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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. 为阐明加巴喷丁的棘上作用机制，采用全细胞膜片钳对周围神经损伤小鼠和假手术小鼠的脑干切片蓝斑（LC）神经元进行记录，研究加巴喷丁对突触传递的影响。加巴喷丁（10-100 μM）浓度依赖性地减少了部分神经结扎小鼠（Seltzer模式）切片中gaba受体介导的EPSCs，而谷氨酸介导的EPSCs几乎没有受到影响。相比之下，加巴喷丁没有减少假手术小鼠切片中的IPSCs。由于加巴喷丁减少edipsc并增加配对脉冲比，它作用于LC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chelerythrine可以消除加巴喷丁对ipsc的抑制作用，这表明pica介导的磷酸化似乎是重要的，更重要的是神经病变条件下加巴喷丁的棘上反应性。加巴喷丁对gaba能突触传递产生pica依赖性突触前抑制，从而消除了仅在神经性疼痛状态下对LC神经元的抑制作用（降去甲肾上腺素能系统的解除抑制）。我们研究了外源性或通过选择性抑制剂肌氨酸和NFPS阻断甘氨酸转运蛋白1 （GlyT1）来增加脊髓甘氨酸对小鼠神经性和炎症性疼痛的治疗作用。甘氨酸、肌氨酸和NFPS改善Seltzer模型小鼠的热、机械超敏反应，降低STZ注射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第二阶段舔/咬行为。在Seltzer模型小鼠海马切片中，LTP维持在显著低于假药小鼠的水平。当NFPS存在时，从未观察到LTP的这种损伤。综上所述，通过GlyT1阻断，内源性甘氨酸的增加不仅对脊柱水平的疼痛传递产生净抑制影响，而且还能在棘上缓解突触效能下降，这可能与慢性疼痛患者经常描述的认知障碍有关。在初级传入纤维与浅表背角神经元之间疼痛传递的药理学和生理学研究中，使用了大鼠背根附着脊髓切片。然而，使用小鼠脊髓片连接背根的突触传递几乎没有评估。我们将这种大鼠脊髓切片制备方法应用于成年小鼠，并研究了HCN通道是否有助于周围神经损伤后a -和c -纤维介导的EPSCs。与我们的行为研究一致，鞘内注射HCN通道阻滞剂ZD7288降低了Seltzer模型小鼠的热和机械超敏反应，7288减少了a -和c -纤维介导的epsc。少