Activation of central melanocortin-4 receptor suppresses lipopolysaccharide-induced
fever in rats.
Sinha, Partha S., Helgi B. Schiöth, and Jeffrey B. Tatro.
Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine,
Departments of 1Pharmacology and Experimental Therapeutics and 3Medicine, Tupper
Research Institute, Tufts University School of Medicine and Tufts-New England Medical
Center, Boston, Massachusetts 02111; and 2Department of Neuroscience, Uppsala
University, 751 24 Uppsala, Sweden
APStracts 10:0071R, 2003.
Activation of central melanocortin receptors (MCR) inhibits fever, but the identity of the
MCR subtype(s) mediating this antipyretic effect is unknown. To determine whether
selective central melanocortin receptor-4 (MC4R) activation produces antipyretic effects,
the MC4R selective agonist MRLOB-0001 (CO-His-d-Phe-Arg-Trp-Dab-NH2) was
administered intracerebroventricularly to rats treated with Escherichia coli
lipopolysaccharide (LPS, 30 µg/kg ip). Treatment with MRLOB-0001 (150 ng icv) did
not lower core body temperature (Tc) in afebrile rats but did suppress LPS-induced
increases in Tc and associated decreases in tail skin temperature (Tsk), an indicator of
vasomotor thermoeffector function. In contrast, systemic treatment with MRLOB-0001
(150 ng iv) did not produce similar antipyretic effects. Coadministration of the selective
MC4R antagonist HS014 (1 µg icv) blocked the antipyretic effects of MRLOB-0001.
HS014 alone (1 µg icv) had no significant effect on LPS-induced increases in Tc or
decreases in Tsk and in afebrile rats had no significant effects on Tc or Tsk. We conclude
that pharmacological activation of central MC4R suppresses febrile increases in Tc and
that inhibition of heat conservation pathways may contribute to this effect. These findings
suggest that the central MC4R may mediate the long-recognized antipyretic effects of
centrally administered melanocortins.
Received 18 September 2002; accepted in final form 14 February 2003
APS Manuscript Number R581-2.
Article publication pending Am J Physiol Regul Integr Comp Physiol
ISSN 1080-4757 Copyright 2003 The American Physiological Society.
Published in APStracts on 25 March 2003