Effect of general hyperthermia and local cooling on fentanyl tolerance in rats

Ju. Ju. Ivnitsky; O. A. Vakunenkova; A. I. Golovko; N. V. Lapina; V. L. Rejniuk

doi:10.47183/mes.2025-311

Effect of general hyperthermia and local cooling on fentanyl tolerance in rats

Ju. Ju. Ivnitsky, O. A. Vakunenkova, A. I. Golovko, N. V. Lapina, V. L. Rejniuk

https://doi.org/10.47183/mes.2025-311

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Abstract

Introduction. The toxicity of a number of xenobiotics increases with air temperature. However, it remains unknown whether this applies to narcotic analgesics and whether this dependence can be corrected by first aid measures recommended for heat stroke.

Objective. Evaluation of the effect of elevated air temperatures and local cooling on the acute toxicity of fentanyl.

Materials and methods. Three series of experiments were conducted. In the first series, the effect of elevated air temperatures on the dose dependence of the lethal and narcotic effects of fentanyl was studied. In total, 11 groups of 20 rats each were formed, which were intravenously administered fentanyl at doses of 50, 100, 200, 300, or 400 μg/kg, and one group (n = 14) without drug administration. Following fentanyl administration, one subset of rats (n = 100) was kept for 24 h at an air temperature of 22 °C; the second subset (n = 100) was kept for 40 min in a thermal chamber at 40 °C and then for 24 h at 22 °C. Those not receiving fentanyl were observed in a thermal chamber until the first case of death, then for 24 h at 22 °С. In the second series of experiments, the effect of head cooling on lethality, latent awakening time, and rectal temperature of rats (n = 49) 40 min after intravenous administration of fentanyl at a dose of 300 μg/kg (LD₅) was studied. Four groups of animals were formed, which were kept after fentanyl administration for 40 min at 22 or 40 °С with or without local cooling of the neurocranium, followed by observation for 24 h at 22 °С. In the third series of experiments, following the same scheme, the effect of cooling the middle third of the ventral surface of the torso on lethality, latent awakening time, and rectal temperature of rats (n = 48) 40 min after fentanyl administration at the same dose was studied. Statistical analysis was performed using the OriginPro software.

Results. A 40-min exposure at 40 °С was non-lethal for intact rats. After administration of fentanyl at doses of 100–400 μg/kg, lethality reached 0–5% and 60–95% at 22 °С and 40 °С, respectively. Hyperthermia induced by 40 °С exposure under fentanyl administration at a dose of 300 μg/kg was mitigated by head cooling and prevented by cooling the ventral surface of the torso. Cooling the ventral surface of the torso, rather than the head, reduced lethality from 100% to 8%. At 22 °С, both local cooling methods deepened fentanyl-induced hypothermia without significantly affecting lethality or anesthesia duration.

Conclusions. The general overheating potentiates the lethal and narcotic effects of fentanyl in rats. Under these conditions, cooling the ventral surface of the torso is an effective measure to prevent hyperthermia and lethality, while head cooling is ineffective. At room temperature, both local cooling methods deepen fentanyl-induced hypothermia without significantly affecting lethality. The efficacy of cooling the ventral surface of the torso requires evaluation not only during combined overheating but also during isolated overheating of the organism.