration.

Conclusions. Hypoxemia, lactic acidemia, and hyperammonemia were necessary conditions for the aggravating effect of heat stress on acute fentanyl intoxication in rats. Conversely, irreversible thermal damage to biological tissues, organism dehydration, cerebral edema, swelling, hyperemia, and glutamine accumulation in the brain were not identified as such necessary conditions.

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