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

Abstract

A suspension of killed cells of either Escherichia coli, Shigella dysenteriae or Salmonella typhosa was micro-injected through cannulae implanted at specific sites within the diencephalon and mid-brain of an unanesthetized monkey [Macaca mulatta]. A biphasic, monophasic or an undifferentiated fever was induced by each microorganism, but the type of response depended solely upon the injection locus. The rise in body temperature was, in each instance, dependent upon the concentration of the endotoxin. Tolerance to the pyrexic effect of repeated injections of endotoxin did not develop. The febrile response having the shortest latency, greatest maximum rise in temperature and largest 10-h fever index was evoked by micro-injections into the anterior hypothalamic, preoptic area. When given i.v., at least 100 times more endotoxin was required to evoke a fever similar to that produced by micro-injection into the anterior hypothalamic, preoptic region. Tolerance developed rapidly to the febrile effect of endotoxin administered by this route although toxic reactions were not observed. After the fever evoked by the hypothalamic injection of endotoxin had reached a plateau, 300-1200 mg Na salicylate administered intragastrically produced a dose-dependent fall in temperature, but had no effect on the body temperature of an afebrile monkey. In the rhesus monkey, a bacterial pyrogen can evoke a fever which is apparently mediated entirely by an action on the CNS, the principal site being the anterior hypothalamic, preoptic area. The 1st 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 NA salicylate counteracts a centrally evoked fever is not compatible with the hypothesis that an antipyretic exerts its action by preventing a circulating pyrogen from entering the CNS.