Endocannabinoid signaling dissociates thermoregulatory and behavioral components of the sickness response to systemic inflammation.

Systemic inflammation triggers a coordinated sickness response that includes behavioral suppression, anorexia, and thermoregulatory alterations, often viewed as a unified syndrome. However, increasing evidence suggests that distinct neural circuits govern different components of sickness behavior. Whether central endocannabinoid system (ECS) signaling differentially regulates behavioral and thermoregulatory responses during systemic inflammation remains unclear. We therefore investigated the role of central ECS signaling in specific sickness domains induced by lipopolysaccharide (LPS). Male Wistar rats received intracerebroventricular pretreatment with the CB1 receptor antagonist AM251, the endocannabinoid transport inhibitor VDM11, the CB1 agonist WIN55,212-2, or vehicle prior to intraperitoneal administration of LPS (1 mg/kg) or saline. Behavioral responses were assessed using the open field test, forced-swim test, and 24-h food intake. Core body temperature was continuously monitored by telemetry for 6 h, and thermal indices were calculated for hypothermia (0-2 h) and fever (3-6 h). LPS induced a robust sickness phenotype characterized by reduced locomotion, increased immobility, hypophagia, and a biphasic thermoregulatory response. Central ECS manipulations produced minimal effects on behavioral endpoints. In contrast, thermoregulation was selectively sensitive to ECS modulation: CB1 receptor blockade enhanced LPS-induced hypothermia and markedly reduced fever, whereas increasing endocannabinoid tone attenuated hypothermia without affecting fever. These findings demonstrate that central ECS signaling selectively modulates thermoregulatory, but not behavioral, components of the sickness response, supporting a modular organization of sickness behavior.