Subdiaphragmatic vagotomy blocks the sleep- and fever-promoting effects of interleukin-1beta

The mechanism by which peripheral cytokines signal the central nervous system to elicit central manifestations of the acute phase response remains unknown. Recent evidence suggests that cytokines may signal the brain via the vagus nerve. To test this possibility, we examined sleep-wake activity and brain temperature (Tbr) after the intraperitoneal administration of saline or three doses (0.1, 0.5, and 2.5 microg/kg) of interleukin-1beta (IL-1beta) in subdiaphragmatically vagotomized (Vx) and sham-operated (Sham) rats. The lowest dose of IL-1beta (0.1 microg/kg) increased non-rapid eye movement sleep (NREMS) and slightly elevated Tbr in Sham rats; both responses were blocked in Vx animals. The middle dose tested (0.5 microg/kg) increased NREMS and Tbr in Sham animals; however, in Vx rats, the increase in NREMS was attenuated and the increase in Tbr was blocked. The highest dose of IL-1beta used (2.5 microg/kg) induced increases in NREMS, decreases in rapid eye movement sleep, and a hypothermic response followed by a biphasic fever; these responses were similar in both Sham and Vx rats. These data provide strong evidence that the subdiaphragmatic vagus plays an important role in communicating both sleep and fever signals to the brain. However, there is clearly an alternative pathway by which IL-1 can signal the brain; whether it occurs through activation of other vagal afferents or through direct or indirect actions on the brain remains unknown.