Millan M J, Audinot V, Honoré P, Bervoets K, Veiga S, Brocco M
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125, Chemin de Ronde, 78290-Croissy-sur-Seine, Paris, France.
Eur J Pharmacol. 2000 Jan 24;388(1):37-47. doi: 10.1016/s0014-2999(99)00820-1.
The open channel blocker at N-methyl-D-aspartate (NMDA) receptors, dizocilpine, stereospecifically elicited spontaneous tail-flicks in rats - a reaction similar to those elicited by other drugs (tenocyclidine, phencyclidine and ketamine) acting as open channel blockers. Their relative potencies were strongly correlated with affinities at NMDA binding sites and labeled by [3H]dizocilpine in the frontal cortex (r=0.94) and, as determined previously [Millan, M. J., Seguin, L., 1994. Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice, Neurosci. Lett., 178 (1994) 139-143], potency for eliciting antinociception (0. 93). The competitive antagonists at the NMDA receptor recognition site, (+/-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), 4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), D, L-(E)-2-amino-4-methylphosphono-3-pentanoic acid (CGP37849) and (3E)-1-ethyl ester-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP39551), likewise dose-dependently evoked spontaneous tail-flick. In contrast, antagonists/weak partial agonists at the coupled, glycine B site, 7-chloro-4-hydroxy-3-(3-phenoxy) phenyl-2(H)-quinolinone (L701,324), (+)-1-hydroxy-3-aminopyrrolidine-2-one ((+)-HA966), (3R, 4R)-3-amino-1-hydroxy-4-methyl-2-pyrrolidinone (L687,414), 6, 7-dichloro-1, 4-dihydro-5-nitro, 2,3 quinoxalinedione (ACEA1021) and 2-carboxy-4,6-dichloro (1H)-indole-3-propanoic acid (MDL29,951), were inactive. NMDA abolished induction of spontaneous tail-flick by CPP and CGS19755, but not by dizocilpine. Upon bilateral injection into the nucleus accumbens, dizocilpine immediately and dose-dependently elicited spontaneous tail-flick, but it was ineffective in the ventrotegmental area and striatum. Similarly, injection of CPP into the nucleus accumbens elicited spontaneous tail-flick. Neither dizocilpine nor CPP elicited spontaneous tail-flick upon administration onto lumbar spinal cord. In conclusion, a pharmacologically specific spontaneous tail-flick-response is elicited by both open channel blockers and recognition site antagonists, but not glycine B site antagonists, at NMDA receptors. Their actions, mediated in the nucleus accumbens, may be differentiated by their respective resistance and sensitivity to NMDA.
N-甲基-D-天冬氨酸（NMDA）受体的开放通道阻滞剂地佐环平，能特异性地引发大鼠的自发性甩尾反应——这一反应与其他作为开放通道阻滞剂的药物（替环己哌啶、苯环利定和氯胺酮）所引发的反应相似。它们的相对效力与在NMDA结合位点的亲和力密切相关，并能被额叶皮质中的[3H]地佐环平标记（r = 0.94），且如先前测定的那样[Millan, M. J., Seguin, L., 1994. 与N-甲基-D-天冬氨酸（NMDA）受体偶联的甘氨酸B位点上化学结构多样的配体选择性阻断小鼠福尔马林诱导疼痛的后期阶段，神经科学快报，178 (1994) 139 - 143]，引发抗伤害感受的效力为0.93。NMDA受体识别位点的竞争性拮抗剂，（±）3 - （2 - 羧基哌嗪 - 4 - 基） - 丙基 - 1 - 膦酸（CPP）、4 - 膦酰甲基 - 2 - 哌啶羧酸（CGS19755）、D，L - （E） - 2 - 氨基 - 4 - 甲基膦酰基 - 3 - 戊酸（CGP37849）和（3E） - 1 - 乙酯 - 2 - 氨基 - 4 - 甲基 - 5 - 膦酰基 - 3 - 戊烯酸（CGP39551），同样呈剂量依赖性地诱发自发性甩尾。相比之下，偶联的甘氨酸B位点的拮抗剂/弱部分激动剂，7 - 氯 - 4 - 羟基 - 3 - （3 - 苯氧基）苯基 - 2（H） - 喹啉酮（L701,324）、（+） - 1 - 羟基 - 3 - 氨基吡咯烷 - 2 - 酮（（+） - HA966）、（3R，4R） - 3 - 氨基 - 1 - 羟基 - 4 - 甲基 - 2 - 吡咯烷酮（L687,414）、6,7 - 二氯 - 1,4 - 二氢 - 5 - 硝基 - 2,3 - 喹喔啉二酮（ACEA1021）和2 - 羧基 - 4,6 - 二氯（1H） - 吲哚 - 3 - 丙酸（MDL29,951）则无活性。NMDA可消除CPP和CGS19755诱导的自发性甩尾，但不能消除地佐环平诱导的。双侧注射到伏隔核后，地佐环平立即且呈剂量依赖性地引发自发性甩尾，但在腹侧被盖区和纹状体中无效。同样，向伏隔核注射CPP也会引发自发性甩尾。地佐环平和CPP经腰椎脊髓给药均不会引发自发性甩尾。总之，NMDA受体上的开放通道阻滞剂和识别位点拮抗剂均可引发药理学上特异性的自发性甩尾反应，但甘氨酸B位点拮抗剂则不能。它们在伏隔核介导的作用，可能因其对NMDA的各自抗性和敏感性而有所不同。
