NMDA受体NR2B亚基拮抗剂候选化合物筛选及评价
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摘要
到目前为止,阿片类药物依然是其它药物无法替代的强效镇痛药,然而其强大的致躯体依赖和精神依赖潜能导致其在社会上的滥用。阿片依赖的病理生理学基础是机体长期接触阿片类物质产生的代偿性适应,涉及许多神经递质及其受体系统的改变。谷氨酸NMDA受体作用系统是阿片受体系统外最重要的阿片功能调节系统之一。
谷氨酸是中枢神经系统中重要的兴奋性神经递质,在突触传递和神经元可塑性方面具有非常重要的作用。NMDA受体是一个重要的离子型谷氨酸受体,该受体是一种配体门控型阳离子通道,由基本亚基NR1和至少一个NR2调节亚基组成异聚体。NMDA受体的功能特性主要由组成异聚体的NR2亚基的特异性决定。编码NR2的基因有4种,即NR2A、NR2B、NR2C和NR2D。大量研究表明NR2B亚基直接参与了药物依赖的形成、发展和维持等全部病理生理过程,与阿片依赖关系十分密切。本研究旨在筛选和评价具有抗阿片依赖作用的新型选择性NR2B亚基拮抗剂,为阿片类药物脱毒和防复吸提供潜在的先导化合物。
本课题以哌啶类化合物为先导结构,经过结构改造,合成了一系列候选化合物。由于激活NMDA受体后会导致钙离子大量内流,能够引发膜电流,因此我们在表达NMDA受体(NR1A/NR2B)的爪蟾卵母细胞上,利用双电极电压钳技术对化合物阻断NMDA受体通道电流作用进行初步筛选。此外,大量研究表明NR2B拮抗剂有一定的外周镇痛作用,因此我们采用醋酸扭体镇痛实验对候选化合物进行了镇痛活性初筛。结果显示Y-IP5等化合物阻断NMDA受体通道电流作用较强,Y-IP9、Y-IP10等化合物具有显著的镇痛作用。初步构效关系分析如下:
1)当以哌嗪环代替哌啶环时,化合物保留镇痛活性,但通道电流阻断作用显著减弱;2)当以烷基胺如(美)金刚胺、苏胺等取代哌嗪环或哌啶环时,镇痛活性和通道电流阻断作用均显著减弱;3)当哌嗪环1位N原子和芳基之间的连接链为丙酰基时镇痛活性较好;连接链为丙酰基或乙酰胺基时通道电流阻断作用较强;4)当哌嗪环1位取代基上的芳基为苯并噁唑酮或苯并噻唑酮时,有显著的镇痛活性或通道电流阻断作用,进一步说明以杂环或苯酚的生物等排体代替苯酚基团的可行性。
进一步选择在小鼠醋酸扭体模型上镇痛作用显著的化合物Y-IP9和Y-IP10和对NMDA受体通道电流阻断作用较强的化合物Y-IP5进行了药效学评价。Y-IP9、Y-IP10均具有显著的镇痛作用,在小鼠醋酸扭体模型上镇痛ED50值分别为3.3 mg·kg-1和3.8 mg·kg-1;对大鼠糖尿病性神经源性痛也都表现出显著的镇痛作用;Y-IP9、Y-IP10与大鼠脑膜制备阿片受体无亲和力,表明其镇痛作用不是通过阿片受体介导的。Y-IP9、Y-IP10具有一定的抗阿片依赖作用,均能显著抑制吗啡诱导小鼠条件性位置偏爱(CPP)的形成,而Y-IP10对吗啡所致小鼠躯体依赖的表达也有显著的抑制作用。Y-IP9、Y-IP10均能显著抑制小鼠的自发活动。
Y-IP5阻断NMDA受体通道电流作用强,浓度为10μM时电流抑制率达到84.4%。该化合物能一定程度上对抗吗啡耐受。Y-IP5在(2.5-10.0 mg·kg-1)剂量范围内不影响小鼠的自发活动,但能剂量依赖性地抑制吗啡急性处理引起的活动增强。Y-IP5显著抑制小鼠吗啡躯体依赖的形成,并能显著抑制吗啡所致小鼠行为敏化及CPP的形成;表明其具有明显的抗阿片躯体和精神依赖潜能。
综上所述,Y-IP5表现出明显的抗阿片耐受和依赖的作用,有可能作为一个潜在的防治阿片类药物依赖的先导化合物,其药理学作用值得进一步深入研究。
Opioids have long been used for the treatment of moderate to severe pain. Despite their strong antinociceptive effects, the use of opioids in the treatment of pain is restricted by their physical and psychological dependence. In addition, opioids induce drug addiction among people. The pathophysiological mechanism of opioid dependence is related to the adaptation of many neurotransmitters and their receptors after chronic opioid treatment. Many studies demonstrated that glutamate-NMDA receptor system was an important modulatory system that has effect on the pharmacological actions of opioids.
Glutamate is a major excitatory neurotransmitter in mammal central nervous system. NMDA receptor is an important ionotropic glutamate receptor, which is a ligand-gated positive ion channel composed by one NR1 subunit and at least one NR2 subunit. There are 4 genes encoding the NR2 subunit, including NR2A, NR2B, NR2C and NR2D. The property of NMDA receptor depended on the NR2 subunit which formed the heteromeric. NMDA receptor, especially NR2B subunit, plays important role in the pathophysiological process of drug dependence. Therefore, the main purpose of this investigation is to screen and evaluate novel selective NR2B antagonist that has inhibitory effect on opioid dependence, hopefully we can find potential new drugs for the prevention and therapy of opioid dependence and relapse.
4-substituted piperdines were chosen as the lead structure. A series of novel compounds were designed and synthesized in this study. Because activation of NMDA receptors results in calcium influx which evokes membrane current. Xenopus oocytes expressing NMDA receptors (NR1A/NR2B) were established in this test. Two-electrode voltage clamp experiment was used to screen these compounds which had inhibitory effect on membrane current evoked by NMDA receptor channel in Xenopus oocytes. In addition, many studies revealed that this kind of antagonist had peripheral analgesic activity. Mice acetic acid writhing test was also used to screen these compounds. Y-IP5 blocked membrane current evoked by NMDA receptor channel significantly. Y-IP9 and Y-IP10 had relatively strong analgesic activity. Based on the results of preliminary screening, the structure-activity relationship was analyzed as follow:
1) When the piperdine ring of lead structure was replaced by piperazine ring, the analgesic activity was retained,but the ability to block membrane current was attenuated. 2) When the piperazine ring or piperdine ring was replaced by bulky amino groups such as memantine, both the analgesic activity and the ability to block membrane current were attenuated significantly. 3) When the linker between 1-site of piperazine ring and aryl was ethylenecarbonyl, the analgesic activity and the ability to block membrane current were strong. 4) When the aryl group was 2-benzoxazolone-6-yl or 2-benzothioazolone-yl, the analgesic activity and the ability to block membrane current were retained or enhanced.
Among these compounds, Y-IP9 and Y-IP10 had relatively strong analgesic activity. Y-IP5 blocked membrane current significantly. The pharmacological properties of these three compounds were investigated thereafter.
Y-IP9 and Y-IP10 showed potent antinociceptive effects with ED50 of 3.31 mg·kg-1 and 3.80 mg·kg-1 respectively in the mice acetic acid writhing test. In rat diabetic neuropathy pain model these two compounds also showed antinociceptive effects. Y-IP9 and Y-IP10 bound opioid receptors with low affinity, which implicated their analgesic action were not related to activation of opioid receptor. Both Y-IP9 and Y-IP10 inhibited the development of morphine-induced conditioned place preference in mice. Y-IP10 also inhibited the expression of physical dependence in morphine-dependent mice. In addition, both Y-IP9 and Y-IP10 inhibited locomotor activity in mice. Y-IP5 blocked membrane current evoked by NMDA receptor channel with the inhibition rate of 84.4%. In chronic morphine tolerance model, Y-IP5 inhibited the development of morphine-induced tolerance. Y-IP5 didn’t influence locomotor activity in mice, but inhibited acute morphine-induced hyperactivity. Y-IP5 inhibited the development of morphine-induced physical dependence. Furthermore, Y-IP5 inhibited the development of morphine-induced behavioral sensitization and conditioned place preference in mice.
In conclusion, Y-IP5 was found to have inhibitory effect on tolerance to and dependence on opioid, it could be taken as a potential leading compound in prevention and therapy of opioid dependence. Further investigation still needs to do to evaluate the possible effect of Y-IP5 on opioid dependence.
谷氨酸是中枢神经系统中重要的兴奋性神经递质,在突触传递和神经元可塑性方面具有非常重要的作用。NMDA受体是一个重要的离子型谷氨酸受体,该受体是一种配体门控型阳离子通道,由基本亚基NR1和至少一个NR2调节亚基组成异聚体。NMDA受体的功能特性主要由组成异聚体的NR2亚基的特异性决定。编码NR2的基因有4种,即NR2A、NR2B、NR2C和NR2D。大量研究表明NR2B亚基直接参与了药物依赖的形成、发展和维持等全部病理生理过程,与阿片依赖关系十分密切。本研究旨在筛选和评价具有抗阿片依赖作用的新型选择性NR2B亚基拮抗剂,为阿片类药物脱毒和防复吸提供潜在的先导化合物。
本课题以哌啶类化合物为先导结构,经过结构改造,合成了一系列候选化合物。由于激活NMDA受体后会导致钙离子大量内流,能够引发膜电流,因此我们在表达NMDA受体(NR1A/NR2B)的爪蟾卵母细胞上,利用双电极电压钳技术对化合物阻断NMDA受体通道电流作用进行初步筛选。此外,大量研究表明NR2B拮抗剂有一定的外周镇痛作用,因此我们采用醋酸扭体镇痛实验对候选化合物进行了镇痛活性初筛。结果显示Y-IP5等化合物阻断NMDA受体通道电流作用较强,Y-IP9、Y-IP10等化合物具有显著的镇痛作用。初步构效关系分析如下:
1)当以哌嗪环代替哌啶环时,化合物保留镇痛活性,但通道电流阻断作用显著减弱;2)当以烷基胺如(美)金刚胺、苏胺等取代哌嗪环或哌啶环时,镇痛活性和通道电流阻断作用均显著减弱;3)当哌嗪环1位N原子和芳基之间的连接链为丙酰基时镇痛活性较好;连接链为丙酰基或乙酰胺基时通道电流阻断作用较强;4)当哌嗪环1位取代基上的芳基为苯并噁唑酮或苯并噻唑酮时,有显著的镇痛活性或通道电流阻断作用,进一步说明以杂环或苯酚的生物等排体代替苯酚基团的可行性。
进一步选择在小鼠醋酸扭体模型上镇痛作用显著的化合物Y-IP9和Y-IP10和对NMDA受体通道电流阻断作用较强的化合物Y-IP5进行了药效学评价。Y-IP9、Y-IP10均具有显著的镇痛作用,在小鼠醋酸扭体模型上镇痛ED50值分别为3.3 mg·kg-1和3.8 mg·kg-1;对大鼠糖尿病性神经源性痛也都表现出显著的镇痛作用;Y-IP9、Y-IP10与大鼠脑膜制备阿片受体无亲和力,表明其镇痛作用不是通过阿片受体介导的。Y-IP9、Y-IP10具有一定的抗阿片依赖作用,均能显著抑制吗啡诱导小鼠条件性位置偏爱(CPP)的形成,而Y-IP10对吗啡所致小鼠躯体依赖的表达也有显著的抑制作用。Y-IP9、Y-IP10均能显著抑制小鼠的自发活动。
Y-IP5阻断NMDA受体通道电流作用强,浓度为10μM时电流抑制率达到84.4%。该化合物能一定程度上对抗吗啡耐受。Y-IP5在(2.5-10.0 mg·kg-1)剂量范围内不影响小鼠的自发活动,但能剂量依赖性地抑制吗啡急性处理引起的活动增强。Y-IP5显著抑制小鼠吗啡躯体依赖的形成,并能显著抑制吗啡所致小鼠行为敏化及CPP的形成;表明其具有明显的抗阿片躯体和精神依赖潜能。
综上所述,Y-IP5表现出明显的抗阿片耐受和依赖的作用,有可能作为一个潜在的防治阿片类药物依赖的先导化合物,其药理学作用值得进一步深入研究。
Opioids have long been used for the treatment of moderate to severe pain. Despite their strong antinociceptive effects, the use of opioids in the treatment of pain is restricted by their physical and psychological dependence. In addition, opioids induce drug addiction among people. The pathophysiological mechanism of opioid dependence is related to the adaptation of many neurotransmitters and their receptors after chronic opioid treatment. Many studies demonstrated that glutamate-NMDA receptor system was an important modulatory system that has effect on the pharmacological actions of opioids.
Glutamate is a major excitatory neurotransmitter in mammal central nervous system. NMDA receptor is an important ionotropic glutamate receptor, which is a ligand-gated positive ion channel composed by one NR1 subunit and at least one NR2 subunit. There are 4 genes encoding the NR2 subunit, including NR2A, NR2B, NR2C and NR2D. The property of NMDA receptor depended on the NR2 subunit which formed the heteromeric. NMDA receptor, especially NR2B subunit, plays important role in the pathophysiological process of drug dependence. Therefore, the main purpose of this investigation is to screen and evaluate novel selective NR2B antagonist that has inhibitory effect on opioid dependence, hopefully we can find potential new drugs for the prevention and therapy of opioid dependence and relapse.
4-substituted piperdines were chosen as the lead structure. A series of novel compounds were designed and synthesized in this study. Because activation of NMDA receptors results in calcium influx which evokes membrane current. Xenopus oocytes expressing NMDA receptors (NR1A/NR2B) were established in this test. Two-electrode voltage clamp experiment was used to screen these compounds which had inhibitory effect on membrane current evoked by NMDA receptor channel in Xenopus oocytes. In addition, many studies revealed that this kind of antagonist had peripheral analgesic activity. Mice acetic acid writhing test was also used to screen these compounds. Y-IP5 blocked membrane current evoked by NMDA receptor channel significantly. Y-IP9 and Y-IP10 had relatively strong analgesic activity. Based on the results of preliminary screening, the structure-activity relationship was analyzed as follow:
1) When the piperdine ring of lead structure was replaced by piperazine ring, the analgesic activity was retained,but the ability to block membrane current was attenuated. 2) When the piperazine ring or piperdine ring was replaced by bulky amino groups such as memantine, both the analgesic activity and the ability to block membrane current were attenuated significantly. 3) When the linker between 1-site of piperazine ring and aryl was ethylenecarbonyl, the analgesic activity and the ability to block membrane current were strong. 4) When the aryl group was 2-benzoxazolone-6-yl or 2-benzothioazolone-yl, the analgesic activity and the ability to block membrane current were retained or enhanced.
Among these compounds, Y-IP9 and Y-IP10 had relatively strong analgesic activity. Y-IP5 blocked membrane current significantly. The pharmacological properties of these three compounds were investigated thereafter.
Y-IP9 and Y-IP10 showed potent antinociceptive effects with ED50 of 3.31 mg·kg-1 and 3.80 mg·kg-1 respectively in the mice acetic acid writhing test. In rat diabetic neuropathy pain model these two compounds also showed antinociceptive effects. Y-IP9 and Y-IP10 bound opioid receptors with low affinity, which implicated their analgesic action were not related to activation of opioid receptor. Both Y-IP9 and Y-IP10 inhibited the development of morphine-induced conditioned place preference in mice. Y-IP10 also inhibited the expression of physical dependence in morphine-dependent mice. In addition, both Y-IP9 and Y-IP10 inhibited locomotor activity in mice. Y-IP5 blocked membrane current evoked by NMDA receptor channel with the inhibition rate of 84.4%. In chronic morphine tolerance model, Y-IP5 inhibited the development of morphine-induced tolerance. Y-IP5 didn’t influence locomotor activity in mice, but inhibited acute morphine-induced hyperactivity. Y-IP5 inhibited the development of morphine-induced physical dependence. Furthermore, Y-IP5 inhibited the development of morphine-induced behavioral sensitization and conditioned place preference in mice.
In conclusion, Y-IP5 was found to have inhibitory effect on tolerance to and dependence on opioid, it could be taken as a potential leading compound in prevention and therapy of opioid dependence. Further investigation still needs to do to evaluate the possible effect of Y-IP5 on opioid dependence.
引文
1. 宋普球, 陈光辉, 刘竹焕, 钱韵旭. 阿片成瘾的治疗及戒毒中药的研究进展. 现代中西医结合杂志, 2005. 14(23): 3173-3174.
2. 韩济生. 神经科学原理. 北京医科大学出版社 1999,第二版: 1144-1145.
3. Williams JT, Christie MJ, and Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev, 2001. 81(1): 299-343.
4. 李锦. 阿片功能调节剂. 中国药理学会通讯, 2002. 19: 14-15.
5. Nakagawa T. Involvement of glial glutamate transporters in morphine dependence and naloxone-precipitated withdrawal. Yakugaku Zasshi, 2001. 121(9): 671-677.
6. Guo M, Xu NJ, Li YT, et al. Morphine modulates glutamate release in the hippocampal CA1 area in mice. Neurosci Lett, 2005. 381(1-2): 12-15.
7. Tokuyama S, Zhu H, Wakabayashi H, et al. The role of glutamate in the locus coeruleus during opioid withdrawal and effects of H-7, a protein kinase inhibitor, on the action of glutamate in rats. J Biomed Sci, 1998. 5(1): 45-53.
8. Laulin JP, Larcher A, Celerier E, et al. Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Ear J neurosci, 1998. 10:782-785.
9. Mcnally GP, Westbrook RF. Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats. Behav Neurosci, 1998. 966-978.
10. Taniguchi K, Shinjo K, Mizutani M, et al. Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist. Br J Pharmacol, 1997. 122(5): 809-812.
11. Nakazato E, Kato A, and Watanabe S. Brain but not spinal NR2B receptor is responsible for the anti-allodynic effect of an NR2B subunit-selective antagonist CP-101,606 in a rat chronic constriction injury model. Pharmacology, 2005. 73(1): 8-14.
12. Nishimura W, Muratani T, Tatsumi S, et al. Characterization of N-methyl-D-aspartate receptor subunits responsible for postoperative pain. Eur J Pharmacol, 2004. 503(1-3): 71-75.
13. Kolesnikov Y, Jain S, Wilson R, et al. Lack of morphine and enkephalin tolerance in 129/SvEv mice: Evidence for a NMDA receptor defect. J Pharmacol Exp Ther, 1998. 284:455-459.
14. Wang HL, Zhao Y, Xiang XH, et al. Blockade of ionotropic glutamatergic transmission in the ventral tegmental area attenuates the physical signs of morphine withdrawal in rats. Prog Neuropsychopharmacol Biol Psychiatry, 2004. 28(7):1079-1087.
15. Zhu H, Ho IK. NMDA-R1 antisense oligonucleotide attenuates withdrawal signs from morphine. Eur J Pharmacol, 1998. 352(2-3):151-156.
16. Muir KW and Lees KR. Clinical experience with excitatory amino acid antagonist drugs. Stroke,1995. 26(3): 503-513.
17. Paoletti P and Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol, 2007. 7(1): 39-47.
18. Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science, 1992. 256(5060): 1217-1221.
19. Moriyoshi K, Masu M, Ishii T, et al. Molecular cloning and characterization of the rat NMDA receptor. Nature, 1991. 354(6348): 31-37.
20. Oh S, Kim JI, Chung MW, et al. Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats. Neurochem Res, 2000. 25(12): 1603-1611.
21. Bajo M, Crawford EF, Roberto M, et al. Chronic morphine treatment alters expression of N-methyl-D-aspartate receptor subunits in the extended amygdala. J Neurosci Res, 2006. 83(4): 532-537.
22. Ma YY, Guo CY, Yu P, et al. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Exp Neurol, 2006. 200(2): 343-355.
23. Narita M, Aoki T, and Suzuki T. Molecular evidence for the involvement of NR2B subunit containing N-methyl-D-aspartate receptors in the development of morphine-induced place preference. Neuroscience, 2000. 101(3): 601-606.
24. Chizh BA, Headley PM. NMDA antagonists and neuropathic pain-multiple drug targets and multiple uses. Curr Pharm Design, 2005. 11(23): 2977-2994.
25. Kwon MO, Herrling P. List drugs in development for neurodegenerative diseases. Neurodegenerative Dis, 2006. 3: 148-186.
26. Chazot PL. The NMDA receptor NR2B subunit: a valid therapeutic target for multiple CNS pathologies. Curr Med Chem, 2004. 11(3): 389-396.
27. Chizh BA, Headley PM, and Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci, 2001. 22(12): 636-642.
28. Williams K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol, 1993. 44(4): 851-859.
29. Tamiz AP, Whittemore ER, Zhou ZL, et al. Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors. J Med Chem, 1998. 41(18): 3499-3506.
30. Narita M, Soma M, Mizoguchi H, et al. Implications of the NR2B subunit-containing NMDA receptor localized in mouse limbic forebrain in ethanol dependence. Eur J Pharmacol, 2000. 401(2): 191-195.
31. Pinard E, Alanine A, Bourson A, et al. Discovery of (R)-1-[2-hydroxy-3-(4-hydroxy-phenyl)- propyl]-4-(4-methyl-benzyl)-piperidi n-4-ol: a novel NR1/2B subtype selective NMDA receptor antagonist. Bioorg Med Chem Lett, 2001. 11(16): 2173-2176.
32. Fischer G, Mutel V, Trube G, et al. Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther, 1997. 283(3): 1285-1292.
33. Hang LH, Dai TJ and Zeng YM. Spinal N-methyl-D-aspartate receptors may mediate the analgesic effects of emulsified halogenated anesthetics. Pharmacology, 2006. 76(3): 105-109.
34. Xu AJ, Duan SM, and Zeng YM. Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats. Acta Pharmacol Sin, 2004. 25(1): 9-14.
35. Edwards MA, Loxley RA, Williams AJ, et al. Lack of functional expression of NMDA receptors in PC12 cells. Neurotoxicology, 2007. 28(4): 876-885.
36. Layton ME,Kelly MJ,Rodzinak KJ. Recent advances in the development of NR2B subtype-selective NMDA receptor antagonists. Curr Top Med Chem, 2006. 6(3): 697–709.
37. Le DA, Lipton SA. Potential and current use of N-methyl-D-aspartate(NMDA) receptor antagonists in diseases of aging. Drugs Aging , 2001. 18(10): 717–724.
38. Wei F, Wang GD, Kerchner GA, et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci, 2001. 4:164– 169.
39. Zhu MY, Piletz JE, Halaris A, et al. Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells. Cell Mol Neurobiol, 2003. 23(4-5): 865-872.
40. Mazzio E, Huber J, Darling S, et al. Effect of antioxidants on L-glutamate and N-methyl-4-phenylpyridinium ion induced-neurotoxicity in PC12 cells. Neurotoxicology, 2001. 22(2): 283-288.
41. Morrow TJ. Animal models of painful diabetic neuropathy: the STZ rat model. Curr Protoc Neurosci, 2004. 9: 9-18.
42. Pithova P, Patkova H, Galandakova I, et al. Differences in ulcer location in diabetic foot syndrome. Vnitr Lek, 2007. 53(12): 1278-1285.
43. Fang M, Kovacs KJ, Fisher LL, et al. Thrombin inhibits NMDA-mediated nociceptive activity in the mouse: possible mediation by endothelin. J Physiol, 2003. 549(3): 903-917.
44. Li J, Li X, Pei G, et al. Analgesic effect of agmatine and its enhancement on morphine analgesia in mice and rats. Zhongguo Yao Li Xue Bao, 1999. 20(1): 81-85.
45. Nishiyama T. Interaction between a NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 in antinociception in the spinal cord. Acta Anaesthesiol Scand, 2008. 52(4): 493-498.
46. Thomasy SM, Moeller BC, and Stanley SD. Comparison of opioid receptor binding in horse, guinea pig, and rat cerebral cortex and cerebellum. Vet Anaesth Analg, 2007. 34(5): 351-358.
47. Jang S, Kim H, Kim D, et al. Attenuation of morphine tolerance and withdrawal syndrome by coadministration of nalbuphine. Arch Pharm Res, 2006. 29(8): 677-684.
48. He L and Whistler JL. The biochemical analysis of methadone modulation on morphine-induced tolerance and dependence in the rat brain. Pharmacology, 2007. 79(4): 193-202.
49. Wei J, Dong M, Xiao C, et al. Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice. Neurosci Lett, 2006. 405(1-2): 137-141.
50. el-Kadi AO and Sharif SI. The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice. Gen Pharmacol, 1994. 25(7): 1505-1510.
51. Zhu YP, Long ZH, Zheng ML, et al. Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice. J Zhejiang Univ Sci B, 2006. 7(12): 998-1005.
52. Rezayof A, Golhasani-Keshtan F, Haeri-Rohani A, et al. Morphine-induced place preference: involvement of the central amygdala NMDA receptors. Brain Res, 2007. 1133(1): 34-41.
53. Ikemoto M, Takita M, Imamura T, et al. Increased sensitivity to the stimulant effects of morphine conferred by anti-adhesive glycoprotein SPARC in amygdala. Nat Med, 2000. 6(8): 910-915.
54. Eun JS, Bae K, Yun YP, et al. Inhibitory effects of paeonol on morphine-induced locomotor sensitization and conditioned place preference in mice. Arch Pharm Res, 2006. 29(10): 904-910.
55. Mendez IA and Trujillo KA. NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology (Berl), 2008. 196(3): 497-509.
56. Cheng C, Fass DM and Reynolds IJ. Emergence of excitotoxicity in cultured forebrain neurons coincides with larger glutamatestimulated [Ca2+]i increases and NMDA receptor mRNA levels. Brain Res, 1999. 849: 97–108.
57. Menniti F, Chenard B, Collins M, et al. CP-101,606, a potent neuroprotectant selective for forebrain neurons. Eur J Pharmacol, 1997. 331(2-3): 117-126.
58. 张开镐. 药物依赖性的动物实验(一).中国药物依赖性杂志, 1999. 8:23–26.
59. Hoffman DC. The use of place conditioning in studying the neuropharmacology of drug reinforcement. Brain Res Bull, 1989. 23(4-5): 373-387.
60. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science, 1991. 251:85-87.
61. Robinson TE and Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev, 1993. 18(3): 247-291.
62. Wolf ME, Jeziorski M. Coadministration of MK-801 with amphetamine, cocaine or morphine prevents rather than transiently masks the development of behavioral sensitization. Brain Res, 1993. 613:291–294.
63. Ian A, Mendez Keith A, Trujillo. NMDA receptor antagonists inhibit opiate antinociceptivetolerance and locomotor sensitization in rats. Psychopharmacology, 2008. 196:497–509.
1. Paoletti P and Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol, 2007. 7(1): p. 39-47.
2. Mayer ML. Glutamate receptors at atomic resolution. Nature, 2006. 440(7083): p. 456-462.
3. Rachline J, et al. The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. JNeurosci, 2005. 25(2): p. 308-317.
4. Monyer H, et al. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron, 1994. 12(3): p. 529-540.
5. Hatton, CJ and Paoletti P. Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron, 2005. 46(2): p. 261-274.
6. Khan AM, et al. Lateral hypothalamic NMDA receptor subunits NR2A and/or NR2B mediate eating: immunochemical/behavioral evidence. Am J Physiol, 1999. 276(3 Pt 2): p. R880-891.
7. Malenka RC and Bear MF. LTP and LTD: an embarrassment of riches. Neuron, 2004. 44(1): p. 5-21.
8. Oh S, et al. Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats. Neurochem Res, 2000. 25(12): p. 1603-1611.
9. Bajo M., et al. Chronic morphine treatment alters expression of N-methyl-D-aspartate receptor subunits in the extended amygdala. J Neurosci Res, 2006. 83(4): p. 532-537.
10. Ma YY, et al. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Exp Neurol, 2006. 200(2): p. 343-355.
11. Hendricson AW, et al. Aberrant synaptic activation of N-methyl-D-aspartate receptors underlies ethanol withdrawal hyperexcitability. J Pharmacol Exp Ther, 2007. 321(1): p. 60-72.
12. Narita M, Aoki T, and Suzuki T. Molecular evidence for the involvement of NR2B subunit containing N-methyl-D-aspartate receptors in the development of morphine-induced place preference. Neuroscience, 2000. 101(3): p. 601-606.
13. Kato H, et al. Role of tyrosine kinase-dependent phosphorylation of NR2B subunit-containing NMDA receptor in morphine reward. Nihon Arukoru Yakubutsu Igakkai Zasshi, 2007. 42(1): p. 13-20.
14. Kato H, et al. Implication of Src family kinase-dependent phosphorylation of NR2B subunit-containing NMDA receptor in the rewarding effect of morphine. Nihon Shinkei Seishin Yakurigaku Zasshi, 2006. 26(3): p. 119-124.
15. Narita M, et al. Involvement of protein kinase Cgamma isoform in morphine-induced reinforcing effects. Neuroscience, 2001. 103(2): p. 309-314.
16. Loftis JM and Janowsky A. Regulation of NMDA receptor subunits and nitric oxide synthase expression during cocaine withdrawal. J Neurochem, 2000. 75(5): p. 2040-2050.
17. Pierce RC, et al. Calcium-mediated second messengers modulate the expression of behavioral sensitization to cocaine. J Pharmacol Exp Ther, 1998. 286(3): p. 1171-1176.
18. Zhang X, et al. Reversal of cocaine-induced behavioral sensitization and associated phosphorylation of the NR2B and GluR1 subunits of the NMDA and AMPA receptors. Neuropsychopharmacology, 2007. 32(2): p. 377-387.
19. Liu XY, et al. Modulation of D2R-NR2B interactions in response to cocaine. Neuron, 2006.52(5): p. 897-909.
20. Narita M, et al. Implications of the NR2B subunit-containing NMDA receptor localized in mouse limbic forebrain in ethanol dependence. Eur J Pharmacol, 2000. 401(2): p. 191-195.
21. Pawlak R, et al. Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors. Proc Natl Acad Sci U S A, 2005. 102(2): p. 443-448.
22. Marutha Ravindran CR and Ticku MK. Role of CpG islands in the up-regulation of NMDA receptor NR2B gene expression following chronic ethanol treatment of cultured cortical neurons of mice. Neurochem Int, 2005. 46(4): p. 313-327.
23. Wang J, et al. Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior. J Neurosci, 2007. 27(13): p. 3593-3602.
24. Narita M, et al. Changes in function of NMDA receptor NR2B subunit in spinal cord of rats with neuropathy following chronic ethanol consumption. Life Sci, 2007. 80(9): p. 852-859.
2. 韩济生. 神经科学原理. 北京医科大学出版社 1999,第二版: 1144-1145.
3. Williams JT, Christie MJ, and Manzoni O. Cellular and synaptic adaptations mediating opioid dependence. Physiol Rev, 2001. 81(1): 299-343.
4. 李锦. 阿片功能调节剂. 中国药理学会通讯, 2002. 19: 14-15.
5. Nakagawa T. Involvement of glial glutamate transporters in morphine dependence and naloxone-precipitated withdrawal. Yakugaku Zasshi, 2001. 121(9): 671-677.
6. Guo M, Xu NJ, Li YT, et al. Morphine modulates glutamate release in the hippocampal CA1 area in mice. Neurosci Lett, 2005. 381(1-2): 12-15.
7. Tokuyama S, Zhu H, Wakabayashi H, et al. The role of glutamate in the locus coeruleus during opioid withdrawal and effects of H-7, a protein kinase inhibitor, on the action of glutamate in rats. J Biomed Sci, 1998. 5(1): 45-53.
8. Laulin JP, Larcher A, Celerier E, et al. Long-lasting increased pain sensitivity in rat following exposure to heroin for the first time. Ear J neurosci, 1998. 10:782-785.
9. Mcnally GP, Westbrook RF. Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats. Behav Neurosci, 1998. 966-978.
10. Taniguchi K, Shinjo K, Mizutani M, et al. Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist. Br J Pharmacol, 1997. 122(5): 809-812.
11. Nakazato E, Kato A, and Watanabe S. Brain but not spinal NR2B receptor is responsible for the anti-allodynic effect of an NR2B subunit-selective antagonist CP-101,606 in a rat chronic constriction injury model. Pharmacology, 2005. 73(1): 8-14.
12. Nishimura W, Muratani T, Tatsumi S, et al. Characterization of N-methyl-D-aspartate receptor subunits responsible for postoperative pain. Eur J Pharmacol, 2004. 503(1-3): 71-75.
13. Kolesnikov Y, Jain S, Wilson R, et al. Lack of morphine and enkephalin tolerance in 129/SvEv mice: Evidence for a NMDA receptor defect. J Pharmacol Exp Ther, 1998. 284:455-459.
14. Wang HL, Zhao Y, Xiang XH, et al. Blockade of ionotropic glutamatergic transmission in the ventral tegmental area attenuates the physical signs of morphine withdrawal in rats. Prog Neuropsychopharmacol Biol Psychiatry, 2004. 28(7):1079-1087.
15. Zhu H, Ho IK. NMDA-R1 antisense oligonucleotide attenuates withdrawal signs from morphine. Eur J Pharmacol, 1998. 352(2-3):151-156.
16. Muir KW and Lees KR. Clinical experience with excitatory amino acid antagonist drugs. Stroke,1995. 26(3): 503-513.
17. Paoletti P and Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol, 2007. 7(1): 39-47.
18. Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science, 1992. 256(5060): 1217-1221.
19. Moriyoshi K, Masu M, Ishii T, et al. Molecular cloning and characterization of the rat NMDA receptor. Nature, 1991. 354(6348): 31-37.
20. Oh S, Kim JI, Chung MW, et al. Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats. Neurochem Res, 2000. 25(12): 1603-1611.
21. Bajo M, Crawford EF, Roberto M, et al. Chronic morphine treatment alters expression of N-methyl-D-aspartate receptor subunits in the extended amygdala. J Neurosci Res, 2006. 83(4): 532-537.
22. Ma YY, Guo CY, Yu P, et al. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Exp Neurol, 2006. 200(2): 343-355.
23. Narita M, Aoki T, and Suzuki T. Molecular evidence for the involvement of NR2B subunit containing N-methyl-D-aspartate receptors in the development of morphine-induced place preference. Neuroscience, 2000. 101(3): 601-606.
24. Chizh BA, Headley PM. NMDA antagonists and neuropathic pain-multiple drug targets and multiple uses. Curr Pharm Design, 2005. 11(23): 2977-2994.
25. Kwon MO, Herrling P. List drugs in development for neurodegenerative diseases. Neurodegenerative Dis, 2006. 3: 148-186.
26. Chazot PL. The NMDA receptor NR2B subunit: a valid therapeutic target for multiple CNS pathologies. Curr Med Chem, 2004. 11(3): 389-396.
27. Chizh BA, Headley PM, and Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci, 2001. 22(12): 636-642.
28. Williams K. Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol, 1993. 44(4): 851-859.
29. Tamiz AP, Whittemore ER, Zhou ZL, et al. Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors. J Med Chem, 1998. 41(18): 3499-3506.
30. Narita M, Soma M, Mizoguchi H, et al. Implications of the NR2B subunit-containing NMDA receptor localized in mouse limbic forebrain in ethanol dependence. Eur J Pharmacol, 2000. 401(2): 191-195.
31. Pinard E, Alanine A, Bourson A, et al. Discovery of (R)-1-[2-hydroxy-3-(4-hydroxy-phenyl)- propyl]-4-(4-methyl-benzyl)-piperidi n-4-ol: a novel NR1/2B subtype selective NMDA receptor antagonist. Bioorg Med Chem Lett, 2001. 11(16): 2173-2176.
32. Fischer G, Mutel V, Trube G, et al. Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther, 1997. 283(3): 1285-1292.
33. Hang LH, Dai TJ and Zeng YM. Spinal N-methyl-D-aspartate receptors may mediate the analgesic effects of emulsified halogenated anesthetics. Pharmacology, 2006. 76(3): 105-109.
34. Xu AJ, Duan SM, and Zeng YM. Effects of systemic, intracerebral, or intrathecal administration of an N-methyl-D-aspartate receptor antagonist on associative morphine analgesic tolerance and hyperalgesia in rats. Acta Pharmacol Sin, 2004. 25(1): 9-14.
35. Edwards MA, Loxley RA, Williams AJ, et al. Lack of functional expression of NMDA receptors in PC12 cells. Neurotoxicology, 2007. 28(4): 876-885.
36. Layton ME,Kelly MJ,Rodzinak KJ. Recent advances in the development of NR2B subtype-selective NMDA receptor antagonists. Curr Top Med Chem, 2006. 6(3): 697–709.
37. Le DA, Lipton SA. Potential and current use of N-methyl-D-aspartate(NMDA) receptor antagonists in diseases of aging. Drugs Aging , 2001. 18(10): 717–724.
38. Wei F, Wang GD, Kerchner GA, et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci, 2001. 4:164– 169.
39. Zhu MY, Piletz JE, Halaris A, et al. Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells. Cell Mol Neurobiol, 2003. 23(4-5): 865-872.
40. Mazzio E, Huber J, Darling S, et al. Effect of antioxidants on L-glutamate and N-methyl-4-phenylpyridinium ion induced-neurotoxicity in PC12 cells. Neurotoxicology, 2001. 22(2): 283-288.
41. Morrow TJ. Animal models of painful diabetic neuropathy: the STZ rat model. Curr Protoc Neurosci, 2004. 9: 9-18.
42. Pithova P, Patkova H, Galandakova I, et al. Differences in ulcer location in diabetic foot syndrome. Vnitr Lek, 2007. 53(12): 1278-1285.
43. Fang M, Kovacs KJ, Fisher LL, et al. Thrombin inhibits NMDA-mediated nociceptive activity in the mouse: possible mediation by endothelin. J Physiol, 2003. 549(3): 903-917.
44. Li J, Li X, Pei G, et al. Analgesic effect of agmatine and its enhancement on morphine analgesia in mice and rats. Zhongguo Yao Li Xue Bao, 1999. 20(1): 81-85.
45. Nishiyama T. Interaction between a NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 in antinociception in the spinal cord. Acta Anaesthesiol Scand, 2008. 52(4): 493-498.
46. Thomasy SM, Moeller BC, and Stanley SD. Comparison of opioid receptor binding in horse, guinea pig, and rat cerebral cortex and cerebellum. Vet Anaesth Analg, 2007. 34(5): 351-358.
47. Jang S, Kim H, Kim D, et al. Attenuation of morphine tolerance and withdrawal syndrome by coadministration of nalbuphine. Arch Pharm Res, 2006. 29(8): 677-684.
48. He L and Whistler JL. The biochemical analysis of methadone modulation on morphine-induced tolerance and dependence in the rat brain. Pharmacology, 2007. 79(4): 193-202.
49. Wei J, Dong M, Xiao C, et al. Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice. Neurosci Lett, 2006. 405(1-2): 137-141.
50. el-Kadi AO and Sharif SI. The influence of various experimental conditions on the expression of naloxone-induced withdrawal symptoms in mice. Gen Pharmacol, 1994. 25(7): 1505-1510.
51. Zhu YP, Long ZH, Zheng ML, et al. Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice. J Zhejiang Univ Sci B, 2006. 7(12): 998-1005.
52. Rezayof A, Golhasani-Keshtan F, Haeri-Rohani A, et al. Morphine-induced place preference: involvement of the central amygdala NMDA receptors. Brain Res, 2007. 1133(1): 34-41.
53. Ikemoto M, Takita M, Imamura T, et al. Increased sensitivity to the stimulant effects of morphine conferred by anti-adhesive glycoprotein SPARC in amygdala. Nat Med, 2000. 6(8): 910-915.
54. Eun JS, Bae K, Yun YP, et al. Inhibitory effects of paeonol on morphine-induced locomotor sensitization and conditioned place preference in mice. Arch Pharm Res, 2006. 29(10): 904-910.
55. Mendez IA and Trujillo KA. NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology (Berl), 2008. 196(3): 497-509.
56. Cheng C, Fass DM and Reynolds IJ. Emergence of excitotoxicity in cultured forebrain neurons coincides with larger glutamatestimulated [Ca2+]i increases and NMDA receptor mRNA levels. Brain Res, 1999. 849: 97–108.
57. Menniti F, Chenard B, Collins M, et al. CP-101,606, a potent neuroprotectant selective for forebrain neurons. Eur J Pharmacol, 1997. 331(2-3): 117-126.
58. 张开镐. 药物依赖性的动物实验(一).中国药物依赖性杂志, 1999. 8:23–26.
59. Hoffman DC. The use of place conditioning in studying the neuropharmacology of drug reinforcement. Brain Res Bull, 1989. 23(4-5): 373-387.
60. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science, 1991. 251:85-87.
61. Robinson TE and Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev, 1993. 18(3): 247-291.
62. Wolf ME, Jeziorski M. Coadministration of MK-801 with amphetamine, cocaine or morphine prevents rather than transiently masks the development of behavioral sensitization. Brain Res, 1993. 613:291–294.
63. Ian A, Mendez Keith A, Trujillo. NMDA receptor antagonists inhibit opiate antinociceptivetolerance and locomotor sensitization in rats. Psychopharmacology, 2008. 196:497–509.
1. Paoletti P and Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol, 2007. 7(1): p. 39-47.
2. Mayer ML. Glutamate receptors at atomic resolution. Nature, 2006. 440(7083): p. 456-462.
3. Rachline J, et al. The micromolar zinc-binding domain on the NMDA receptor subunit NR2B. JNeurosci, 2005. 25(2): p. 308-317.
4. Monyer H, et al. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron, 1994. 12(3): p. 529-540.
5. Hatton, CJ and Paoletti P. Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron, 2005. 46(2): p. 261-274.
6. Khan AM, et al. Lateral hypothalamic NMDA receptor subunits NR2A and/or NR2B mediate eating: immunochemical/behavioral evidence. Am J Physiol, 1999. 276(3 Pt 2): p. R880-891.
7. Malenka RC and Bear MF. LTP and LTD: an embarrassment of riches. Neuron, 2004. 44(1): p. 5-21.
8. Oh S, et al. Modulation of NMDA receptor subunit mRNA in butorphanol-tolerant and -withdrawing rats. Neurochem Res, 2000. 25(12): p. 1603-1611.
9. Bajo M., et al. Chronic morphine treatment alters expression of N-methyl-D-aspartate receptor subunits in the extended amygdala. J Neurosci Res, 2006. 83(4): p. 532-537.
10. Ma YY, et al. The role of NR2B containing NMDA receptor in place preference conditioned with morphine and natural reinforcers in rats. Exp Neurol, 2006. 200(2): p. 343-355.
11. Hendricson AW, et al. Aberrant synaptic activation of N-methyl-D-aspartate receptors underlies ethanol withdrawal hyperexcitability. J Pharmacol Exp Ther, 2007. 321(1): p. 60-72.
12. Narita M, Aoki T, and Suzuki T. Molecular evidence for the involvement of NR2B subunit containing N-methyl-D-aspartate receptors in the development of morphine-induced place preference. Neuroscience, 2000. 101(3): p. 601-606.
13. Kato H, et al. Role of tyrosine kinase-dependent phosphorylation of NR2B subunit-containing NMDA receptor in morphine reward. Nihon Arukoru Yakubutsu Igakkai Zasshi, 2007. 42(1): p. 13-20.
14. Kato H, et al. Implication of Src family kinase-dependent phosphorylation of NR2B subunit-containing NMDA receptor in the rewarding effect of morphine. Nihon Shinkei Seishin Yakurigaku Zasshi, 2006. 26(3): p. 119-124.
15. Narita M, et al. Involvement of protein kinase Cgamma isoform in morphine-induced reinforcing effects. Neuroscience, 2001. 103(2): p. 309-314.
16. Loftis JM and Janowsky A. Regulation of NMDA receptor subunits and nitric oxide synthase expression during cocaine withdrawal. J Neurochem, 2000. 75(5): p. 2040-2050.
17. Pierce RC, et al. Calcium-mediated second messengers modulate the expression of behavioral sensitization to cocaine. J Pharmacol Exp Ther, 1998. 286(3): p. 1171-1176.
18. Zhang X, et al. Reversal of cocaine-induced behavioral sensitization and associated phosphorylation of the NR2B and GluR1 subunits of the NMDA and AMPA receptors. Neuropsychopharmacology, 2007. 32(2): p. 377-387.
19. Liu XY, et al. Modulation of D2R-NR2B interactions in response to cocaine. Neuron, 2006.52(5): p. 897-909.
20. Narita M, et al. Implications of the NR2B subunit-containing NMDA receptor localized in mouse limbic forebrain in ethanol dependence. Eur J Pharmacol, 2000. 401(2): p. 191-195.
21. Pawlak R, et al. Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors. Proc Natl Acad Sci U S A, 2005. 102(2): p. 443-448.
22. Marutha Ravindran CR and Ticku MK. Role of CpG islands in the up-regulation of NMDA receptor NR2B gene expression following chronic ethanol treatment of cultured cortical neurons of mice. Neurochem Int, 2005. 46(4): p. 313-327.
23. Wang J, et al. Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior. J Neurosci, 2007. 27(13): p. 3593-3602.
24. Narita M, et al. Changes in function of NMDA receptor NR2B subunit in spinal cord of rats with neuropathy following chronic ethanol consumption. Life Sci, 2007. 80(9): p. 852-859.