Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice
Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice
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DOI：
10.1124/jpet.108.136267
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发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
Dohi, Toshihiro
中科院分区：
文献类型：
--
作者：
Morita, Katsuya;Motoyama, Naoyo;Dohi, Toshihiro
神经性疼痛对常规镇痛剂是难治的，因此需要新的药物用于治疗。甘氨酸能神经元定位于特定的脑区域，包括脊髓，在那里它们在疼痛信号转导的调节中起重要作用。甘氨酸转运体（GlyT）1存在于神经胶质细胞中，GlyT 2存在于神经元中，通过清除突触释放的甘氨酸或向神经元供应甘氨酸，调节甘氨酸能神经传递，从而改变脊髓中疼痛信号的传递。在这项研究中，我们证明了i。静脉或鞘内给予GlyT 1抑制剂、顺式-N-甲基-N（6-甲氧基-1-苯基-1，2，3，4-四氢萘-2-基甲基）氨基甲基羧酸（ORG 25935）或肌氨酸，和GlyT 2抑制剂，4-苄氧基-3，5-二甲氧基- N-[1-（二甲氨基环戊基）甲基]苯甲酰胺（ORG 25543）和（O-[（2-苄氧基苯基-3-氟苯基）甲基]-L-丝氨酸）（ALX 1393），或通过GlyTs mRNA的小干扰RNA敲低脊髓GlyTs在部分周围神经结扎模型和其他神经病理性疼痛中产生了显著的抗异常性疼痛作用小鼠模型。抗异常性疼痛作用通过脊髓甘氨酸受体α 3介导。这些结果确立了GlyTs作为开发神经性疼痛药物的靶分子。然而，这些刺激甘氨酸能神经元活性的操作在神经损伤后的4天期间没有效果，而抑制甘氨酸能神经元活性的操作在该阶段保护免受异常性疼痛的发展。结果表明，应考虑其抑制剂的给药时机，因为甘氨酸能对疼痛的控制在术后3至4天的关键期内逆转。这也可能为理解神经病理性疼痛发展的潜在分子机制提供重要信息。
Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i. v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl) amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4- benzyloxy- 3,5- dimethoxy- N-[1-(dimethylaminocyclopently)methyl] benzamide (ORG25543) and (O-[(2benzyloxyphenyl-3-fluorophenyl) methyl]-L-serine) (ALX1393), or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor alpha 3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.