Medical Science Research Center and Department of Physiology, Korea University College of Medicine, Seoul 136-705, Korea.
Korean J Physiol Pharmacol. 2010 Apr;14(2):59-69. doi: 10.4196/kjpp.2010.14.2.59. Epub 2010 Apr 30.
Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these aims, we first analyzed the pain behaviors following the spinal administration of GABA antagonists (1 microg bicuculline/rat and 5 microg phaclofen/rat), agonists (1 microg muscimol/rat and 0.5 microg baclofen/rat) or GABA transporter (GAT) inhibitors (20 microg NNC-711/rat and 1 microg SNAP-5114/rat) into naïve or neuropathic animals. Then, using Western blotting, PCR or immunohistochemistry, we compared the quantities of spinal GABA, its synthesizing enzymes (GAD65, 67) and its receptors (GABA(A) and GABA(B)) and transporters (GAT-1, and -3) between two groups of rats with different severity of neuropathic pain following partial injury of tail-innervating nerves; the allodynic and non-allodynic groups. Intrathecal administration of GABA antagonists markedly lowered tail-withdrawal threshold in naïve animals, and GABA agonists or GAT inhibitors significantly attenuated neuropathic pain in nerve-injured animals. However, any quantitative changes in spinal GABAergic elements were not observed in both the allodynic and non-allodynic groups. These results suggest that although the impairment in spinal GABAergic inhibition may play a role in mediation of neuropathic pain, it is not accomplished by the quantitative change in spinal elements for GABAergic inhibition and therefore these elements are not related to the generation of neuropathic pain following peripheral nerve injury.
脊髓内抑制功能的损伤是外周神经损伤后导致神经病理性疼痛的原因之一，这种损伤被认为是由 GABA 能神经元数量的改变引起的。在本研究中，我们通过药理学方法调节脊髓 GABA 能活性来验证神经病理性疼痛是否可以被诱导或逆转，以及外周神经损伤后脊髓 GABA 能神经元数量的改变是否与 GABA 能抑制的损伤或神经病理性疼痛有关。为此，我们首先分析了向正常或神经病理性动物鞘内给予 GABA 拮抗剂（1μg 印防己毒素/只和 5μg 荷包牡丹碱/只）、激动剂（1μg 毒蕈碱/只和 0.5μg 巴氯芬/只）或 GABA 转运体（GAT）抑制剂（20μg NNC-711/只和 1μg SNAP-5114/只）后动物的疼痛行为。然后，我们通过 Western blot、PCR 或免疫组织化学方法，比较了两组具有不同程度神经病理性疼痛的大鼠（痛觉过敏和非痛觉过敏组）脊髓 GABA 及其合成酶（GAD65、67）和受体（GABA(A)和 GABA(B)）和转运体（GAT-1 和 GAT-3）的含量。尾神经部分损伤后，两组大鼠的神经病理性疼痛严重程度不同。鞘内给予 GABA 拮抗剂明显降低了正常动物的尾部退缩阈值，而 GABA 激动剂或 GAT 抑制剂显著减轻了神经损伤动物的神经病理性疼痛。然而，在痛觉过敏和非痛觉过敏组中均未观察到脊髓 GABA 能神经元数量的任何变化。这些结果表明，尽管脊髓 GABA 能抑制的损伤可能在神经病理性疼痛的发生中起作用，但这并不是由脊髓 GABA 能抑制的数量变化引起的，因此这些神经元与外周神经损伤后神经病理性疼痛的发生无关。
