Prostaglandins and the central nervous system.

PROSTAGLANDINS (PGs) are natural constituents of the brain and spinal cord. They are released from the central nervous system (CNS) spontaneously, in response to electrical and chemical stimulation and during fever. In addition to their action on brain-stem neurones when applied iontophoretically (Avanzino, Bradley and Wolstencroft, 1966) they have potent CNS effects which are now considered. Body temperature Probably the current most investigated aspect of PGs is their effect on body temperature (Tb). Thus PGEs infused into the brain of many species at various ambient temperatures (Ta), elevated Tb (Feldberg, 1975), the site of action (preoptic and anterior hypothalamic areas) being ostensibly indistinguishable from that for fever evoked by endogenous pyrogens. Exceptions to such a general finding are of interest in that some overlooked pharmacological feature of PGs may emerge. The adult spiny anteater is one such exception, since intraventricular PGE1 and PGE2 lowered Tb over a wide range of Ta although intravenous bacterial pyrogen (Eberthella typhi) induced fever (Baird, Hales and Lang, 1974). In the young chick, another non-placental animal, PGEs infused into the hypo-thalamus at thermoneutrality elevated Tb, whereas below thermoneutrality such infusion lowered Tb, partly by physical and partly by chemical thermo-regulatory mechanisms (Artunkal and Marley, 1974). During fever produced by endotoxin or endo-genous pyrogen, increased PG-like activity occurs in the cerebrospinal fluid (CSF) (Feldberg, 1975). The current hypothesis is that these agents enhance synthesis of PGs in brain, particularly within the preoptic/anterior hypothalamic area, through stimulation of the rate-controlling step releasing the precursor fatty acids; the PGs formed act locally on neurones to produce fever. PGs synthetized at other sites may act there to affect behaviour, or may do so at sites reached after transfer into the CSF. The aspirin-like drugs reduce fever and prevent release of PGEs into the CSF. Their therapeutic action is ascribed to inhibition of prostaglandin synthetase (Vane, 1971), brain synthetase being more sensitive to aspirin-like drugs than that of other tissues (Flower and Vane, 1972). If PG synthesis is an essential link in the action of pyrogen then it should not be possible to dissociate fever and brain synthesis of PGs. This has proved not to be the case for rabbits in which sustained fever was induced by intravenous infusion of endogenous pyrogen, yet the prior infusion of sodium salicyclate sufficient to inhibit PG synthesis by at least 50/4 did not significantly diminish fever although preventing an increase in PGs in …