title: Orexin neurons are indispensable for prostaglandin E2-induced fever and defence against environmental cooling in mice.
abstract: 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 E2 (PGE2) 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 PGE2-induced fever and intolerance to cold (5°C) exposure, and these findings were similar to the results previously obtained with stress-induced thermogenesis. PGE2-induced shivering was also attenuated in ORX-AB mice. Both mutants responded similarly to environmental heating (39°C). In WT and ORX-KO mice, the administration of PGE2 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 PGE2-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 PGE2-induced fever.
authors: T. Kuwaki: Department of Physiology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka 8-35-1, Kagoshima 890-8544, Japan. kuwaki@m3.kufm.kagoshima-u.ac.jp.
authors: Yoshiko
authors: Y
authors: Takahashi
authors: Wei
authors: W
authors: Zhang
authors: Kohei
authors: K
authors: Sameshima
authors: Chiharu
authors: C
authors: Kuroki
authors: Ami
authors: A
authors: Matsumoto
authors: Jinko
authors: J
authors: Sunanaga
authors: Yu
authors: Y
authors: Kono
authors: Takeshi
authors: T
authors: Sakurai
authors: Yuichi
authors: Y
authors: Kanmura
authors: Tomoyuki
authors: T
authors: Kuwaki
mesh_terms: D000818:Animals; D003080:Cold Temperature; D015232:Dinoprostone / Q000378:metabolism*; D005334:Fever / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins; D011903:Raphe Nuclei / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D022722:Thermogenesis / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D015232:Dinoprostone
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