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-MSH suppresses LPS fever via central melanocortin
receptors independently of its suppression of corticosterone and
IL-6 release
1 Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Department of Medicine and the Tupper Research Institute, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts 02111; and 2 Department of Chemistry, University of Arizona, Tucson, Arizona 85721
Systemically
administered 
-melanocyte-stimulating hormone (-MSH) inhibits
endotoxin (lipopolysaccharide; LPS)- or interleukin (IL)-1-induced
fever and adrenocortical activation, but the sites of these actions and
the mechanisms involved are unknown. The aims of this study were,
first, to determine whether melanocortin receptors (MCR) located within
the central nervous system mediate the suppressive effects of
peripherally administered -MSH on LPS-induced fever and activation
of the pituitary-adrenal axis and, second, to determine whether
systemic -MSH suppresses the LPS-induced rise in plasma IL-6 levels,
potentially contributing to its antipyretic effect. Male rats received
Escherichia coli LPS (25 µg/kg ip).
Core body temperatures (Tb) were
determined hourly by radiotelemetry (0-8 h), and blood was
withdrawn via venous catheters for plasma hormone immunoassays
(0-2 h) and IL-6 bioassay (0-8 h). -MSH (100 µg/kg ip)
completely prevented the onset of LPS-induced fever during the first
3-4 h after LPS and suppressed fever throughout the next 4 h but
did not affect Tb in afebrile rats
treated with intraperitoneal saline rather than LPS. Intraperitoneal
-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and
corticosterone (CS) levels. Intracerebroventricular injection of
SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist,
completely blocked the antipyretic effect of intraperitoneal -MSH
during the first 4 h after LPS but had no effect on -MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered -MSH during the early phase of fever is
mediated by MCR within the brain. In contrast, the inhibition of
LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal -MSH appears to be mediated by a different mechanism(s), and these
effects do not contribute to its antipyretic action.
lipopolysaccharide; adrenocorticotropic hormone; interleukin-6; rat; SHU-9119; -melanocyte-stimulating hormone
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