Fever produced by endotoxin injected into the hypothalamus of the monkey and its antagonism by salicylate.

1. A suspension of the killed cell bodies of either E. coli, S. dysenteriae or S. typhosa was micro-injected through cannulae implanted chronically at specific sites within the diencephalon and mid-brain of the unanaesthetized monkey. A biphasic, monophasic or an undifferentiated fever could be induced by each type of micro-organism, but the type of response depended solely upon the locus of injection.2. Although little difference in the potency of the three pyrogens was found, the rise in body temperature was in each instance dependent upon the concentration of the endotoxin. A more intense fever was accompanied by shivering, vasoconstriction of the ear vessels, piloerection and huddling behaviour. Tolerance to the pyrexic effect of repeated injections of endotoxin did not develop.3. The febrile response having the shortest latency, greatest maximum rise in temperature and largest 10-hr fever index was evoked by micro-injections into the anterior hypothalamic, preoptic area. The incidence of biphasic fevers was also greater after endotoxin was injected into this same region. Endotoxin given similarly in the posterior hypothalamus or in the mesencephalon had either no effect or produced a smaller elevation in temperature after a longer latency. The distance of an injection site from the coronal plane formed by the optic chiasm and anterior commissure correlated significantly with the latency and magnitude of the temperature change as well as the fever index.4. When given intravenously, endotoxin in a quantity at least 100 times greater was required to evoke a fever similar to that produced when the pyrogen was micro-injected into the anterior hypothalamic, preoptic region. However, a biphasic fever was evoked with a latency of from 3 to 15 min when a larger amount of endotoxin was injected intravenously. Tolerance developed rapidly to the febrile effect of endotoxin administered by this route although toxic reactions were not observed.5. After the fever evoked by the hypothalamic injection of endotoxin had reached a plateau, 300-1200 mg sodium salicylate administered intragastrically produced a dose-dependent fall in temperature, but had no effect on the body temperature of an afebrile monkey.6. It is concluded that in the rhesus monkey, a bacterial pyrogen can evoke a fever which is mediated entirely by an action on the central nervous system, the principal site being the anterior hypothalamic, preoptic area. The first phase of a biphasic fever caused by bacteria acting either by the central or peripheral route seems to be due either to a direct action of the pyrogen on the cells of the anterior hypothalamus, or to the secondary release within this region of an intermediary thermogenic substance such as 5-hydroxytryptamine or prostaglandin. The finding that sodium salicylate counteracts a centrally evoked fever is not compatible with the hypothesis that an antipyretic exerts its action by preventing a pyrogen that is circulating in the blood stream from entering the central nervous system.