GABAergic interneurons at supraspinal and spinal levels differentially modulate the antinociceptive effect of nitrous oxide in Fischer rats.
BACKGROUND
The study hypothesizes that nitrous oxide (N(2)O) releases opioid peptide in the brain stem, which results in inhibition of gamma-aminobutyric acid-mediated (GABAergic) neurons that tonically inhibit the descending noradrenergic inhibitory neurons (DNIN), resulting in activation of DNIN. In the spinal cord, activation of DNIN leads to the release of norepinephrine, which inhibits nociceptive processing through direct activation of alpha2 adrenoceptor and indirect activation of GABAergic neurons through alpha1 adrenoceptor. Arising from this hypothesis, it follows that GABAergic neurons will modulate the antinociceptive effect of N(2)O in diametrically opposite directions at supraspinal and spinal levels. The authors have tested this tenet and further examined the effect of midazolam, a GABA-mimetic agent, on N(2)O-induced antinociceptive effect.


METHODS
Adult male Fischer rats were administered muscimol (GABA(A) receptor agonist) intracerebroventricularly (icv), gabazine (GABA(A) receptor antagonist) intrathecally (intrathecal), or midazolam intraperitoneally (intraperitoneal). Fifteen minutes later, they were exposed to air or 75% N(2)O and were subjected to the plantar test after 30 min of gas exposure. In some animals administered with midazolam, gas exposure was continued for 90 min, and the brain and spinal cord were examined immunohistochemically.


RESULTS
The N(2)O-induced antinociceptive effect, which was attenuated by icv muscimol, intrathecal gabazine, and intraperitoneal midazolam. Midazolam inhibited N(2)O-induced c-Fos expression (a marker of neuronal activation) in the pontine A7 and spinal cord.


CONCLUSIONS
The GABAergic neurons modulate the antinociceptive effect of N(2)O in opposite directions at supraspinal and spinal levels. The pronociceptive effects of enhancement at the supraspinal GABAergic site predominate in response to systemically administered midazolam.
Orii
Ryo
R
Department of Anaesthetics and Intensive Care, Imperial College of Science, Technology and Medicine, University of London, United Kingdom.
Ohashi
Yoko
Y
Halder
Sunil
S
Giombini
Mariangela
M
Maze
Mervyn
M
Fujinaga
Masahiko
M
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology*; D009609:Nitrous Oxide / Q000494:pharmacology*; D010149:Postoperative Pain / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018712:Analgesics, Non-Narcotic; D018756:GABA Antagonists; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D009609:Nitrous Oxide