Corticotropin-releasing factor mediates the antinociceptive action of nitrous oxide in rats.
BACKGROUND
Exposure to nitrous oxide activates brainstem noradrenergic nuclei and descending inhibitory pathways, which produce the acute antinociceptive action of nitrous oxide. Because corticotropin-releasing factor (CRF) can produce activation of noradrenergic neurons in the locus ceruleus, the authors sought to determine whether it might be responsible for the antinociceptive action of nitrous oxide.


METHODS
Male Sprague-Dawley rats (250-300 g) were exposed for 60 min to room air or 25, 50 or 70% nitrous oxide in oxygen. Brain sections including the hypothalamus were immunostained for both c-Fos (a marker of neuronal activation) and CRF and the percentage of CRF-positive neurons expressing c-Fos was determined. The functional consequences of changes in CRF were investigated by assessing the effect of intracerebroventricular administration of a CRF antagonist (alpha-helical CRF9-41, 20 microg/10 microl) on both activation of locus ceruleus noradrenergic neurons and the antinociception (with the tail-flick latency test) produced by nitrous oxide.


RESULTS
Inhalation of nitrous oxide induced a dose-dependent increase in c-Fos expression in CRF-positive neurons in the paraventricular nucleus of the hypothalamus. Intracerebroventricular administration of CRF antagonist inhibited nitrous oxide-induced c-Fos expression in the locus ceruleus and the antinociceptive effect of nitrous oxide.


CONCLUSIONS
Nitrous oxide activates the CRF system in the brain, which results in stimulation of noradrenergic neurons in the locus ceruleus and its consequent antinociceptive effect.
Sawamura
Shigehito
S
Department of Anesthesiology, Tokyo University Hospital, Bunkyo, Japan. sawamura-tky@umin.ac.jp
Obara
Mizuki
M
Takeda
Kenji
K
Maze
Mervyn
M
Hanaoka
Kazuo
K
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009609:Nitrous Oxide / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D016760:Proto-Oncogene Proteins c-fos; C069206:alpha helical corticotropin-releasing hormone; D003346:Corticotropin-Releasing Hormone; D014446:Tyrosine 3-Monooxygenase; D009609:Nitrous Oxide