Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-
induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the
fever response to systemic
inflammation. We studied the interaction between central CCK signaling and the
cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with
intraperitoneal infusion of the nonselective COX
enzyme inhibitor metamizol (120 mg/kg) or a selective
COX-2 inhibitor,
meloxicam, or
etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by
metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with
metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by
metamizol. CCK-
induced hyperthermia was also completely blocked with both selective
COX-2 inhibitors studied. Finally, the
CCK2 receptor antagonist
YM022 (10 µg/kg icv) attenuated the late phases of
fever induced by bacterial
lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes
hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central
cholecystokinin signaling and the
cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of
cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of
cyclooxygenase. We also show that the activation of
cyclooxygenase-2 is required for the hyperthermic effect of
cholecystokinin and that
cholecystokinin is a modulator of
endotoxin-induced
fever.