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Modulation of synaptic transmission as the therapeutic strategies for chronic pain

调节突触传递作为慢性疼痛的治疗策略

基本信息

批准号：
18590150
负责人：
TANABE Mitsuo
金额：
$ 2.57万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590150/
关键词：
neuropethic pain antiepileptics gabapentin protein kinase A HCN channels spinal slice svnaptic transmission glycine transporters SSRI プレギャバリンノルアドレナリン青斑核

项目摘要

1. To clarify the supraspinal mechanism of action of gabapentin, whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury or mice subjected to a sham operation, and the effects of gabapentin on synaptic transmission were studied. Gabapentin (10-100 μM) concentration-dependently reduced the GABAAreceptor-mediated IPSCs in slices prepared from partial nerve-ligated mice (the Seltzer mode)), whereas glutamate-mediated EPSCs were hardly affected. By contrast, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Since gabapentin reducedIPSCs together with an increase in the paired-pulse ratio, it acts on the presynaptic GABAergic nerve terminals in the LC. Moreover, the protein kinase A inhibitor 11-89 but not the protein kinase C inhibitor chelerythrine abolished the inhibitory action of gabapentin on IPSCs, suggesting that PICA-mediated phosphorylation seems to be impo … More rtant for supraspinal gabapentin responsiveness in neuropathic conditions.Together, gabapentin generates PICA-dependent presynaptic inhibition of GABAergic synaptic transmission, and thereby removes the inhibitory influence on LC neurons (disinhibition of the descending noradrenergic system) only under neuropathic pain states.2. We addressed the therapeutic impact of increasing spinal glycine applied exogenously or via blockade of glycine transporter 1 (GlyT1) using its selective inhibitors sarcosine and NFPS on neuropathic and inflammatory pain in mice. Glycine, sarcosine and NFPS ameliorated thermal and mechanical hypersensitivity in Seltzer model mice, and reduced mechanical hypersensitivity in STZ injected diabetic mice. Moreover, they selectively inhibited the second phase of formalin evoked licking/biting behavior. In hippocampal slices prepared from Seltzer model mice, LTP was maintained at a significantly lower level than that in sham-treated mice. Such impairment of LTP was never observed when it was induced in the presence of NFPS. Together, an increase in endogenous glycine via GlyT1 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 inpatients with chronic pain.3. In the pharmacological and physiological studies related with pain transmission between primary afferent fibers and superficial dorsal horn neurons, spinal cord slices with attached dorsal roots prepared from rats have been used. However, synaptic transmission using mice spinal cord slices attached dorsal roots is hardly evaluated. We adapted this rat spinal slice preparation to adult mice, and addressed whether HCN channels contribute to Aδ-and C-fiber-mediated EPSCs after peripheral nerve injury. Consistent with our behavioral study demonstrating that intrathecal injection of the HCN channel blocker ZD7288 reduced thermal and machanical hypersensitivity in Seltzer model mice, 7288 reduced Aδ-and C-fiber-mediated EPSCs. Less

1.为了阐明加巴喷丁的脊髓上作用机制，对周围神经损伤后的小鼠或假手术小鼠制备的脑干切片中的蓝斑（LC）神经元进行全细胞膜片钳记录，并研究加巴喷丁对突触传递的影响。加巴喷丁 (10-100 μM) 浓度依赖性地减少部分神经结扎小鼠（Seltzer 模式）制备的切片中 GABAA 受体介导的 IPSC，而谷氨酸介导的 EPSC 几乎不受影响。相比之下，加巴喷丁并没有减少假手术小鼠切片中的 IPSC。由于加巴喷丁减少了IPSC并增加了配对脉冲比，因此它作用于LC中的突触前GABA能神经末梢。此外，蛋白激酶 A 抑制剂 11-89 而不是蛋白激酶 C 抑制剂白屈菜红碱消除了加巴喷丁对 IPSC 的抑制作用，这表明 PICA 介导的磷酸化似乎对于神经性病症中脊髓上加巴喷丁的反应性至关重要。加巴喷丁共同产生 PICA 依赖性突触前细胞抑制GABA能突触传递，从而消除仅在神经病理性疼痛状态下对LC神经元的抑制影响（去抑制降去甲肾上腺素系统）。2．我们探讨了外源性增加脊髓甘氨酸或通过使用其选择性抑制剂肌氨酸和 NFPS 阻断甘氨酸转运蛋白 1 (GlyT1) 对小鼠神经性疼痛和炎性疼痛的治疗影响。甘氨酸、肌氨酸和 NFPS 改善了 Seltzer 模型小鼠的热和机械超敏反应，并降低了注射 STZ 的糖尿病小鼠的机械超敏反应。此外，它们选择性地抑制福尔马林引起的舔/咬行为的第二阶段。在从 Seltzer 模型小鼠制备的海马切片中，LTP 维持在显着低于假治疗小鼠的水平。当 NFPS 存在时诱导 LTP 时，从未观察到这种 LTP 损伤。总之，通过 GlyT1 阻断增加内源性甘氨酸不仅会对脊髓水平的疼痛传递产生净抑制影响，而且还能在脊髓上缓解突触功效下降，这可能与慢性疼痛住院患者经常描述的认知障碍有关。3。在与初级传入纤维和浅表背角神经元之间的疼痛传递相关的药理学和生理学研究中，使用了从大鼠制备的附有背根的脊髓切片。然而，使用附着在背根上的小鼠脊髓切片的突触传递几乎没有被评估。我们将这种大鼠脊髓切片制备方法应用于成年小鼠，并探讨了周围神经损伤后 HCN 通道是否有助于 Aδ 纤维和 C 纤维介导的 EPSC。我们的行为研究表明，鞘内注射 HCN 通道阻滞剂 ZD7288 可以降低 Seltzer 模型小鼠的热和机械超敏性，7288 可以减少 Aδ 纤维和 C 纤维介导的 EPSC。较少的