Separate mechanisms inside and outside the blood—brain barrier inducing metabolic changes in febrile rabbits

1. We investigated the acute phase response induced by either intravenous (I.V.) or intracerebroventricular injections of bacterial endotoxin or endogenous pyrogen. These caused either monophasic or biphasic fever, and the response includes changes in plasma concentration of iron, zinc, copper, fibrinogen and in circulating leucocyte count. 2. The I.V. injection of a small dose of endotoxin or endogenous pyrogen produced a monophasic fever, while a large dose produced a biphasic fever. The ventricular injection of endogenous pyrogen produced a fever similar to the second phase of the biphasic fever. 3. The I.V. injection of a small dose of endotoxin or endogenous pyrogen produced a low plasma zinc 8 h after injection, while the ventricular injection of endogenous pyrogen produced a low plasma zinc 24 h after injection. The I.V. injection of a large dose of endotoxin or endogenous pyrogen induced a low plasma zinc 8 and 24 h after injection, suggesting that the hypozincaemia induced by the large dose was mediated by both peripheral and central action of endogenous pyrogen with different time courses. 4. The I.V. injection of the small dose did not affect the level of the plasma copper concentration but the I.V. injection of the large dose and the ventricular injection increased it 24 h after injection. It is considered that the plasma copper concentration is mainly controlled by the central action of endogenous pyrogen. 5. The changes in the plasma iron and fibrinogen concentration and the circulating white blood cell count induced by the different doses and by the different routes showed very similar patterns, indicating that these are simultaneously controlled by both peripheral and central actions of endogenous pyrogen. 6. The present results show that there are two separate mechanisms involved in the acute phase response, one inside and one outside the blood—brain barrier. From the consideration that endogenous pyrogen released from the phagocytic leucocytes induces fever and acute phase response by its action on both the peripheral target organs and the central nervous system, it is suggested that endogenous pyrogen acts both centrally and peripherally, in the same manner as other hormonal agents such as corticosteroids.