This proposal is designed to investigate the mechanisms by which normal body temperature regulation is altered when man or animals become infected by pathogens that cause a cardinal sign of disease - fever. It will examine in detail the manner by which endogenous pyrogen acts upon the central nervous system to produce fever. Based upon results obtained from previous research supported by this grant, a hypothesis on the nature and site of action of endogenous pyrogen at the blood-brain interface is presented. The model proposed contains both anatomical and physiological elements that can account for the sequence of events that occurs from when endogenous pyrogen is released from mononuclear cells in the circulation until body temperature rises. Several experimental protocols are described that will test directly the validity of this hypothesis. A study of the hypothesized site of release of prostaglandins is proposed, leading to an examination of the properties of neurons located in the periventricular region of the hypothalamus that may be responsible for fever production. Methods are described for the exposure, recording and marking of cells, in order to investigate the connectivity of individual neurons in this region to other CNS centers believed to be involved in thermoregulation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Pathology A Study Section (PTHA)
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John B. Pierce Laboratory, Inc.
New Haven
United States
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Shimada, S G; Otterness, I G; Stitt, J T (1994) A study of the mechanism of action of the mild analgesic dipyrone. Agents Actions 41:188-92
Stitt, J T (1991) Differential sensitivity in the sites of fever production by prostaglandin E1 within the hypothalamus of the rat. J Physiol 432:99-110
Stitt, J T; Shimada, S G (1991) Site of action of calcium channel blockers in inhibiting endogenous pyrogen fever in rats. J Appl Physiol 71:956-60
Stitt, J T; Shimada, S G (1991) Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits. J Appl Physiol 71:951-5
Shimada, S G; Stitt, J T; Angelogianni, P (1990) Effects of cold and capsaicin desensitization on prostaglandin E hypothermia in rats. J Appl Physiol 68:2618-22
Stitt, J T; Shimada, S G (1989) Enhancement of the febrile responses of rats to endogenous pyrogen occurs within the OVLT region. J Appl Physiol 67:1740-6
Stitt, J T; Shimada, S G (1989) Immunoadjuvants enhance the febrile responses of rats to endogenous pyrogen. J Appl Physiol 67:1734-9
Stitt, J T; Shimada, S G (1987) A comparison of the febrile responses of the Brattleboro and Sprague-Dawley strains of rats to endotoxin and endogenous pyrogens. Can J Physiol Pharmacol 65:1377-81
Stitt, J T; Bernheim, H A (1985) Differences in endogenous pyrogen fevers induced by iv and icv routes in rabbits. J Appl Physiol 59:342-7
Stitt, J T (1985) Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol 368:501-11

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