A cyclooxygenase-2 inhibitor attenuates spontaneous and TNF-alpha-induced non-rapid eye movement sleep in rabbits.

Sleep is regulated in part by the brain cytokine network, including tumor necrosis factor-alpha (TNF-alpha). TNF-alpha activates the transcription factor nuclear factor-kappaB, which in turn promotes transcription of many genes, including cyclooxygenase-2 (COX-2). COX-2 is in the brain and is an enzyme responsible for production of prostaglandin D2. The hypothesis that central COX-2 plays a role in the regulation of spontaneous and TNF-alpha-induced sleep was investigated. Three doses (0.5, 5, and 50 microg) of NS-398, a highly selective COX-2 inhibitor, were injected intracerebroventricularly. The highest dose decreased non-rapid eye movement sleep. The intermediate and highest doses decreased electroencephalographic slow-wave activity; the greatest reduction occurred after 50 microg of NS-398 during the first 3-h postinjection period. Rapid eye movement sleep and brain temperature were not altered by any dose of NS-398. Pretreatment of rabbits with 5 or 50 microg of NS-398 blocked the TNF-alpha-induced increases in non-rapid eye movement sleep, electroencephalographic slow-wave activity, and brain temperature. These data suggest that COX-2 is involved in the regulation of spontaneous and TNF-alpha-induced sleep.