正中神經損傷對楔狀神經核及背根神經節中甘胺酸、伽傌-胺基丁酸及其受體的影響

陳淑華

doi:10.6342/NTU.2012.2012.03414

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正中神经损伤对楔状神经核及背根神经节中甘胺酸、伽傌-胺基丁酸及其受体的影响

The Effects of Median Nerve Injury on Glycine, GABA and Corresponding Receptor Expressions in the Cuneate Nucleus and Dorsal Root Ganglion

陈淑华 , 博士　　导师：吕俊宏　　

繁体中文 DOI： 10.6342/NTU.2012.2012.03414

萤光金；楔状丘脑投射神经元；甘胺酸；普乐芬；神经胜肽Y ； c-Fos蛋白；步态行为分析； Fluorogold ； Cuneothalamic projection neuron ； Glycine ； baclofen ； neuropeptide Y ； c-Fos ； CatWalk

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摘要 │ 参考文献 (136) │ 国际计量

摘要〈TOP〉

一般正常状况下，楔状神经核仅接收颈部、前肢及躯干上部的初级传入神经所传递的触觉、震动觉及本体感觉等非伤害性讯息，尔後将讯息再向上投射至丘脑腹基底核。已知正中神经截断会引起损伤侧楔状神经核内出现神经胜肽Y (neuropeptide Y, NPY)及c-Fos免疫反应，但缺乏探讨楔状神经核的抑制性系统在正中神经损伤後所产生的改变，以及其在神经胜肽Y和c-Fos免疫表现、神经病变疼痛产生方面扮演的角色之相关研究。而甘胺酸及伽傌-胺基丁酸为楔状神经核内的两个重要抑制性神经传递物质，主要以突触前或突触後抑制作用参与讯息的调控。因此本研究期望提供正中神经截断後，甘胺酸和伽傌-胺基丁酸神经元及其受体数量上的变化，以及它们与神经病变疼痛行为表现之间的关连性。我们将利用免疫组织化学法来观察正中神经截断後，甘胺酸、伽傌-胺基丁酸、甘胺酸受体、伽傌-胺基丁酸A和B受体免疫反应神经元在楔状神经核和背根神经节内的变化。并藉由神经胜肽Y和c-Fos蛋白表现的变化情形，作为评估生理食盐水 (控制组)、甘胺酸或伽傌-胺基丁酸B受体促效剂 (甘胺酸, glycine或普乐芬, baclofen)，以及拮抗剂 (番木虌硷, strychnine或法克罗芬, phaclofen)处理後对於神经病变疼痛讯息传递的影响，进一步透过CatWalk步态分析方式确认受体促效剂是否可以缓解大白鼠正中神经引发之神经病变疼痛症状。
首先证实在楔状神经核内甘胺酸受体免疫反应神经元约有半数是具有萤光金 (fluorogold)标志的楔状丘脑投射神经元。而在正中神经截断二和四周後，受伤侧楔状神经核内甘胺酸受体免疫反应神经元数量明显地递减，但是甘胺酸免疫反应神经元却没有变化。相较於控制组，正中神经截断4周後在电刺激前给予番木虌硷处理可显着地降低神经胜肽Y释放的程度 (NPY release level)；并且甘胺酸和番木虌硷处理组的楔状神经核内c-Fos免疫反应神经元数量也会显着地减少。但是在CatWalk的行为分析时，所测量的前脚掌印宽度和面积参数却显示出甘胺酸只轻微地恢复其接近正常值。
另一方面，在单侧正中神经截断後4周，受伤侧楔状神经核内伽傌-胺基丁酸免疫反应神经元和背根神经节内伽傌-胺基丁酸B受体免疫反应神经元的比例下降至最低点，但不影响楔状神经核内伽傌-胺基丁酸B受体，以及楔状神经核和背根神经节内伽傌-胺基丁酸A受体的免疫反应。於双侧正中神经截断4周时，在电刺激单侧受伤的正中神经前，分别於腹腔给予生理食盐水、普乐芬或法克罗芬，我们发现普乐芬处理组的楔状神经核内神经胜肽Y释放程度和c-Fos免疫反应神经元数量有明显地降低。但是法克罗芬处理後的情形却是完全相反的，两者皆比生理食盐水处理组的数值高。而且，利用CatWalk步态分析方式，我们更确认正中神经截断後所引起的感觉异常可因普乐芬的治疗而趋於正常。
总结来说，我们的研究结果显示正中神经截断後，会降低楔状神经核内伽傌-胺基丁酸、甘胺酸受体和伽傌-胺基丁酸B受体的表现量，进而阻碍甘胺酸和伽傌-胺基丁酸的抑制调节作用，而促使神经伤害诱发产生的神经胜肽Y释放，因此楔状神经核神经元被诱发而产生c-Fos蛋白。但是甘胺酸处理不仅增加对楔状神经核神经元的突触後抑制作用，也压制部分含有甘胺酸受体的伽傌-胺基丁酸神经元的活性，使得其对初级传入神经终末的突触前抑制作用受到影响而导致神经胜肽Y缓慢的释放。由於以上两种相互抵触的作用才会呈现甘胺酸处理後，c-Fos蛋白略微减少而神经病变疼痛行为也只有轻微改善的现象。相对地，普乐芬直接阻断神经胜肽Y释放，使得楔状神经核内神经元的c-Fos蛋白表现减少，以致传递到丘脑的神经病变疼痛讯息因此减弱。所以我们推测在楔状神经核内，伽傌-胺基丁酸B受体可能在止痛方面扮演着比甘胺酸受体更重要的角色，而且希望这些研究结果和CatWalk分析参数，能有效於提供未来研究正中神经伤害所造成的神经病变疼痛的机制和治疗方针。

并列摘要〈TOP〉

Under normal conditions, the cuneate nucleus (CN) transmits the information related to innocuous tactile, vibratile and proprioceptive sensations from forelimb through primary afferent fibers and relays the information to the contralateral ventrobasal nucleus of thalamus. The upregulation of expressions of neuropeptide Y (NPY) and c-Fos in the ipsilateral CN following median nerve transection (MNT) is well known, but the effect of MNT on the alterations of the inhibitory modulation in the CN associated with the contribution to the expressions of NPY and c-Fos, and neuropathic pain still needs to be investigated. Glycine and γ-aminobutyric acid (GABA) are considered to be the two major components in the inhibitory modulation and integration, which are caused by pre- and postsynaptic inhibition to regulate the information processing. This study aimed to investigate the relationship between temporal changes in glycine and GABA transmission in the CN and behavioral abnormalities after MNT. Immunohistochemistry methods were used to appraise changes of glycine-, GABA-, glycine receptor (GlyR)-, GABAAR- and GABABR-like immunoreactive (LI) neurons in the CN and dorsal root ganglion after MNT. The alterations in NPY and c-Fos expressions were used to assess the effects of saline, receptor agonist (glycine or baclofen) or antagonist (strychnine or phaclofen) treatment. The CatWalk method was used to assess the efficiency of glycine or baclofen treatment on the neuropathic signs of rats with MNT.
At first, approximately half of GlyR-LI neurons were fluorogold-labeled cuneothalamic projection neurons in the CN. Following MNT, the number of GlyR-LI neurons significantly decreased in the injured side of CN at 2 and 4 weeks, but the number of glycine-LI neurons remained unchanged. Four weeks after bilateral MNT given with electrical stimulation, strychnine significantly decreased the NPY release level in the stimulated side CN compared to that of the saline group. However, numbers of c-Fos-LI neurons in the glycine and strychnine groups were both significantly less than that in the saline group. But the paw print width and area in CatWalk analysis showed only a moderate recovery.
On the other hand, following unilateral MNT, the percentage of GABA-LI neurons in the CN and that of GABABR-LI in the dorsal root ganglion in the injured side decreased and reached a nadir at 4 weeks after median nerve transection. Four weeks after bilateral median nerve transection and intraperitoneal application with saline, baclofen, or phaclofen before unilateral electrical stimulation of the injured median nerve, we found that the neuropeptide Y release level and the number of c-Fos-like immunoreactive neurons in the baclofen group were significantly attenuated, whereas those in the phaclofen group had increased compared to the saline group. Furthermore, using the CatWalk method, we confirmed that the behavioral abnormalities in rats following median nerve transection were reversed by baclofen treatment. 
Overall, the results indicate that median nerve transection reduces glycine and GABA transmission by decreasing the expression of GABA, glycine and GABAB receptors, promoting injury-induced neuropeptide Y release and consequently evoking c-Fos expression in cuneate nucleus neurons. But glycine increases glycine-mediated postsynaptic inhibition of cuneate neurons, and also blocks GABAergic neurons containing GlyRs which mediate presynaptic inhibition causing temperate NPY release. Consequently, the compromise results showed a weak reduction in c-Fos expression and a slight amelioration of neuropathic behaviors. In the contrast, baclofen treatment direct block neuropeptide Y release, subsequently lessening c-Fos expression in cuneate neurons and consequently attenuating neuropathic signal transmission to the thalamus. Therefore the results suggest the GABABR in the CN may serve as a major potential target for analgesia than GlyR, and we expect that the experimental results and CatWalk analysis parameters presented here will be useful in studying mechanisms and treatment options of neuropathic pain resulting from median nerve injury.

参考文献 ( 136 ) 〈TOP〉

Aguilar J, Rivadulla C, Soto C, Canedo A. 2003. New corticocuneate cellular mechanisms underlying the modulation of cutaneous ascending transmission in anesthetized cats. J. Neurophysiol. 89:3328-3339.
连结：
Aguilar J, Soto C, Rivadulla C, Canedo A. 2002. The lemniscal-cuneate recurrent excitation is suppressed by strychnine and enhanced by GABAA antagonists in the anaesthetized cat. Eur. J. Neurosci. 16:1697-1704.
连结：
Amir R, Devor M. 1996. Chemically mediated cross-excitation in rat dorsal root ganglia. J. Neurosci. 16:4733-4741.
连结：
Andersen P, Eccles JC, Oshima T, Schmidt RF. 1964a. Mechanisms of Synaptic Transmission In The Cuneate Nucleus. J. Neurophysiol. 27:1096-1116.
连结：
Andersen P, Eccles JC, Schmidt RF, Yokota T. 1964b. Identification of relay cells and interneurons in the cuneate nucleus. J. Neurophysiol. 27:1080-1095.
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