Influence of the duration of experimental fever on salicylate antipyresis in the rabbit

Abstract

Summary1. Steady state fever has been produced in rabbits with a priming injection followed by a sustaining infusion of homologous plasma containing endogenous pyrogen (EP). This fever appears to last as long as the infusion continues. 2. Intravenous salicylate given 1 h after the start of the EP infusion produced only a small antipyretic effect. The same dose of salicylate given 4 h after the start of an EP infusion resulted in rapid and progressive defervescence. Intermediate antipyretic responses were obtained when salicylate was administered intravenously 2 and 3 h after the start of an EP infusion.3. Less than 1 % of the systemic dose, when injected into a lateral cerebral ventricle, produced a significantly smaller response at 1 h than at 4 h after the start of an EP infusion. At both these times the fall in temperature following the intraventricular salicylate injection was dose dependent, but the slope of the dose-response line was significantly steeper at 4 h than at 1 hour. 4. It is suggested that salicylates produce their antipyretic effects by antagonizing the action of EP within the nervous system, and that the hypothalamic EP concentration falls during the course of an EP infusion.

A dissociation between fever and prostaglandin concentration in cerebrospinal fluid.

“…The failure of the salicylate to produce antipyresis confirms earlier reports of its weak antipyretic properties in rabbits (Grundman, 1969;Cranston et al 1970Cranston et al , 1971van Miert et al 1972). We have now shown that in spite of its failure to produce antipyresis, the salicylate prevented the appearance of prostaglandin in c.s.f.…”

“…Since the dose of leucocyte pyrogen used in our experiments was submaximal (cf. Cranston et al 1971) partial inhibition of prostaglandin synthesis might have been expected to cause partial abatement of the fever; none was observed. Veale & Cooper (1975) have recently reported that it is possible to create lesions in the brains of rabbits which render them insensitive to the hyperthermic effects of prostaglandins; they still develop fever in response to pyrogen.…”

“…All previous work on the relation between prostaglandin release and fever has been concerned with fevers following single injections of pyrogen. The second was to examine the action of sodium salicylate which, though inhibiting prostaglandin synthesis (Flower 1974), is only weakly antipyretic in rabbits (Grundman, 1969; Cranston et al 1970;van Miert, van Essen & Tromp, 1972), especially if administered early in the course of fever (Cranston, Luff, Rawlins & Wright, 1971).…”

Evidence that brain prostaglandin synthesis is not essential in fever.

“…Rectal temperature, measured by an indwelling thermistor, was recorded automatically at 5 min intervals. Using techniques described previously (Cranston, Luff, Rawlins & Wright, 1971) a guide tube was screwed to the skull plate. A sterilized stainless-steel cannula (0-56 nun o.d.)…”

Effects of intracerebral micro‐injection of sodium salicylate on temperature regulation in the rabbit

“…There is also evidence to suggest that salicylates might exert at least part of their action within the central nervous system since injections of small doses of sodium salicylate into the lateral cerebral ventricles of rabbits with experimental fever cause rapid, dosedependent defervescence (Cranston, Luff, Rawlins & Rosendorff, 1970). Further evidence suggests that salicylates exert their central effect on temperature by competitively antagonizing the effects of endogenous pyrogen within the brain (Cranston, Luff, Rawlins & Wright, 1971). The nature of this antagonism is not known, but if salicylates exerted their effects by antagonizing endogenous pyrogen directly, they might be expected to act at the same sites within the central nervous system as endogenous pyrogen.…”