Recently, we found that the thermal response to norepinephrine (NE) differed unexpectedly when it was microdialyzed, rather microinjected, into the preoptic area (PO) of conscious guinea pigs; i.e., NE produced a fall rather than a rise in core temperature (Tco). Our studies showed that the Tco rise following microinjected NE was due largely to prostaglandin E2 (PGE2) released as a result of tissue injury caused by the microinjection procedure itself, and was not due to the drug, i.e., it was artefactual. Our microdialysis data further suggested that there exists a functional antagonism between endogenous NE and PGE2; it appeared that their relative concentrations in the PO might mutually influence Tco.
The first aim of this proposed study, therefore, is to evaluate this apparent functional NE- PGE2 antagonism. Various other studies have lately indicated that different responses to NE administration in vivo or application in vitro are activated depending on the NE dose, and that these different effects are mediated by different noradrenergic receptor subtypes. Subtype populations and densities have also been shown to be inconstant, subject to change under certain conditions. Since the different thermoreregulatory effects of centrally administrated NE have also been reported to depend on dosage and various other conditions, the second aim of this proposed study is to determine whether the direction of thermal responses to NE is adrenoceptor subtype-dependent, and to investigate the influence on the thermal response of selected experimental conditions.
The third aim of the present study is to delineate the function(s) of NE during fever in the context of the above hypotheses, since the literature on the role of central NE in the febrile response, though extensive, is inconclusive, probably because of the variability of experimental conditions used in all the studies. Evaluation of the intrinsic thermoregulatory effects of this transmitter will be made easier by the availability now of more specific receptor agonists and antagonists and by the use of microdialysis, which minimizes the confounding effects of traumatic reactions that affect other modes of drug administration. The results of this study should help to resolve the discrepancies among earlier findings and clarify the role of NE in the central control of body temperature. They may also be pertinent to other functions in which hypothalamic NE has been implicated, e.g., in the interactions between the neuroendocrine and immune systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022716-05
Application #
3405545
Study Section
Neurology C Study Section (NEUC)
Project Start
1986-09-01
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Blatteis, C M; Sehic, E (1998) Cytokines and fever. Ann N Y Acad Sci 840:608-18
Blatteis, C M; Sehic, E; Li, S (1998) Afferent pathways of pyrogen signaling. Ann N Y Acad Sci 856:95-107
Sehic, E; Gerstberger, R; Blatteis, C M (1997) The effect of intravenous lipopolysaccharide on NADPH-diaphorase staining (= nitric oxide synthase activity) in the organum vasculosum laminae terminalis of guinea pigs. Ann N Y Acad Sci 813:383-91
Blatteis, C M; Sehic, E (1997) Circulating pyrogen signaling of the brain. A new working hypothesis. Ann N Y Acad Sci 813:445-7
Sehic, E; Hunter, W S; Ungar, A L et al. (1997) Blockade of Kupffer cells prevents the febrile and preoptic prostaglandin E2 responses to intravenous lipopolysaccharide in guinea pigs. Ann N Y Acad Sci 813:448-52
Sehic, E; Blatteis, C M (1996) Blockade of lipopolysaccharide-induced fever by subdiaphragmatic vagotomy in guinea pigs. Brain Res 726:160-6
Sehic, E; Szekely, M; Ungar, A L et al. (1996) Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs. Brain Res Bull 39:391-9
Romanovsky, A A; Shido, O; Ungar, A L et al. (1994) Peripheral naloxone attenuates lipopolysaccharide fever in guinea pigs by an action outside the blood-brain barrier. Am J Physiol 266:R1824-31
Blatteis, C M; Xin, L; Quan, N (1994) Neuromodulation of fever. A possible role for substance P. Ann N Y Acad Sci 741:162-73
Romanovsky, A A; Shido, O; Ungar, A L et al. (1993) Genesis of biphasic thermal response to intrapreoptically microinjected clonidine. Brain Res Bull 31:509-13

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