Fever has always been recognised as the major sign of infectious disease as well as being associated with other illnesses. The suggestion of publishing a volume dedicated exclusively to the subject of fever in the Handbook of Experimental Pharmacology series was one that greatly appealed to me, and I felt very honoured when I was invited to edit it. The first ideas about this volume were conceived in the latter part of 1977 and by the middle of 1978 the first authors had been approached. As is usual with such publications, by the time the first manuscripts were beginning to arrive in the late spring of 1979 there were still a few chapters for which authors had not yet been found. Finally by the end of 1981 the volume was complete. Because of the span of time over which the chapters were written, some refer to more recent work than others; however, I do not feel that this detracts from the overall contribution of all the chapters.

Inhalt

1 Body Heat.- 2 Fever and its Role in Disease: Rationale for Antipyretics.- A. Fever.- B. The Role of Fever in Disease.- C. Antipyretic Drugs.- D. Effects of Antipyresis on Survival.- E. Clinical Indications and Contraindications for Antipyretic Therapy.- References.- 3 Thermoregulation: Its Change During Infection with Endotoxin-Producing Micro-organisms.- A. Introduction.- B. The Elevated Set-Point Concept of Fever.- C. The Pyrogens.- I. Bacterial Endotoxins.- II. Endogenous (Leucocyte) Pyrogens.- III. The Prostaglandins.- D. Pyrogen Action.- I. Points of Action in the Central Nervous System.- II. Effects on the Electrical Activities of Hypothalamic Neurones.- E. Areas of Current Concern and Doubt.- I. More than One Central Point of Action of Pyrogens?.- II. The Biphasic Pattern of Experimentally Induced Fever: Two Causative Factors?.- III. The Pyrogenic Metabolites of Arachidonic Acid.- IV. Are Pyrogens Only Pyrogens?.- V. Is Fever of Physiological Benefit?.- F. Mechanisms of Thermoregulation.- I. The Set-Point Machinery: Theory.- II. The Antiquity of Homeostasis and of Pyrogen Responsiveness.- III. The Pattern of Neural Connections.- G. Models for Thermoregulation.- I. Point (or Points) of Action of Pyrogens.- II. Neuronal Model of Central Thermoregulatory Connections in Sheep.- III. Point of Action of Bacterial Endotoxin in Sheep.- IV. Neuronal Theory of Fever Induction.- H. Thermoregulatory Agents.- I. Central Nervous 5HT.- II. Central Nervous Norepinephrine.- III. The Central Thermoregulatory Effects of ACh.- J. Other Set-Point Theories.- I. The Monoamine Balance Set-Point Theory.- II. The Ionic Balance Set-Point Theory.- K. Concluding Comments.- I. The Independence of Fever from the Influence of Ambient Temperature.- II. The Upper Limit to the Febrile Response.- III. More than One Pathway from Infection to Fever?.- References.- 4 Exogenous Pyrogens.- A. Introduction.- I. General Considerations.- B. Viruses.- I. Experimental Fevers with Viruses.- II. Interferon.- C. Gram-Positive Organisms.- I. Intact Organisms.- II. Extracellular Products.- III. Cell Wall Components.- D. Gram-Negative Bacteria.- I. Cell Wall Structure.- II. Pyrogenicity of LPS.- III. LPS Fever and EP Production.- IV. LPS Structure and Ability to Produce Fever.- V. Lipid A and Pyrogenicity.- VI. Pyrogenic Tolerance to LPS.- E. Mycobacteria.- I. Febrile Reactions of BCG-Sensitized Animals.- II. Release of EP from Cells Incubated with Tuberculin.- F. Fungi.- I. Pyrogenicity of Fungal Cells.- II. Fever from Fungal Products.- G. Non-Microbial Antigens.- I. Antibody-Mediated Fever.- II. Cell-Mediated Immune Fever.- H. Pyrogenic Steroids.- I. Fever in Humans.- II. Pyrogenic Steroid-Induced EP.- J. Miscellaneous Exogenous Pyrogens.- I. Polynucleotides.- II. Colchicine and Vinblastine.- III. Bleomycin.- IV. Synthetic Adjuvants.- References.- 5 Endogenous Pyrogens.- A. Introduction.- B. Nomenclature.- C. Assay of Endogenous Pyrogen.- D. Sources of LP.- I. Cells Capable of Pyrogen Release.- II. Animal Species Releasing EP.- E. Cellular Events.- F. Isolation and Characterization of EP.- I. Methods for Purification.- II. Heterogeneity of EP.- References.- 6 Role of Central Neurotransmitters in Fever.- A. Introduction.- B. Noradrenaline.- I. Depleting Agents.- II. Sympathomimetic Agents and Monoamine Oxidase Inhibitors.- III. Adrenoceptor Antagonists.- IV. Brain Catecholamine Levels.- V. Conclusion.- C. 5-Hydroxytryptamine.- I. Depleting Agents.- II. 5-Hydroxytryptamine Agonists and Uptake Inhibitors.- III. Indoleamine Antagonists.- IV. Brain 5-Hydroxytryptamine Levels and Turnover.- V. Conclusion.- D. Acetylcholine.- I. Cholinergic Antagonists.- II. Cholinomimetics and Anticholinesterases.- III. Conclusion.- E. Other Amines.- I. Dopamine.- II. ?-Aminobutyric Acid.- III. Histamine and Taurine.- F. Peptides.- I. Kinins.- II. Thyroid-Releasing Hormone.- III. Opioids.- G. Conclusion.- References.- 7 The Role of Ions in Thermoregulation and Fever.- A. Introduction.- B. Systemic Effects of Altered Ion Levels.- C. Action of Cations in the Cerebral Ventricles.- D. Action of Cations on the Hypothalamus.- I. Anatomical Localization of Ion-Induced Temperature Changes.- II. Specificity of Cation Actions.- E. Exercise, Cations, and Temperature Set-Point.- I. Hypothalamic Na+:Ca2+Ratio and Exercise.- F. Fever, Na+:Ca2+ Ratio, and Set-Point Shift.- I. In Vivo Cation Activity in the Diencephalon.- II. Antipyresis and Na+:Ca2+Efflux.- G. Critique of the Ionic Set-Point Mechanism for Body Temperature.- I. Experimental Evidence for the Ionic Set-Point Theory.- II. Primate Model of Temperature Control.- References.- 8 Electrophysiology of the Anterior Hypothalamus: Thermoregulation and Fever.- A. Introduction.- B. Microelectrode Recording Techniques.- I. Single-Unit Recordings.- II. Functional Characterization of Neurones.- 1. Physiological Stimuli.- 2. Electrical Stimuli.- 3. Pharmacological Stimuli.- III. In Vitro Recording.- IV. Data Analysis.- 1. Mean Firing Frequency and Thermosensitivity.- 2. Patterns of Neuronal Discharge.- V. Critique of Microelectrophysiology.- 1. Non-Random Selection of Neuronal Population.- 2. Lack of Positive Functional Characterization.- C. Thermosensitivity of PO/AH Neurones.- I. Thermoresponsiveness.- 1. Proportions of Thermosensitive Cells.- 2. Ratio of Warm-to Cool-Sensitive Cells.- II. Detectors Versus Interneurones.- 1. Thermal Response Form.- 2. Extrahypothalamic Inputs.- 3. Firing Pattern Analysis.- III. In Vitro Recording of PO/AH Activity.- D. Pyrogenic and Antipyretic Actions.- I. Pyrogens and Antipyretics.- 1. Pyrogenic Agents.- 2. Antipyretics.- II. Electrophysiology of Pyrogen Action.- 1. Bacterial and Leucocyte Pyrogens.- 2. Prostaglandins.- 3. Pyrogen Action on Peripheral Receptors.- III. Electrophysiology of Antipyretic Action.- E. Summary.- References.- 9 Cyclic Nucleotides and Fever.- A. Introduction.- B. Temperature Responses to Cyclic AMP in Different Species.- I. Mice.- II. Rats.- III. Rabbits.- IV. Cats.- V. Dogs.- VI. Primates.- VII. Birds.- C. Enzymes Related to Cyclic AMP.- I. Adenylate Cyclase.- 1. Activators of Adenylate Cyclase.- 2. Inhibitors of Adenylate Cyclase.- II. Cyclic Nucleotide Phosphodiesterase.- 1. Activators of Cyclic Nucleotide Phosphodiesterase.- 2. Inhibitors of Cyclic Nucleotide Phosphodiesterase.- D. Endogenous Cyclic AMP in Fever.- I. Cyclic AMP in Brain Tissue.- II. Cyclic AMP in Cerebrospinal Fluid.- E. Cyclic GMP in Fever.- F. Summary.- References.- 10 Prostaglandins in Fever and the Mode of Action of Antipyretic Drugs.- A. Introduction.- B. Temperature Responses to Prostaglandins.- I. Cats.- 1. Prostaglandins E1 and E2.- 2. Prostaglandins Fl? and F2?.- 3. Prostaglandin A1.- 4. Prostaglandin D2.- 5. Environmental Temperature and PGE1 Response.- II. Rabbits.- III. Sheep.- 1. Adult Sheep.- 2. New-born Lambs.- IV. Rats.- V. Mice.- VI. Guinea-pigs.- VII. Monkeys.- VIII. Man.- IX. Monotremes.- X. Birds.- 1. Adult Chickens.- 2. Chicks.- XI. Miscellaneous Species.- C. Prostacyclin.- D.…