Interaction between norepinephrine and prostaglandin E(2) in the preoptic area of guinea pigs

The release of norepinephrine (NE) and prostaglandin E(2) (PGE(2)) in the preoptic-anterior hypothalamus (POA) by systemically administered pyrogens suggests that both substances may mediate the febrile response. To investigate their possible interaction, we measured directly the levels of PGE(2) in the extracellular fluid of the POA of conscious guinea pigs micro-dialyzed intrapreoptically with exogenous NE over the entire course of their febrile response to endotoxin. Acidified and buffered NE (NE(a), NE(b)), artificial cerebrospinal fluid (aCSF(a), aCSF(b)), and vehicle (Veh(a), Veh(b)) were tested. All but aCSF(b) depressed the febrile response to endotoxin. The microdialysis of aCSF(a), aCSF(b), Veh(a), Veh(b), and NE(a) did not change basal preoptic PGE(2) levels. However NE(b), at a dose that by itself did not affect body temperature (T-b), caused a large elevation in preoptic PGE(2). The intravenous injection of endotoxin increased the level of PGE(2) in the POA. NE(b) potentiated this increase, whereas NE(a), aCSF(a), and Veh(b) reduced it; Veh(a) reduced it for the first 60 min and enhanced it for the last 90 min of the experiment. Thus these data suggest that the low pH of the NE solute and/or its Veh may confound the observed effects of NE on the T-b and preoptic PGE(2) induced by endotoxin. We surmise that this is due to a neurotoxic action of the antioxidants and the acidity of the solution on thermosensitive neurons in the POA. Hence, the results of experiments using exogenous, usually acidified, NE preparations that often also contain additives should be interpreted with caution.