EVIDENCE FOR AN INTRAMEDULLARY PROSTAGLANDIN-DEPENDENT MECHANISM IN THE ACTIVATION OF STRESS-RELATED NEUROENDOCRINE CIRCUITRY BY INTRAVENOUS INTERLEUKIN-1

We have provided evidence that the stimulatory effects of intravenous interleukin-1 (IL-1) on neurosecretory neurons in the paraventricular nucleus (PVH) that express corticotropin-releasing factor (CRF) depend specifically on the integrity of catecholaminergic projections origin ating in caudal medulla. Here we report on experiments designed to tes t alternative means by which circulating IL-1 might access medullary a minergic neurons, including mechanisms involving sensory components of the vagus, the area postrema, or perivascular cells bearing IL-1 rece ptors. Neither abdominal vagotomy nor area postrema lesions reliably a ltered Fos expression induced in the medulla or PVH in response to a m oderately suprathreshold dose of IL-1 beta. Cytokine-stimulated increa ses in CRF mRNA in the PVH were also unaffected by either ablation. By contrast, systemic administration of the cyclooxygenase inhibitor ind omethacin resulted in parallel dose-related attenuations of IL-1 effec ts in hypothalamus and medulla. Microinjections of prostaglandin E2 (P GE2; greater than or equal to 10 ng) in rostral ventrolateral medulla, the principal seat of IL-1-sensitive neurons that project to the PVH, provoked discrete patterns of cellular activation in hypothalamus and medulla that mimicked those seen in response to intravenous IL-1. We interpret these findings as supporting the hypothesis that paracrine e ffects of PGE2 released from perivascular cells in the medulla as a co nsequence of IL-1 stimulation and, acting through prostanoid receptors on or near local aminergic neurons that project to the PVH, contribut e to the stimulatory effects of increased circulating IL-l on neurons constituting the central limb of the hypothalamo-pituitary-adrenal axi s.