Hypothalamic PGE2 and cAMP production and adrenocortical activation following intraperitoneal endotoxin injection: in vivo microdialysis studies in Lewis and Fischer rats.

Inflammatory disease-susceptible Lewis (LEW) rats exhibit reduced glucocorticoid release in response to inflammatory and neurotransmitter stimuli, compared to histocompatible Fischer (F/344) rats. This compromised hypothalamo-pituitary-adrenal (HPA) axis activity has been ascribed to a primary defect in hypothalamic corticotrophin-releasing factor-41 (CRF) secretion, possibly caused by abnormal signal transduction in the CRF neuron. In the present study, we have used in vivo microdialysis to asses the role of hypothalamic prostaglandin E2 (PGE2) and cyclic adenosine monophosphate (cAMP) in endotoxin-mediated HPA axis activation in adult hyporesponsive LEW and hyperresponsive F/344 rats. Basal plasma corticosterone concentration was significantly higher in F/344 relative to LEW rats; however, the basal levels of PGE2 and cAMP, recovered from microdialysis probes in the anterior hypothalamus, were significantly greater in the LEW rat. Lipopolysaccharide (LPS) (200 micrograms/kg) caused a time-dependent increase in corticosterone secretion, the magnitude of which was markedly greater in the F/344 rat. Both LEW and F/344 rats displayed a similar PGE2 profile in response to LPS, although in absolute terms the response was more pronounced in LEW rats. LPS caused a dose-related increase in cAMP production in the LEW rat and comparison with F/344 animals, following the 200 micrograms/kg dose of LPS, revealed a larger and more prolonged cAMP response in the LEW strain. Simultaneous administration of indomethacin (50 mg/kg) with LPS (200 micrograms/kg) in the LEW rat completely blocked the PGE2 and cAMP responses to the toxin and whilst the corticosterone response to LPS was significantly attenuated at 140 min, no difference was apparent by 240 min. Hence, PGE2 and cAMP participate in the hypothalamic response to endotoxin-mediated adrenocortical activation in both LEW and F/344 adult rats but the steroid and second messenger profiles are strain-specific. The cAMP response to LPS appears to depend on products of arachidonic acid metabolism, such as PGE2, and hence basal and stimulated production of these mediators may be effected by the steroid milieu.