Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 591, Issue 22, Pages 5623-5643Publisher
WILEY-BLACKWELL
DOI: 10.1113/jphysiol.2013.261271
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Funding
- Ministry of Education, Science, Culture and Sports, Japan
- Grants-in-Aid for Scientific Research [24390057] Funding Source: KAKEN
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We recently showed using prepro-orexin knockout (ORX-KO) mice and orexin neuron-ablated (ORX-AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress-induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E-2 (PGE(2)) injections which mimic inflammatory fever and environmental cold exposure, to ORX-KO mice, ORX-AB mice and their wild-type (WT) litter mates. ORX-AB mice, but not ORX-KO mice, exhibited a blunted PGE(2)-induced fever and intolerance to cold (5 degrees C) exposure, and these findings were similar to the results previously obtained with stress-induced thermogenesis. PGE(2)-induced shivering was also attenuated in ORX-AB mice. Both mutants responded similarly to environmental heating (39 degrees C). In WT and ORX-KO mice, the administration of PGE(2) and cold exposure activated orexin neurons, as revealed by increased levels of expression of c-fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX-AB mice. In addition, we found that glutamate receptor antagonists (d-(-)-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE(2)-induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress-induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE(2)-induced fever.
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