Glycine Transporter Inhibitors as a Potential Therapeutic Strategy for Chronic Pain with Memory Impairment
Glycine Transporter Inhibitors as a Potential Therapeutic Strategy for Chronic Pain with Memory Impairment
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DOI：
10.1097/aln.0b013e31816c9044
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发表时间：
2008-05
期刊：
影响因子：
8.8
通讯作者：
M. Tanabe;K. Takasu;S. Yamaguchi;D. Kodama;H. Ono
中科院分区：
文献类型：
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作者：
M. Tanabe;K. Takasu;S. Yamaguchi;D. Kodama;H. Ono
背景：脊髓背角兴奋性和抑制性平衡受损在慢性疼痛的病理生理学中起着至关重要的作用。作者阐述了外源性或通过使用甘氨酸转运蛋白1的选择性抑制剂肌氨酸和N-[3-（4 ′-氟苯基）-3-（4′-苯基苯氧基）丙基]肌氨酸阻断甘氨酸转运蛋白1增加脊髓甘氨酸对小鼠神经性和炎症性疼痛的治疗影响。方法：采用坐骨神经部分结扎致小鼠热、机械性超敏反应（Seltzer模型）或链脲佐菌素致小鼠机械性超敏反应，分别鞘内注射甘氨酸、肌氨酸和N-[3-（4 ′-氟苯基）-3-（4′-苯苯氧基）丙基]肌氨酸。这些药物也被鞘内注射在小鼠中，以评估它们对福尔马林诱发的伤害性行为的影响。在Seltzer模型小鼠制备的海马脑片中，研究了阻断甘氨酸转运体1对破伤风诱导的Schaffer侧支突触长时程增强的脊髓上效应。结果：甘氨酸、肌氨酸和N-[3-（4 ′-氟苯基）-3-（4′-苯基苯氧基）丙基]肌氨酸均能改善Seltzer模型小鼠的热敏感性和机械敏感性，降低链脲佐菌素注射糖尿病小鼠的机械敏感性。此外，它们选择性地抑制福尔马林诱发的舔/咬行为的第二阶段。在从Seltzer模型小鼠制备的海马切片中，长时程增强维持在比假处理小鼠显著更低的水平。当N-[3-（4 ′-氟苯基）-3-（4 ′-苯氧基）丙基]肌氨酸存在时，从未观察到长时程增强的这种损害。结论：内源性甘氨酸通过甘氨酸转运体1阻断的增加不仅导致在脊髓水平的疼痛传递的净抑制作用，但也supraspinally缓解突触效能下降，可能与慢性疼痛患者中经常描述的认知障碍。
Background:Impaired excitatory and inhibitory balance in the spinal dorsal horn has a crucial role in the pathophysiology of chronic pain. The authors addressed the therapeutic impact of increasing spinal glycine applied exogenously or via blockade of glycine transporter 1 using its selective inhibitors sarcosine and N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine on neuropathic and inflammatory pain in mice. Methods:Mice with thermal and mechanical hypersensitivity after partial ligation of the sciatic nerve (Seltzer model) or mice with mechanical hypersensitivity after streptozotocin injection received intrathecal injection of glycine, sarcosine, and N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine. These drugs were also intrathecally injected in mice to assess their effects on formalin-evoked nociceptive behaviors. The supraspinal effect of blockade of glycine transporter 1 was studied on tetanus-induced long-term potentiation of the Schaffer-collateral synapses in hippocampal slices prepared from Seltzer model mice. Results:Glycine, sarcosine, and N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine ameliorated thermal and mechanical hypersensitivity in Seltzer model mice, and reduced mechanical hypersensitivity in streptozotocin-injected diabetic mice. Moreover, they selectively inhibited the second phase of formalin-evoked licking/biting behavior. In hippocampal slices prepared from Seltzer model mice, long-term potentiation was maintained at a significantly lower level than that in sham-treated mice. Such impairment of long-term potentiation was never observed when it was induced in the presence of N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine. Conclusions:An increase in endogenous glycine via glycine transporter 1 blockade not only results in a net inhibitory influence on pain transmission at the spinal level but also supraspinally relieves decreased synaptic efficacy presumably related to cognitive disturbance often described in patients with chronic pain.