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Preoptic Nitric Oxide Modulates Endotoxic Fever by Controlling Local Norepinephrine Activity

Lipopolysaccharide (LPS) injected iv stimulates norepinephrine (NE) release in the preoptic‐anterior hypothalamus (POA). Since NE upregulates neuronal nitric oxide (NO) synthases and NO induces cyclooxygenase (COX)‐2‐dependent prostaglandin (PG)E2, we investigated whether NO mediates the production of COX‐2‐catalyzed PGE2 induced by the NE activation of POA α2‐adrenoceptors (AR). We injected LPS (2 μg/kg iv) into guinea pigs prepared with intraPOA microdialysis probes and, continuously microdialyzed SIN‐1 (NO donor, 20 μg/ μl) or carboxy‐PTIO (NO scavenger, 20 μg/ μl). POA interstitial fluid NE, PGE2 and core temperature (Tc) were measured. We also microdialyzed clonidine (α2‐AR agonist, 2 μg/μl) with and without SIN‐1 or carboxy‐PTIO, or (+)‐catechin (an antioxidant, 3μg/μl) into the POA of other animals, and likewise determined POA PGE2 and Tc. SIN‐1 and carboxy‐PTIO depressed and augmented, respectively, the rises in POA NE, PGE2 and Tc produced by iv LPS. Similarly, they prevented and increased, respectively, the delayed elevations of POA PGE2 and Tc induced by clonidine. (+)‐Catechin prevented LPS‐induced elevation of PGE2, but not that of Tc. We conclude that NO is an inhibitory modulator of LPS‐induced release of POA NE, acting as a central antipyretic. These data also implicate free radicals in the formation of preoptic PGE2 and question its obligatory role in fever production.