A careful distinction has to be made between the loci of action in the CNS of endogenous mediators of fever generated by disease processes and the loci revealed by their topical administration for experimental purposes. The techniques for the demonstration of such loci have included the observation of the effects of naturally occurring or experimental lesions, the effects of topical application to various brain regions (by micro-injection perfusion, or micro-dialysis) and the localization of high densities of specific receptors for the fever mediators.

A number of attempts were made in the last century and early in this century to locate regions of the brain responsible for thermoregulation, and then to associate these with the actions of pyrogenic substances. Ott (1887) proposed four ‘thermotaxic’ regions of the brain namely, the corpus striatum, the tuber cinereum (probably identical to the anterior hypothalamus), and two areas of the cerebral cortex, and Ott in his 1914 lectures proposed these areas as the loci of action of pyrogenic substances. In 1915, Hashimoto injected pyrogens through cannulae into thermosensitive structures in the diencephalon, and found that these injections were more effective than systemic injections of the pyrogens. Likewise, Sheth & Borison (1960) injected salmonella endotoxin into the subarachnoid space or into the cerebral ventricles in cats and dogs and found that fever followed more readily than when the pyrogen was given intravenously.