Neurotransmitter Mechanisms of Ketamine and Ketamine–Magnesium Sulfate-Induced Hypothermia: Evidence for Serotonergic and Adrenergic Involvement Without GABAA Contributions

Ketamine and a ketamine-magnesium sulfate combination lower body temperature in rats through serotonergic and adrenergic mechanisms, but not through GABAA receptors. Giving yohimbine, an α2-adrenergic blocker, deepened ketamine-induced hypothermia at doses of 0.5 and 1 mg/kg, while only the highest dose (3 mg/kg) enhanced the combination's effect. Methysergide, a serotonin blocker, had opposite effects depending on dose: 1 mg/kg worsened ketamine hypothermia, whereas 0.5 mg/kg reduced the combination's cooling effect. Bicuculline, a GABAA antagonist, did not change hypothermia from either treatment. These findings clarify neurotransmitter pathways involved in NMDA antagonist-related thermoregulation.

Study at a glance

Abstract

Background: Ketamine and magnesium sulfate are commonly used perioperatively to prevent shivering, a frequent and clinically relevant complication of spinal and general anesthesia. Although their hypothermic effects are well documented, the neurotransmitter mechanisms underlying these effects remain insufficiently understood. This study examines whether serotonergic, adrenergic (α2), and GABAergic (GABAA) systems contribute to hypothermia induced by ketamine and a ketamine-magnesium sulfate combination. Methods: Body temperature was measured in Wistar rats after administration of ketamine (10 mg/kg) or the ketamine (5 mg/kg)-magnesium sulfate (5 mg/kg) combination. To assess neurotransmitter involvement, animals received yohimbine (α2 antagonist), methysergide (non-selective 5-HT antagonist), or bicuculline (GABAA antagonist) prior to ketamine or the drug combination. Data were analyzed using two-way repeated measures ANOVA followed by Tukey's post hoc test. Results: Yohimbine at 0.5 and 1 mg/kg significantly potentiated ketamine-induced hypothermia, while only 3 mg/kg enhanced the effect of the ketamine-magnesium sulfate combination. Methysergide had a bidirectional influence: 1 mg/kg methysergide deepened ketamine-induced hypothermia, whereas 0.5 mg/kg methysergide attenuated the hypothermic effect of the ketamine-magnesium sulfate combination. Bicuculline (1-2 mg/kg) did not alter the hypothermic responses to ketamine or the combination. Conclusions: These findings indicate that ketamine- and ketamine-magnesium sulfate-induced hypothermia is primarily modulated by serotonergic and adrenergic mechanisms, whereas GABAA receptor-dependent pathways do not appear to play a major role under the experimental conditions used. These results provide new mechanistic insights into NMDA antagonist-related thermoregulation and may help inform anesthetic strategies for shivering prevention and maintenance of perioperative thermal stability.