The role of cyclo-oxygenase and lipoxygenase in the interleukin-1-induced activation of the HPA axis: dependence on the route of injection.
Interleukin-1 (IL-1) has been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis, and to elevate cerebral concentrations of tryptophan and the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG). Eicosanoids have been shown to be involved in a number of the effects of IL-1, but their role in the activation of the HPA axis is controversial. We studied the effects of various cyclo- and lipoxygenase inhibitors on the neurochemical and HPA responses to IL-1. Pretreatment of mice with the cyclo-oxygenase inhibitors, indomethacin (10-25 mg/kg) or ibuprofen (10 mg/kg) failed to prevent the elevations of plasma corticosterone, or hypothalamic MHPG or tryptophan that followed intraperitoneally (IP) administered IL-1. Similar results were obtained with the nonspecific oxygenase inhibitor, BW 755C, and the lipoxygenase inhibitor, BW A4C. However, the cyclo-oxygenase inhibitor, diclofenac, did attenuate the IL-1-induced elevation of plasma corticosterone and the neurochemical changes. To resolve the conflicting data on the effect of indomethacin on the IL-1-induced elevation of plasma concentration, we studied the effects of indomethacin on the response to IL-1 injected intravenously (IV). By contrast with the response to IP IL-1, that to IV IL-1 was attenuated by indomethacin. Time course of the HPA response to IL-1 is more rapid following IP injections than IV, therefore we assessed the effects of IV IL-1, earlier than that to IP IL-1. Forty min following IP IL-1, the corticosterone response to IL-1 was markedly attenuated. This suggests that more than one mechanism is involved in the HPA response to IL-1. The more rapid one, predominant in the case of IV injections, is sensitive to cyclo-oxygenase inhibitors, whereas the slower one is not.
Dunn
A J
AJ
Department of Pharmacology and Therapeutics, Louisiana State University Medical Center, Shreveport 71130-3932.
Chuluyan
H E
HE
D000818:Animals; D003345:Corticosterone / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000032:analysis; D051379:Mice; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014364:Tryptophan / Q000032:analysis
D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D008734:Methoxyhydroxyphenylglycol; D014364:Tryptophan; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D003345:Corticosterone