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Selected findings

FeverFact: When young, mice deficient in transient receptor potential vanilloid-1 (TRPV1) channels exhibit marked locomotor hyperactivity. Pharmacological experiments with TRPV1 agonists and an antagonist suggest that TRPV1 receptors located outside the brain send signals to the brain to suppress locomotion. From: Garami A, Pakai E, Oliveira DL, Steiner AA, Wanner SP, Almeida MC, Lesnikov VA, Gavva NR, Romanovsky AA. Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis. J Neurosci 31: 1721-1733, 2011.

FeverFact: Neurons in the dorsomedial hypothalamus and fibers of passage in the paraventricular hypothalamic nucleus are essential for the development of cold-seeking behavior and hypothermia in endotoxin shock. From: Almeida MC, Steiner AA, Branco LGS, Romanovsky AA. Neural substrate of cold-seeking behavior in endotoxin shock. PLoS One 1: e1, 2006.

FeverFact: Neurons in the dorsomedial hypothalamus and fibers of passage in the paraventricular hypothalamic nucleus are essential for the development of cold-seeking behavior and hypothermia in endotoxin shock. From: Almeida MC, Steiner AA, Branco LGS, Romanovsky AA. Neural substrate of cold-seeking behavior in endotoxin shock. PLoS One 1: e1, 2006.

FeverFact: If animals are allowed to use behavioral mechanisms to regulate body temperature, the fever response to bacterial endotoxin occurs even when the preoptic anterior hypothalamus is lesioned. From: Almeida MC, Steiner AA, Branco LGS, Romanovsky AA. Neural substrate of cold-seeking behavior in endotoxin shock. PLoS One 1: e1, 2006.

FeverFact: Compound AMG 517 (Amgen, Inc.), a highly selective transient receptor potential vanilloid-1 (TRPV1) antagonist, caused hyperthermia in Phase-I clinical trials. From: Gavva NR, Treanor JJS, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136: 202-210, 2008.

FeverFact: Changes in the expression of a large number of proteins involved in the synthesis, transport, and degradation of prostaglandin (PG) E2 were found during lipopolysaccharide fever in rats. The findings suggest that microsomal PGE synthase-1, secretory phospholipase A2-IIA, and 15-hydroxy-PG dehydrogenase may be attractive therapeutic targets in inflammation and fever. From: Ivanov AI, Pero RS, Scheck AC, Romanovsky AA. Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation. Am J Physiol 283: R1104-R1117, 2002; Ivanov AI, Scheck AC, Romanovsky AA. Expression of genes controlling transport and catabolism of prostaglandin E2 in lipopolysaccharide fever. Am J Physiol 284: R698-R706, 2003.

FeverFact: This study reports a novel activity for the platelet-activating factor (PAF): pyrogenic. It shows that PAF is an ultrapotent inductor of fever. From: Ivanov AI, Patel S, Kulchitsky VA, Romanovsky AA. Platelet-activating factor: a previously unrecognized mediator of fever. J Physiol 553: 221-228, 2003.

FeverFact: This is the first in-vivo study showing a massive, coordinated response of ephrins and Eph receptors (both are major players in embryogenesis) to an inflammatory stimulus in adult animals. From: Ivanov AI, Steiner AA, Scheck AC, Romanovsky AA. Expression of Eph receptors and their ligands, ephrins, during lipopolysaccharide fever in rats. Physiol Genomics 21: 152-160, 2005.

Fever Fact: The sickness syndrome, a nonspecific response to infection, changes during the inflammatory response. Early sickness symptoms include hyperalgesia, motor agitation, and fever. Later sickness symptoms include analgesia, sleepiness, and poikilothermia. From: Romanovsky AA, Kulchitsky VA, Akulich NV, Koulchitsky SV, Simons CT, Sessler DI, Gourine VN. First and second phases of biphasic fever: two sequential stages of the sickness syndrome? Am J Physiol 271: R244-R253, 1996.

FeverThought: The idea that the sickness syndrome is a dynamic entity is developed. From: Romanovsky AA, Kulchitsky VA, Akulich NV, Koulchitsky SV, Simons CT, Sessler DI, Gourine VN. First and second phases of biphasic fever: two sequential stages of the sickness syndrome? Am J Physiol 271: R244-R253, 1996.

FeverFact: Hypothermia associated with endotoxin shock involves cold-seeking behavior and a selective decrease in the threshold body temperature for activation of thermogenesis. That shocked rats use behavior to cool themselves suggests that hypothermia in endotoxin shock is brain-mediated. From: Romanovsky AA, Shido O, Sakurada S, Sugimoto N, Nagasaka T. Endotoxin shock: thermoregulatory mechanisms. Am J Physiol 270: R693-R703, 1996.

FeverThought: Hypothermia in endotoxin shock is an adaptive response. From: Romanovsky AA, Shido O, Sakurada S, Sugimoto N, Nagasaka T. Endotoxin shock-associated hypothermia. How and why does it occur? Ann N Y Acad Sci 813: 733-737, 1997.

FeverFact: In a warm environment, rats respond to lipopolysaccharide (LPS) with fever. Total vagotomy attenuates the fever response to a very low (just above the threshold) dose of LPS, but it does not affect the responses to higher doses. From: Romanovsky AA, Simons CT, Szekely M, Kulchitsky VA. The vagus nerve in the thermoregulatory response to systemic inflammation. Am J Physiol 273: R407-R413, 1997.

FeverFact: In a cold environment, rats respond to high, shock-inducing doses of lipopolysaccharide with hypothermia. This is the first study to show that vagotomy results in an exaggeration of the hypothermic response in systemic inflammation. From: Romanovsky AA, Simons CT, Szekely M, Kulchitsky VA. The vagus nerve in the thermoregulatory response to systemic inflammation. Am J Physiol 273: R407-R413, 1997.

FeverFact: The fever response to bacterial lipopolysaccharide of rats consists of at least three phases. Only two febrile phases were identified before these studies. From: Romanovsky AA, Simons CT, Kulchitsky VA. “Biphasic” fevers often consist of more than two phases. Am J Physiol 275: R323-R331, 1998; Romanovsky AA, Kulchitsky VA, Simons CT, Sugimoto N. Methodology of fever research: why are polyphasic fevers often thought to be biphasic? Am J Physiol 275: R332-R338, 1998.

FeverFact: The fever response to lipopolysaccharide of mice consists of at least three phases. From: Rudaya AY, Steiner AA, Robbins JR, Dragic AS, Romanovsky AA. Thermoregulatory responses to lipopolysaccharide in the mouse: dependence on the dose and ambient temperature. Am J Physiol 289: R1244-R1252, 2005.

FeverFact: A new method for determining whether an animal is exposed to subneutral, neutral, or supraneutral thermal conditions is proposed and tested in an extensive study in rats. The method is based on the assumption that, under thermoneutral conditions, an animal uses only those autonomic thermoeffectors that do not impose on its energy or water resources. These economical, first-line responses are skin vasoconstriction and skin vasodilation in specialized heat-exchange organs, such as the rat tail. From: Romanovsky AA, Ivanov AI, Shimansky YP. Selected contribution: Ambient temperature for experiments in rats: a new method for determining the zone of thermal neutrality. J Appl Physiol 92: 2667-2679, 2002.

FeverThought: This is the first textbook chapter that treats the thermoregulatory system as a federation of independent thermoeffectors: without a central coordinator or set point. From: Romanovsky AA. Chapter 23. Temperature regulation. In: Lecture Notes on Human Physiology, 5th edition, ed. by Petersen O. Oxford, UK: Blackwell, 2007, p. 603-615.

FeverThought:  The regulation of body temperature does not require a specialized neuronal network for integrating temperature signals or for coordinating effector responses, and it cannot be adequately described using a single set point. From: Romanovsky AA. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am J Physiol 292: R37-R46, 2007.

FeverFact: The hepatic branch of the vagus nerve plays an indispensable role in triggering the fever response to low (just above the threshold) doses of bacterial lipopolysaccharide. From: Simons CT, Kulchitsky VA, Sugimoto N, Homer LD, Szekely M, Romanovsky AA. Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis? Am J Physiol 275: R63-R68, 1998.

FeverFact. The hypothermic response to bacterial endotoxin is mediated entirely by cyclooxygenase (COX)-1. The hypotensive response to endotoxin is mediated by both COX-1 and COX-2. From: Steiner AA, Hunter JC, Phipps SM, Nucci TB, Oliveira DL, Roberts JL, Scheck AC, Simmons DL, Romanovsky AA. Cyclooxygenase-1 or -2: which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol 297: R485-R494, 2009.

FeverFact: A new function of the leptin receptor (and of leptin, a fat-derived hormone) has been identified: mediation of the recovery from bacterial lipopolysaccharide-induced hypothermia. From: Steiner AA, Dogan MD, Ivanov AI, Patel S, Rudaya AY, Jennings DH, Orchinik M, Pace TWW, O'Connor KA, Watkins LR, Romanovsky AA. A new function of the leptin receptor: mediation of the recovery from lipopolysaccharide-induced hypothermia. FASEB J 18: 1949-1951, 2004.

FeverFact: Lipopolysaccharide (LPS)-induced fever depends on Toll-like receptor 4 (TLR4) signaling. The first phase of LPS fever is triggered via TLR4 in bone marrow-derived cells. The second and third phases involve TLR4 signaling in cells derived from both within and outside the bone marrow. From: Steiner AA, Chakravarty S, Rudaya AY, Herkenham M, Romanovsky AA. Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 107: 4000-4002, 2006.

FeverFact: Prostaglandin E2 that triggers fever is synthesized by macrophages in peripheral, endotoxin-processing tissues – not in the brain, as it was previously believed. From: Steiner AA, Ivanov AI, Serrats J, Hosokawa H, Phayre AN, Robbins JR, Roberts JL, Kobayashi S, Matsumura K, Sawchenko PE, Romanovsky AA. Cellular and molecular bases of the initiation of fever. PLoS Biol 4: e284, 2006.

FeverFact: The tonic activation of transient receptor potential vanilloid-1 (TRPV1) channels in the abdominal viscera by non-thermal factors inhibits the autonomic thermoeffector mechanisms of cold defense and suppresses body temperature. When this activation is blocked (e.g., by pharmacological antagonists of the TRPV1 channel), hyperthermia occurs. This study establishes a physiological mechanism of TRPV1 antagonist-induced hyperthermia. From: Steiner AA, Turek VF, Almeida MC, Burmeister JJ, Oliveira DL, Roberts JL, Bannon AW, Norman MH, Louis J-C, Treanor JJS, Gavva NR, Romanovsky AA. Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J Neurosci 27: 7459-7468, 2007.

FeverThought: Dualism of the thermoregulatory involvement of TRPV1 is proposed. Two populations of TRPV1-expressing neurons have connections with efferent thermoeffector pathways: 1) polymodal, glutamatergic dorsal-root ganglia neurons that innervate the abdominal viscera and 2) higher-order sensory, glutamatergic neurons presumably located in the median preoptic hypothalamic nucleus. From: Romanovsky AA, Almeida MC, Garami A, Steiner AA, Norman MH, Morrison SF, Nakamura K, Burmeister JJ, Nucci TB. The transient receptor potential vanilloid-1 channel: a thermosensor it is not. Pharmacol Rev 61: 228-261, 2009.

FeverFact: TRPV1 antagonists, next-generation pain therapeutics, cause hyperthermia in laboratory animals and humans. This side effect is a major obstacle for further development of these drugs. We show that hyperthermia is caused by those TRPV1 antagonists that block activation of the TRPV1 channel by protons (high acidity) and possibly by chemical ligands, but not by heat. We suggest to concentrate the drug development effort on compounds that do not block TRPV1 activation by protons. Such compounds will not increase body temperature but may still block pain caused by heat and perhaps by chemical ligands. From: Garami A, Shimansky YP, Pakai E, Oliveira DL, Gavva NR, Romanovsky AA. Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia. J Neurosci 30: 1435-1440, 2010.

FeverFact: This study reveals a novel, critical role of brain cannabinoid-1 (CB1) receptors in lipopolysaccharide-induced hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis. From: J Physiol 589: 2415-2431, 2011.

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