Midazolam attenuates the antinociception induced by d-serine or morphine at the supraspinal level in rats.
Our recent study has shown that the intracerebroventricular administration of d-serine, an endogenous and selective agonist for the glycine site of the N-methyl-d-aspartate receptor, alone or in combination with morphine, leads to the potentiation of antinociception on the tail-flick response. Although there is a variety of information concerning the effects of benzodiazepines on opioid-induced antinociception, little is known about the effect of benzodiazepines on the N-methyl-d-aspartate receptor agonist-induced antinociception. To clarify the analgesic interactions among the benzodiazepine/GABA(A), N-methyl-d-aspartate and opioid receptors at the supraspinal level, we investigated the effects of intracerebroventricular administration of midazolam, a benzodiazepine receptor agonist, on the antinociception evoked by the intracerebroventricular application of d-serine or morphine. The intracerebroventricular administration of midazolam alone produced hyperalgesia on the tail-flick response in a benzodiazepine receptor antagonist, flumazenil-reversible manner. The antinociception induced by the intracerebroventricular application of d-serine or morphine was attenuated by the intracerebroventricular administration of midazolam. In addition, this inhibitory effect of midazolam on the antinociception of d-serine or morphine was antagonized by the intracerebroventricular administration of flumazenil. Together with the facts that d-serine and midazolam act as selective agonists for the glycine site of the N-methyl-d-aspartate receptor and benzodiazepine/GABA(A) receptor, respectively, these observations suggest a functional interaction between the NMDA and benzodiazepine/GABA(A) receptors in the regulation of antinociception at the supraspinal level.
Ito
Kenji
K
Department of Anesthesiology, Tokai University School of Medicine, Isehara, Kanagawa, 259-1143, Japan.
Yoshikawa
Masanobu
M
Maeda
Miho
M
Jin
Xing Lu
XL
Takahashi
Shigeru
S
Matsuda
Mitsumasa
M
Tamaki
Raita
R
Kobayashi
Hiroyuki
H
Suzuki
Toshiyasu
T
Hashimoto
Atsushi
A
D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
D000700:Analgesics; D000701:Analgesics, Opioid; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D005442:Flumazenil; D012694:Serine; D009020:Morphine; D008874:Midazolam