Distribution and actions of first signal transducers of fever within the brain

α-Prostaglandins – actions, enzymes, location and receptors

Prostaglandins are highly biologically active substances derived from polyunsaturated fatty acids. Those of particular concern to us in the study of fever are derivatives of arachidonic acid the structural formula of which is given in Fig. 5.1. Arachidonic acid is released from the phospholipids in cell membranes by the action of phospholipases and other lipases. A pathway from arachidonic acid to PGE2 using cyclo-oxygenase, peroxidase and PGE2 isomerase is given in Fig. 5.2. A closely similar prostaglandin, which induces febrile responses, is PGE1, the structural formula of PGE2 is shown in Fig. 5.3.

The immense amount of work on the role of prostaglandins on the CNS mediation of fever began with the observations of Milton & Wendlandt (1970). They injected endotoxin into the lateral cerebral ventricles of cats and observed that the resulting fever was prevented by the drug 4-acetamidophenol, a known antipyretic. Seeking to identify a substance or substances which might act as mediators of fever in the CNS, and which might be excreted into the csf, they noted something which had biological activity when tested on the rat stomach fundus strip, but they did not have sufficient material for its identification. Astutely realizing that the rat fundus strip was known to respond in a similar way to PGE1, they tried injecting microgram amounts of PGE1 into the cat's lateral cerebral ventricle and found that it caused a typical fever.