THE ROLE OF CYCLOOXYGENASE 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.