Modulation of tramadol-induced hyperthermia by risperidone and ambient temperature in rats

Tramadol (TRA) overdose can induce severe hyperthermia associated with monoaminergic dysregulation, particularly serotonin toxicity, and may lead to fatal outcomes. Although supportive treatments such as hydration and external cooling are commonly used, effective pharmacological interventions are yet to be established. Here, we aimed to evaluate the effects of risperidone (RIS) and ambient temperature on TRA-induced hyperthermia and changes in central monoamines in a rat model. Male Wistar rats received intraperitoneal TRA (100 mg/kg) under ambient temperatures of 18 °C, 23 °C, or 28 °C. RIS (0.25 or 0.5 mg/kg) and various monoamine receptor antagonists were administered to assess pharmacological responses. Core body temperature and locomotor activity were continuously monitored via implantable sensors, and in vivo microdialysis was conducted in the anterior hypothalamus to quantify extracellular levels of serotonin (5-HT), norepinephrine (NA), and dopamine (DA). TRA significantly elevated 5-HT, NA, and DA levels in a temperature-dependent manner, with DA and NA being strongly affected by ambient temperature. RIS at 0.25 mg/kg effectively suppressed hyperthermia and reduced DA elevation, whereas the 0.5 mg/kg dose did not. 5-HT2A and D1 receptor antagonists replicated the hyperthermia-suppressive effect, whereas 5-HT1A, 5-HT2B/2C, and D2 antagonists did not. These findings suggest that RIS attenuates TRA-induced hyperthermia primarily via DA suppression through 5-HT2A and D1 receptor antagonism and that elevated environmental temperatures exacerbate monoaminergic dysfunction and hyperthermic outcomes. RIS may represent a potential therapeutic option for managing tramadol toxicity.