Activation of supraspinal NMDA receptors by both D-serine alone or in combination with morphine leads to the potentiation of antinociception in tail-flick test of rats.
Although there is a variety of information concerning the effects of the N-methyl-D-aspartate (NMDA) receptor on opioid-induced antinociception at the spinal level, little is known about the effects at the supraspinal level. To clarify the role of the NMDA receptor on the morphine-induced antinociception at the supraspinal level, we investigated the effects of the intracerebroventricular (i.c.v.) administration of D-serine, a selective agonist for the glycine site of the NMDA receptors, alone or in combination with morphine using the tail-flick test. The i.c.v. administration of D-serine, but not L-serine, alone produced a dose-dependent antinociception in the tail-flick response. D-Serine also dose-dependently potentiated the antinociceptive effect induced by the i.c.v. administration of morphine and the simultaneous administration produced an additive effect. The potentiation of the antinociception produced by both D-serine alone or in combination with morphine was dose-dependently attenuated by the i.c.v. administration of L-701,324, a selective antagonist for the glycine site of the NMDA receptors. In addition, the potentiation of the D-serine-induced antinociception was antagonized by the i.c.v. administration of naloxone, a nonselective opioid receptor antagonist. These observations, together with the fact that D-serine is an endogenous and selective co-agonist for the glycine site of the NMDA receptors, strongly suggested that the activation of the supraspinal NMDA receptors by D-serine leads to the potentiation of the antinociception in the tail-flick test and that endogenous D-serine could modulate the mu-opioid receptor mediated antinociception via the glycine site of the NMDA receptors at the supraspinal level.
Yoshikawa
Masanobu
M
Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan.
Ito
Kenji
K
Maeda
Miho
M
Akahori
Kazuhito
K
Takahashi
Shigeru
S
Jin
Xing Lu
XL
Matsuda
Mitsumasa
M
Suzuki
Toshiyasu
T
Oka
Tetsuo
T
Kobayashi
Hiroyuki
H
Hashimoto
Atsushi
A
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology; D012694:Serine / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects*; D013237:Stereoisomerism
D000700:Analgesics; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D009270:Naloxone; D012694:Serine; D009020:Morphine; C094635:L 701324