A study of pyretics in rats and mice
In this study, the suitability of rodents for the detection and assay of microbial pyrogens was investigated and the pathophysiology of the 'yeast rat' model, currently used for screening antipyretic drugs, was documented. Mice do not consistently develop pyrexia following systemic injections of bacterial endotoxin (BE). These findings are in contrast to the dose-dependent hyperthermia observed in mice following intrahypothalamic injections of prostaglandin E2 (PGE2), a putative central mediator of pyrexia. Hyperthermia was associated with a decrease in skin temperature or an increase in oxygen consumption depending on the ambient temperature. These results suggest that mice have the ability to co-ordinate thermoregulatory mechanisms to raise their body temperature. Unlike PGE2, BE injected into the preoptic and anterior hypothalamic nuclei did not consistently raise body temperature in mice. This suggests that the failure of systemically administered endotoxin to consistently induce pyrexia is not due to insufficient quantities of pyrogen reaching the central thermoregulatory centres. However, central injections of BE may not mimic the central events occurring during the development of pyrexia as a result of peripheral infection. The inconsistent effect of systemic endotoxin on body temperature in mice in this study suggests that this species is unsuitable for the assay of microbial pyrogens. Unlike mice, rats developed pyrexia following systemic injections of BE; the doses of BE required were at least 100 fold greater than those reported for the rabbit (see General Introduction), rendering rats less sensitive than other species as models for the detection and assay of microbial pyrogens. Yeast also raised body temperature in rats. Pyrexia coincided with the acute phase of a yeast-induced inflammatory response. An abscess was formed at the site of injection; this subsequently developed into a chronic granuloma. The pyrogenic response to yeast was not directly attributable to inflammatory mediators associated with increased vascular permeability, phagocytosis or granuloma formation. It is unlikely therefore, that antipyretic activity displayed by drugs tested in the 'yeast rat' model is due to peripheral anti-inflammatory activity. However, results from this study suggest that BE may be a suitable replacement for yeast as a pyrexic challenge in rats for screening antipyretics. BE would be less emotive than yeast and would not induce a chronic granuloma. No endogenous pyrogenic mediators were detected in yeast-treated rats. No endogenous pyrogen (EP) was obtained from rat blood or peritoneal exudates in vitro. Either rats do not release detectable EP or attempts in this study to activate rat white blood cells in vitro do not mimic events occurring in vivo. Athymic rats injected with yeast developed pyrexia which suggests that Interleukin 1 is not an endogenous pyrogenic mediator unless its release is independent of T-cell derived lymphokines. Changes in thermoregulatory behaviour following pyrogen administration in rats were studied as an alternative method for assaying pyrogens. Detectable changes in thermoregulatory behaviour can precede but do not always accompany changes in body temperature in rats. Therefore, body temperature was considered to be a more reliable measure of thermoregulatory changes than behaviour in this study.