SUMMARYI. Several possible mechanisms of the antipyretic action of indomethacin administered i.v. were examined in the unanaesthetized cat.2. Indomethacin did not decrease bacterial endotoxin-induced release of endogenous pyrogen in vivo.3. Indomethacin (5-40 ltg/kg) inhibited the pyrogenic effect of peripherally or centrally administered leucocytic pyrogen. A dose of 10 fg/kg caused a parallel shift to the right of the log dose-response curve for i.v. leucocytic pyrogen and reduced the potency of the pyrogen at least 50 %. 4. Incubation of leucocytic pyrogen with indomethacin did not alter its pyrogenic potency.5. Indomethacin exerted only a slight non-dose-related hypothermic effect in afebrile animals.6. Indomethacin (up to 1 mg/kg) did not diminish the hyperthermic response to intraventricular administration of prostaglandin E1.7. This pattern of activity indicates that indomethacin acts centrally to inhibit an effect of leucocytic pyrogen.

1 The effect of morphine on body temperature was studied in conscious, unrestrained cats provided with implanted third or lateral cerebral ventricular cannulae, jugular venous catheters and retroperitoneal thermocouples. 2 Intraventricular injections of 2.5-50 pg and intravenous injections of 1-10 mg/kg morphine sulphate produced dose-related hyperthermic responses. Similar mean increases in body temperature after administration of a given dose were elicited in cats which had not previously received morphine and, provided that tolerance was avoided by spacing injections at least 72 h apart, in cats which received a series of injections of morphine. Morphine was at least 850 times more potent when injected into the third ventricle than when given intravenously. Increasing the dose of morphine sulphate injected into the third ventricle to 1250 jig only prolonged the hyperthermia. Morphine did not produce hypothermia at any dose tested. 3 Injection of 10 gg morphine sulphate into the third ventricle produced similar hyperthermias at ambient temperatures (tas) of 4-6, 21-23 and 33-36°C. The increase in body temperature was associated with shivering at the lower tas. At the highest ta, shivering was not evoked, but respiratory rate decreased after morphine if it was initially elevated. These results suggest that morphine increased the level at which body temperature was regulated. 4 Neither metiamide nor indomethacin antagonized morphine so histamine and prostaglandins were apparently not required for the hyperthermic effect.

SUMMARY1. Cholera enterotoxin was used to evaluate a possible role of endogenous cyclic AMP in production of hyperthermia. Injection of purified toxin (0-10-10 ,ug in 0t10 ml.) into the lateral cerebral ventricle of unanaesthetized cats caused dose-related hyperthermic responses. Heating the toxin for 40 min at 900 C abolished its hyperthermic activity.2. Intraventricular administration ofdibutyryl cyclic AMP (250-1000 ltg) also caused hyperthermia which, however, was preceded by transient periods of hypothermia and/or excitation in about half of the tests.3. Paracetamol, indomethacin and sodium salicylate inhibited hyperthermic responses to cholera enterotoxin. Paracetamol and indomethacin also inhibited hyperthermia induced by dibutyryl cyclic AMP (sodium salicylate was not tested).4. It is likely that the hyperthermic effect of cholera enterotoxin in the cat is mediated via endogenous cyclic AMP and that the antipyretics inhibit this effect by an action subsequent to the increase in cyclic AMP.5. It is unlikely that prostaglandin-induced hyperthermia in the cat is mediated via cyclic AMP since these antipyretics do not inhibit this response to prostaglandin E1.

induced hyperthermia in only one of two studies. This reduction was comparable to the hypothermic effect of indomethacin in afebrile animals and was attributed to a non-specific action on thermoregulatory function rather than to inhibition of prostaglandin synthesis. Indomethacin antagonized endotoxin and leucocytic pyrogen to a greater degree than it did arachidonate.6. Comparison of the relative effectiveness of the antipyretics in blocking hyperthermic responses to pyrogens and to sodium arachidonate indicates that, if prostaglandins do mediate pyrogen-induced fever, these antipyretics exert their primary action at a step before prostaglandin synthesis.