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We have reviewed the evidence in favor of a prostaglandin mediator of the thermal responses in fever and found that PGE injected into the hypothalamus does not always cause fever, that cerebrospinal fluid concentrations of PGE are not reliable reflections of hypothalamic events, and that antipyretic drugs may act in ways other than inhibiting PGE synthesis. Fever is not blocked by prostaglandin antagonists, nor by ablation of PGE-sensitive areas of the brain. There is poor correlation between the effects of pyrogens and of PGE on cerebral neurons. There is evidence that at least one prostanoid other than prostaglandin is a mediator of fever, but the prostanoid has not been identified yet. We conclude that PGE may contribute to the neural responses in fever but is not essential.

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Rabbits were made febrile by an intravenous injection of homologous endogenous pyrogen (Interleukin 1). When naloxone (0.1 mg/kg i.v.) followed by 0.06 mg (kg X hr)-1 infusion) was given at the same time as the pyrogen, the resulting fever was indistinguishable from that following pyrogen alone. It appears unlikely that opioid receptors which are blocked by naloxone play an important part in the fever process.

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In rabbits the third cerebral ventricle was perfused using a push-pull cannula. Prostaglandin E2 concentration in the perfusate was measured by radioimmunoassay. Prostaglandin concentration rose during fever induced by an intraventricular injection of endogenous pyrogen. Both fever and the increased prostaglandin concentration were suppressed by the intraventricular injection of 100 micrograms of the protein synthesis inhibitor, anisomycin. A possible interpretation of the findings is that anisomycin inhibits the formation of phospholipase A2. If this is true, the implication is that phospholipase A2 has a rapid turnover in brain.

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Injection of two chemically dissimilar inhibitors of phospholipase A2 (mepacrine and parabromophenacylbromide) into the cerebral ventricles of rabbits inhibited the febrile response to endogenous pyrogen given by the same route. 2. The same doses of the inhibitors given intravenously did not affect the febrile response to endogenous pyrogen given into the ventricles, indicating that their action was central. 3. When given intraventricularly the inhibitors did not affect the maintenance of core temperature in a cold environment, indicating that they did not impair thermoregulatory ability. 4. The inhibitors had no effect on the temperature rise following intraventricular injection of arachidonic acid. 5. These observations are compatible with the proposition that one or more metabolic products of arachidonic acid other than prostaglandin are involved in pyrogenesis.

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1. Anisomycin has been given into the cerebral ventricles of rabbits. The inhibitory action of a range of doses on fever and on [14C]leucine incorporation into hypothalamic protein has been studied. 2. Fever was far less sensitive to inhibition by anisomycin than was incorporation of [14C]leucine. The dose--response curves showed a general similarity in shape, which would be compatible with the hypothesis that protein synthesis may be necessary for the production of fever. 3. A comparison was made of the effects of giving anisomycin into the cerebral ventricles 0, 30 or 60 min after the intraventricular injection of leucocyte pyrogen. Anisomycin inhibited fever to some extent even when given 60 min after leucocyte pyrogen. This suggests that if protein synthesis is involved in fever, it may continue at least into the early phase of rising temperature, but probably not to any significant extent after the plateau has been reached.

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1. To test further the hypothesis that brain protein synthesis is necessary for fever, three structurally similar trichothecene antibiotics were injected into the cerebral ventricles of rabbits. They were 3,15-diacetoxy-12-hydroxytrichothec-9-ene (DAHT), 3,15-didesacetyl-calonectrin (DDAC) and T-2 toxin. Their actions on hypothalamic incorporation of [14C]leucine and fever were compared. 2. DDAC (60 micrograms) and T-2 toxin (10 micrograms) strongly inhibited leucine incorporation and fever. DAHT (60 micrograms) did not diminish fever and had a smaller effect upon leucine incorporation. 3. The findings strengthen considerably earlier suggestions that brain protein synthesis is an essential step in pyrogenesis.

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Injection (iv) of human urine into rabbits results in a fall in body temperature accompanied by peripheral vasodilation in a thermoneutral ambient temperature and suppression of shivering metabolism in the cold. There were no consistent changes in mean arterial pressure in response to the injection of urine. If the production of urine is prevented by occlusion of the ureters of rabbits, body temperature falls. Injection of endogenous pyrogen (iv) into rabbits, which have had their ureters occluded, results in a significant attenuation in the magnitude of the fever as compared to controls. These observations suggest that there is an endogenously produced cryogenic substance ("endogenous cryogen") normally excreted in an active form by the kidneys and which when either injected, or prevented from being excreted (by clamping the ureters), results in a regulated fall in body temperature. In addition, in human patients on regular dialysis treatment who still had residual renal function, the oral temperature was slightly below normal before hemodialysis and slightly above normal after hemodialysis, a difference averaging 0.39 degrees C (P less than 0.001). These data are in agreement with the hypothesis that endogenous cryogen is a dialyzable substance, and that its concentration is reduced (and therefore the patient's body temperature rises) during hemodialysis.

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Cycloheximide (40 micrograms) intracerebroventricularly (i.c.v.) had no effect on thermoregulation against cold, but reduced fever due to an i.c.v. injection of leucocyte pyrogen (LP) by 25%, and reduced incorporation of radioactive leucine into hypothalamic protein by 94%.

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1. The protein synthesis inhibitor, anisomycin, was given into the cerebral ventricles of rabbits as a priming dose followed by a continuous infusion. Doses of 100, 200 and 300 microgram followed by infusions at 100, 200 and 300 microgram/hr inhibited the incorporation of [14C] leucine into hypothalamic protein by over 90%. 2. Injection and infusion of anisomycin (300 microgram) suppressed the febrile response to leucocyte (endogenous) pyrogen given into the ventricles (I.C.V.) or I.V. 3. Dialysis experiments showed that anisomycin did not combine irreversibly with leucocyte pyrogen. 4. Anisomycin did not interfere with thermoregulation in a cold environment. 5. It is concluded that pyrogenesis may involve a step which is dependent on synthesis of hypothalamic protein with a rapid turnover.

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1. The dose-response curve for sustained infusions of leucocyte pyrogen has been demonstrated, and an optimum dose indicated for leucocyte pyrogen clearance experiments. 2. The lungs, liver and small bowel are not significantly involved in removal of leucocyte pyrogen from the circulation in conscious rabbits. 3. A single circulation through one kidney removes up to half of the infused dose of leucocyte pyrogen.

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The possible role of various potential chemical mediators in the production of fever is reviewed. A major problem in this field is the very considerable conflict of evidence, let alone interpretation. On the existing evidence, it appears unlikely that monoamines, acetyl choline, or alterations in relative concentrations of sodium and calcium play any major role in the production of fever. Recent evidence makes it unlikely that prostaglandins have a direct role in this mechanism, though the involvement of other metabolites of arachidonic acid has not been excluded. It is possible that protein synthesis may play a part in the central action of leukocyte pyrogen.

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1. Infusions of hot and cold Hartmann's solution were given into the hepatic portal vein and inferior vena cava of conscious rabbits. Similar infusions were given into an ear vein as controls. The time integral of the displacement of brain temperature was measured. 2. There was no evidence for the presence of warm sensors in the inferior vena cava, portal vein, liver or hepatic vein, and no evidence for a concentration of cold sensors in the inferior vena cava. 3. There may be cold-sensitive elements in the portal vein or the tissue perfused by blood passing through it.

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1. In conscious rabbits, paired hot or cold infusions were given into the left atrium or jugular vein. For each pair of infusions the volume and temperature of the fluid was identical. The time course of the displacement of brain temperature was measured. 2. The magnitude of the displacement of brain temperature was not influenced to any major extent by the route of infusion. 3. This evidence suggests that there are no temperature sensors of any importance in the right heart or lungs.

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1. We have tested the hypothesis that a fever caused by pyrogen depends upon the synthesis of prostaglandin E in the brain and that the prostaglandin in turn acts on the hypothalamus to produce fever. 2. In rabbits, fever was produced by the injection of leucocyte pyrogen in a lateral cerebral ventricle. The latency, rate of rise and magnitude of the fever was unaffected by the simultaneous intraventricular injection of two prostaglandin antagonists, SC 19220 and HR 546. 3. Both antagonists effectively attenuated the fever caused by the intraventricular injection of prostaglandin E2. 4. This evidence is not consistent with the hypothesis that prostaglandin E is the principal mediator of fever.

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1. We have studied the effect of fever on the efficacy of the thermoregulatory control system in conscious rabbits. 2. The control system was challenged by a series of systemic thermal loads produced by the intravenous infusion of hot or cold isotonic solutions. The time integral of the consequent upward or downward displacement of brain temperature was used as an index of the response of the control system. Steady-state fever was induced by intravenous infusion of plasma containing leucocyte pyrogen. 3. With cold loads there was a linear relation between load and response. The regression coefficients were not significantly changed by fever in any of the six rabbits. Wth hot loads given to afebrile rabbits the regression of response on load was generally not statistically significant, but the responses were not demonstrably greater in the febrile state. 4. We were not able to demonstrate impairment in the capacity of the febrile animal to compensate for systemic thermal loads.

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1. Sustained fever has been induced in conscious rabbits by I.V. injection and infusion of endogenous pyrogen. 2. Cerebrospinal fluid (e.s.f.) was sampled from the cisterna magna at hourly intervals. The concentration of prostaglandin increased in parallel with rectal temperature. The prostaglandin was identified as one of the E series. 3. When sodium salicylate (1-5 m-mole followed by a continuous infusion of 9 mumole/min) was started 1 hr before endogenous pyrogen, the febrile response to the pyrogen was not significantly diminished but no rise of prostaglandin concentration was detected in c.s.f. 4. This dissociation between fever and prostaglandin concentration means that changes in cisternal prostaglandin concentration cannot be accepted as evidence that prostaglandin mediates the febrile response.

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