Classical
anesthetics of the
gamma-aminobutyric acid type A
receptor (GABA(A))-enhancing class (e.g.,
pentobarbital,
chloral hydrate,
muscimol, and
ethanol) produce
analgesia and unconsciousness (sedation).
Dissociative anesthetics that antagonize the
N-methyl-D-aspartate (
NMDA) receptor (e.g.,
ketamine,
MK-801,
dextromethorphan, and
phencyclidine) produce
analgesia but do not induce complete
loss of consciousness. To understand the mechanisms underlying
loss of consciousness and
analgesia induced by
general anesthetics, we examined the patterns of expression of
c-Fos protein in the brain and correlated these with physiological effects of systemically administering
GABAergic agents and
ketamine at dosages used clinically for
anesthesia in rats. We found that
GABAergic agents produced predominantly delta activity in the electroencephalogram (EEG) and sedation. In contrast,
anesthetic doses of
ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects,
ketamine induced Fos expression in
cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep-promoting ventrolateral preoptic nucleus (VLPO). In contrast,
GABAergic agents suppressed Fos in the same arousal-promoting systems but increased the number of Fos-immunoreactive neurons in the VLPO compared with waking control animals. All
anesthetics tested induced Fos in the spinally projecting noradrenergic A5-7 groups.
6-hydroxydopamine lesions of the A5-7 groups or
ibotenic acid lesions of the ventrolateral periaqueductal gray matter (vlPAG) attenuated antinociceptive responses to noxious thermal stimulation (tail-flick test) by both types of
anesthetics. We hypothesize that neural substrates of sleep-wake behavior are engaged by low-dose
sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the
analgesic effects of both
NMDA receptor antagonists and
GABA(A) receptor-enhancing
anesthetics.