The multiple actions of corticotropin-releasing factor (CRF) on neuroendocrine and behavioural functions can now be examined using new, high affinity, non peptidic antagonists which exhibit central activity upon systemic application. We have shown that compound CP 154,526 (butyl-ethyl-[2.5-dimethyl-7-(2、4、6-trimethyphenyl)-7H-pyrrtly [2.3d]pyrimidin-4-yl]amine) displaces [125][Tyo]CRF from rat hippocampal CRF receptors (ICso= 0.5 nM) and from pituitary CRF receptors (ICso=0.04 nM). The same compound inhibits in a concentration-dependent manner the ovine CRF (0.1 ixM)-stimulated adenylate cyclase activity in membranes of a mouse pituitary adenoma cell line, AtT20, with an ICso value of 50 nM. Systemic application of the CRF receptor antagonist (0.16mg/kgi.p.) blocked recombinant human interleukin-ll3 (5p.g/kgi.p.) induced fever in rats. The CRF receptor antagonist CP 154,526 (lmg/kgi.p.) also exhibited signs of anxiolytic-like activity in the elevated plus-maze test in rats.

Subchronic (36 h) exposure of rats to corticosterone (CS) (100 mg/pellet, subcutaneously), blocked the pyrogenic response to recombinant human interleukin 1b (rhIL-1b, 5 mg/kg, ip.). CS treatment reduced the basal mRNA levels of IL-1a and IL-1b, but elevated the mRNA levels of IL-6 in the hypothalamus and hippocampus as shown by RT-PCR. The CS treatment clamped the cytokine mRNA levels, and injection of rhIL-1b to CS treated rats did not significantly affect these altered mRNA levels. IL-6 bioactivity in serum was not significantly changed by CS treatment, but increased 50 times upon injection of rhIL-1b. rhIL-1b caused a significantly lower induction of serum IL-6 levels in CS pretreated rats (9-fold). The pyrogenic response to injection of rhIL-1b has returned 5 days after the removal of the corticosterone pellet, and the hypothalamic cytokine mRNA levels (IL-1a, IL-1b and IL-6) have returned to basal. These results suggest that altered and clamped hypothalamic IL-1a, IL-1b and IL-6 mRNA levels may be involved in the antipyretic effects of a pretreatment with high doses of CS and that these CS effects are rapidly reversible.

The interleukin-1 (IL-l) system possesses two distinct receptors (type I and type II) which, together with the accessory protein, mediate a multitude of responses to IL-la and IL-l@, including fever. So far, no receptor subtype-specific ligands have been described. Since both types of IL-l receptors occur in the thermoregulatory areas it was unclear which IL-l receptor type mediates fever. We report here that for a series of deletion mutants of human recombinant IL-lb (hrIL-l/I), the affinity of these ligands for the type I IL-1 receptor correlates with their efficacy to evoke the fever response (hrIL-l/I>des-SND 52-54>des-QGE48-50>des-156). Thus, the results suggest that agonist occupancy of the type I IL-l receptor is essential for IL-l/I-mediated fever.