Role of centrally administered melatonin and inhibitors of COX and NOS in LPS-induced hyperthermia and adipsia.

In the present study we have examined the effect of centrally administered non-steroidal anti-inflammatory drugs (NSAIDS), nitric oxide synthase (NOS) inhibitor and melatonin on lipopolysaccharide (LPS)-induced hyperthermia and its anti-dipsogenic effect. Intracerebroventricular (i.c.v.) administration of LPS (100-200 ng/rat) induces a dose dependent elevation in body temperature and decreases water consumption in 24 h water deprived rats. Coadministration of NSAIDS (indomethacin and nimesulide: 10 nM/rat each) with LPS (100 ng) reversed, whereas NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME: 10-20 microg/rat) enhanced LPS-induced hyperthermia. In contrast L-NAME reversed the LPS-induced anti-dipsogenic effect in a dose dependent manner, whereas NSAIDS showed no change in the effect of LPS. Further, centrally administered prostaglandin E2 (PGE2, 0.5-1 microg/rat) produced hyperthermia without affecting the drinking behavior, suggesting that two independent mechanisms operate in LPS-induced hyperthermia and in the anti-dipsogenic effect. The pineal hormone melatonin is known to inhibit cellular damage caused by LPS, produced dose dependent (5-10 nM i.c.v.) inhibition of LPS-induced hyperthermia and adipsia, but failed to reverse the PGE2-induced hyperthermia, shows reversal of LPS-induced hyperthermia by melatonin is due to inhibition of prostaglandin synthesis rather than antagonism of prostaglandin action. The overall study reveals that inhibition of both NO and prostaglandin production by melatonin might be responsible for its reversal of LPS-induced hyperthermia and adipsia.