Scholz Joachim, Abele Andrea, Marian Claudiu, Häussler Annett, Herbert Teri A, Woolf Clifford J, Tegeder Irmgard
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 4309, Charlestown, MA 02129, USA Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie/(ZAFES), Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Pain. 2008 Aug 15;138(1):130-142. doi: 10.1016/j.pain.2007.11.019. Epub 2008 Jan 22.
Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain in the rat: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker CD11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionised calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrates that suppression of this cellular immune response is a promising approach for preventing neuropathic pain.
引发神经性疼痛的周围神经损伤与脊髓中的小胶质细胞激活有关。我们研究了大鼠三种不同周围神经病理性疼痛模型中脊髓小胶质细胞激活的特征：保留神经损伤（SNI）、慢性压迫性损伤和脊神经结扎。在所有模型中，损伤后7天，在同侧背角形成了密集的对小胶质细胞标志物CD11b免疫反应阳性的细胞簇。离子钙结合衔接分子1（Iba1）的小胶质细胞表达增加了高达40%，小胶质细胞活性标志物p38丝裂原活化蛋白激酶的磷酸化增加了45%。溶酶体ED1抗原的表达表明细胞具有吞噬活性。与周围神经损伤不同，脊髓切断术在脊髓灰质内仅产生微弱的小胶质细胞反应，但在腰段和胸段脊髓水平的背索中，小胶质细胞和吞噬细胞有强烈激活。这表明，虽然中枢终末的退变足以引发小胶质细胞激活，但它并不能解释周围神经损伤后背角的炎症反应。在损伤时开始早期鞘内注射低剂量甲氨蝶呤，可减少SNI后的小胶质细胞激活、降低p38磷酸化并减轻疼痛样行为。相比之下，全身或鞘内给予糖皮质激素地塞米松并不能抑制小胶质细胞的激活或减轻疼痛样行为。我们证实小胶质细胞激活对神经损伤后疼痛的发展至关重要，并表明抑制这种细胞免疫反应是预防神经性疼痛的一种有前景的方法。
