SUMMARY1. We investigated the central role of corticotrophin-releasing factor (CRF-41) in psychological stress-induced responses, including cardiovascular, thermoregulatory and locomotive activity in free-moving rats.2. Psychological stress was induced by cage-switch stress. After rats were placed in the novel environment, blood pressure, heart rate, body temperature and locomotive activity significantly increased. The intracerebroventricular (i.c.v.) injection of a-helical CRF(9-41), a CRF-41 receptor antagonist, significantly attenuated the stress-induced hypertension, tachycardia, hyperthermia and increase in locomotive activity. However, in unstressed rats, the i.c.v. injection of a-helical CRF(9-41) had no effect on physiological parameters measured in this study.3. In unstressed rats, the i.c.V. injection of CRF-41 (1 ,ug and 10 ,ug) increased blood pressure, heart rate, body temperature and locomotive activity in a dosedependent manner. The changes in these responses were quite similar to those observed during cage-switch stress.4. The results suggest that central CRF-41 plays an important role in psychological stress-induced hypertension, hyperthermia, tachycardia and increase in locomotive activity. However, it is likely that central CRF-41 does not contribute to normal cardiovascular and body temperature regulation when rats are free from stress.

SUMMARY1. Intravenous bacterial endotoxin, or endogenous pyrogen, in high concentration both caused biphasic fever in rabbits. In low concentration they produced only the first phase of fever.2. Subcutaneous indomethacin suppressed the first phase of fever produced by high concentration of intravenous endotoxin or endogenous pyrogen, but not the second phase.3. Intraventricular cerebral injection of indomethacin reduced the second phase of fever produced by high concentration of intravenous endotoxin or endogenous pyrogen, but not the first phase.4. Intraventricular cerebral injection of endotoxin or of endogeneous pyrogen caused slow monophasic fever. This was suppressed by intraventricular, but not by subcutaneous, indomethacin.5. It is concluded that the first phase of biphasic fever is caused by pyrogen acting via structures outside the blood-brain barrier, presumably peripheral nerves, and the second phase by pyrogen acting via structures within the blood-brain barrier, presumably hypothalamic neurones.

SUMMARY1. We investigated the effect of pre-treatment with intraperitoneal (i.P.) injection of indomethacin, an inhibitor of prostaglandin synthesis, on psychological stressinduced responses including cardiovascular, thermoregulatory and hormonal responses in free-moving rats.2. Psychological stress was induced by cage-switch stress. After the rats were placed in the novel environment, blood pressure, heart rate and body temperature significantly increased. Plasma levels of adrenocorticotrophic hormone (ACTH) and prostaglandin E2 were significantly higher 30 min after exposure to stress, in comparison to the normal levels.3. Pre-treatment with i.P. indomethacin significantly suppressed the increases in body temperature induced by cage-switch stress, but had no effect on increases in blood pressure and heart rate induced by this stress. Indomethacin also significantly suppressed the increases in the plasma levels of ACTH and prostaglandin E2 induced by cage-switch stress. 4. The present results suggest that prostaglandins are involved in the development of hyperthermia and the ACTH response induced by psychological stress.

SUMMARY1. Intravenous (i.v.) injection of human recombinant interleukin-la (IL-la) produced dose-dependent monophasic fevers in rats. Moreover, the i.v. injection of IL-la produced dose-dependent rises in the plasma concentrations of adrenocorticotrophic hormone (ACTH) 30 min after injections with dosages of 5 ,ag/kg and 15,tg/kg of IL-la.2. The febrile responses induced by the i.v. injection of IL-la (15 ,tg/kg) were completely abolished, and conversely hypothermia occurred, when the animals were pre-treated with a cyclo-oxygenase inhibitor, indomethacin (INDO). Pre-treatment with INDO also inhibited the increase in the plasma concentrations of ACTH induced by i.v. injection of IL-la (15 ,tg/kg), indicating that enhancement of plasma concentrations of ACTH induced by i.v. injection of IL-la is processed through the action of prostaglandins.3. Intrapreoptic injection of prostaglandin E2 produced a dose-dependent fever with a rapid onset at doses of 25 and 100 ng. Moreover, the intrapreoptic injection of prostaglandin E2 increased the plasma concentrations of ACTH in a dosedependent manner 30 min after injections.4. The intrapreoptic injection of IL-la (20 ng) caused slow monophasic fever. However, no significant elevation of plasma concentrations of ACTH was observed 30, 90 and 180 min after the intrapreoptic injection of IL-lot, as compared with the ACTH levels at each time in the control group which received an intrapreoptic injection of saline.5. These results suggest that intrapreoptic prostaglandin E plays an important role in the ACTH response by inducing the release of corticotrophin-releasing factor (CRF).

SUMMARY1. The effects of microinjection of prostaglandin D2, E2 and F2<,C and of endogenous pyrogen on the rectal temperature of rabbits were extensively examined in sixtyeight brain regions and in the third cerebral ventricle.2. Intracerebroventricular injection of both prostaglandins E2 and F2X produced dose-dependent fever over a range of 100-1000 ng. The selective brain regions, the nucleus broca ventralis, preoptic area, anterior hypothalamus and the ventromedial hypothalamus, responded to microinjections of a small dose (< 200 ng) of prostaglandins E2 and F2. by producing fever. Furthermore, the lateral hypothalamus, ventral thalamus, substantia nigra and the trigeminal nucleus were also sensitive to high concentrations of prostaglandins E2 and F2., fever being produced.It is likely that prostaglandin D2 is not involved in fever induction.3. The ventricular injection of endogenous pyrogen also produced fever. However, brain regions sensitive to microinjection of endogenous pyrogen were exclusively localized to regions near the organum vasculosum laminae terminalis (OVLT), such as the nucleus broca ventralis and the preoptic area. In contrast to the monophasic fever induced by prostaglandins E2 and F2a, about 30 min after ventricular or cerebral injection of endogenous pyrogen the rectal temperature gradually started to rise and the fever was prolonged over 4 h. 4. We investigated the effect of an inhibitor of prostaglandin synthesis, sodium salicylate, on biphasic fever induced by intravenous injection of bacterial endotoxin. The microinjections of sodium salicylate into the bilateral regions near the OVLT suppressed the second peak but had no effect on the first peak.5. The present study clarifies that there exist two separate mechanisms of induction of biphasic fever. Correlating with the first peak of biphasic fever, prostaglandins synthesized outside the blood-brain barrier act on multiple sites in the central nervous system to induce fever. Correlating with the second peak, endogenous pyrogen acts on regions near the OVLT to synthesize and release pyrogenic prostaglandins.