Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn
Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn
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DOI：
10.1016/s0028-3908(98)00218-4
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发表时间：
1999-05-01
影响因子：
4.7
通讯作者：
Rupniak, NMJ
中科院分区：
文献类型：
--
作者：
Boyce, S;Wyatt, A;Rupniak, NMJ
本研究探讨了含有NR 2B亚单位蛋白的N-甲基-D-天冬氨酸（NMDA）受体在大鼠腰髓中的区域分布，并研究了选择性NR 2B拮抗剂是否会表现出比亚型非选择性NMDA拮抗剂和抗惊厥药更低的副作用倾向。免疫细胞化学研究表明，NR 2B亚基有一个有限的分布，与中度标记的纤维在板层I和II的背角提示初级传入纤维的突触前位置，并可能参与疼痛传递。在体内研究中，使用NMDA/甘氨酸拮抗剂（MK-801，0.02-1 mg/kg i. p.，L-687，414 10-300 mg/kg i.p.，和L-701，324 1-10 mg/kg i.p.）和抗惊厥剂加巴喷丁（10-500 mg/kg p.o.），在抗伤害剂量下诱导旋转杆缺陷。相反，选择性NR 2B拮抗剂（+/-）-CP-101，606（1-100 mg/kg p.o.）和（+/-）-Ro 25-6981（3-100 mg/kg i.p.）显示了一个显著的剂量窗口。（+/-）-CP-101，606在高达100 mg/kg p.o.的剂量下未引起大鼠运动损伤或刺激，其远远超过在神经病大鼠中抑制异常性疼痛的那些（ID 50 4.1 mg/kg，p.o.）。（+/-）-Ro 25-6981也显示出显著的分离（ID 50异常性疼痛3.8 mg/kg，腹膜内），然而，在100 mg/kg时观察到旋转棒性能的一些破坏。抗惊厥药拉莫三嗪（3-500 mg/kg p.o.）也显示了良好的剂量窗口。这些发现表明，NR 2B拮抗剂可能具有治疗人类神经性和其他疼痛病症的临床效用，与现有的NMDA拮抗剂相比，其副作用特征减少。(C)1999爱思唯尔科技有限公司。保留所有权利。
The present study investigated the regional distribution of the N-methyl-D-aspartate (NMDA) receptor containing the NR2B subunit protein in rat lumbar spinal cord and examined whether selective NR2B antagonists would exhibit antinociception with reduced side-effect liability than subtype non-selective NMDA antagonists and anticonvulsants. Immunocytochemical studies showed the NR2B subunit had a restricted distribution, with moderate labelling of fibres in laminas I and II of the dorsal horn suggesting a presynaptic location on primary afferent fibres and possible involvement in pain transmission. In the in vivo studies, the NMDA/glycine antagonists (MK-801, 0.02-1 mg/kg i.p., L-687,414 10-300 mg/kg i.p., and L-701,324 1-10 mg/kg i.p.) and the anticonvulsant, gabapentin (10-500 mg/kg p.o.), induced rotarod deficits at antinociceptive doses. In contrast, the selective NR2B antagonists, (+/-)-CP-101,606 (1-100 mg/kg p.o.) and (+/-)-Ro 25-6981 (3-100 mg/kg i.p.) showed a significant dose window. (+/-)-CP-101,606 caused no motor impairment or stimulation in rats at doses up to 100 mg/kg p.o., which is far in excess of those inhibiting allodynia in neuropathic rats (ID50 4.1 mg/kg, p.o.). (+/-)-Ro 25-6981 also showed a significant separation (ID50 allodynia 3.8 mg/kg, i.p.), however, some disruption of rotarod performance was observed at 100 mg/kg. The anticonvulsant lamotrigine (3-500 mg/kg p.o.) also showed a good dose window. These findings demonstrate that NR2B antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in man with a reduced side-effect profile than existing NMDA antagonists. (C) 1999 Elsevier Science Ltd. All rights reserved.