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The Journal of Neuroscience, December 15, 2000, 20(24):9242-9251
Antinociceptive Action of Nitrous Oxide Is Mediated by
Stimulation of Noradrenergic Neurons in the Brainstem and
Activation of  2B Adrenoceptors
Shigehito
Sawamura1, 3,
Wade S.
Kingery2, 4,
M.
Frances
Davies1, 3,
Geeta S.
Agashe1, 3,
J. David
Clark1, 3,
Brian K.
Kobilka5,
Toshizaku
Hashimoto6, and
Mervyn
Maze6
Departments of 1 Anesthesia and
2 Functional Restoration, Stanford University School of
Medicine, Stanford, California 94305, 3 Anesthesiology Service and 4 Physical
Medicine and Rehabilitation Service, Veterans Affairs, Palo Alto Health
Care System, Palo Alto, California 94304, 5 Howard Hughes
Medical Institute, Stanford University, Stanford, California
94305, and 6 Magill Department of Anaesthetics,
Imperial College School of Medicine, London SW10 9NH, United Kingdom
Although nitrous oxide (N2O) has been used to
facilitate surgery for >150 years, its molecular mechanism of action
is not yet defined. Having established that N2O-induced
release of norepinephrine mediates the analgesic action at
 2 adrenoceptors in the spinal cord, we now investigated
whether activation of noradrenergic nuclei in the brainstem is
responsible for this analgesic action and which 2
adrenoceptor subtype mediates this property. In rats, Fos
immunoreactivity was examined in brainstem noradrenergic nuclei after
exposure to nitrous oxide. After selective lesioning of noradrenergic
nuclei by intracerebroventricular application of the
mitochondrial toxin saporin, coupled to the antibody directed against
dopamine  hydroxylase (DH-saporin), the analgesic and sedative
actions of N2O were determined. Null mice for each of the
three 2 adrenoceptor subtypes (2A,
2B, and 2C), and their wild-type cohorts, were tested for their antinociceptive and sedative response to N2O. Exposure to N2O increased
expression of Fos immunoreactivity in each of the pontine noradrenergic
nuclei (A5, locus coeruleus, and A7). DH-saporin treatment
eliminated nearly all of the catecholamine-containing neurons in the
pons and blocked the analgesic but not the sedative effects of
N2O. Null mice for the 2B adrenoceptor
subtype exhibited a reduced or absent analgesic response to
N2O, but their sedative response to N2O was
intact. Our results support a pivotal role for noradrenergic pontine
nuclei and 2B adrenoceptors in the analgesic, but not
the sedative effects of N2O. Previously we demonstrated
that the analgesic actions of 2 adrenoceptor agonists are mediated by the 2A subtype; taken together with
these data we propose that exogenous and endogenous 2
adrenoceptor ligands activate different 2 adrenoceptor
subtypes to produce their analgesic action.
Key words:
nitrous oxide; locus coeruleus; noradrenergic; analgesia; anesthesia; Fos immunoreactivity
Copyright © 2000 Society for Neuroscience 0270-6474/00/20249242-10$05.00/0
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