F.M. Kirby Neurobiology Center, Children's Hospital and Harvard Medical School, Boston, MA, USA CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097, Valbonne, France Université de Nice-Sophia Antipolos, UMR 6097, Valbonne, France Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe University, Frankfurt, Germany Departments of Anesthesiology and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Pain. 2012 Dec;153(12):2422-2431. doi: 10.1016/j.pain.2012.08.011. Epub 2012 Sep 26.
Peripheral nerve injury provokes heightened excitability of primary sensory afferents including nociceptors, and elicits ectopic activity in lesioned and neighboring intact nerve fibers. The major transmitter released by sensory afferents in the superficial dorsal horn of the spinal cord is glutamate. Glutamate is critically involved in nociceptive signaling and the development of neuropathic pain. We recorded miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II of the rat dorsal horn to assess spontaneous synaptic activity after spared nerve injury (SNI), a model of chronic neuropathic pain. Following SNI, the frequency of mEPSCs doubled, indicating heightened glutamate release from primary afferents or spinal interneurons. Consistent with this finding, glutamate concentrations in the cerebrospinal fluid were elevated at 1 and 4 weeks after SNI. Transmitter uptake was insufficient to prevent the rise in extracellular glutamate as the expression of glutamate transporters remained unchanged or decreased. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride, an antagonist of metabotropic glutamate receptor 5 (mGluR5), reduced the frequency of mEPSCs to its preinjury level, suggesting a positive feedback mechanism that involves facilitation of transmitter release by mGluR5 activation in the presence of high extracellular glutamate. Treatment with the β-lactam antibiotic ceftriaxone increased the expression of glutamate transporter 1 (Glt1) in the dorsal horn after SNI, raised transmitter uptake, and lowered extracellular glutamate. Improving glutamate clearance prevented the facilitation of transmitter release by mGluR5 and attenuated neuropathic pain-like behavior. Balancing glutamate release and uptake after nerve injury should be an important target in the management of chronic neuropathic pain.
周围神经损伤会引起初级感觉传入纤维（包括伤害感受器）的兴奋性增加，并在损伤和相邻的完整神经纤维中引发异位活动。感觉传入纤维在脊髓背角浅层释放的主要递质是谷氨酸。谷氨酸在伤害性信号传递和神经性疼痛的发展中起着至关重要的作用。我们记录了大鼠背角 II 层神经元的微小兴奋性突触后电流（mEPSC），以评估 spared nerve injury（SNI）后（慢性神经性疼痛模型）自发性突触活动。SNI 后，mEPSC 的频率增加了一倍，表明初级传入纤维或脊髓中间神经元的谷氨酸释放增加。这一发现与脑脊液中谷氨酸浓度在 SNI 后 1 周和 4 周时升高一致。由于谷氨酸转运体的表达保持不变或减少，因此转运体摄取不足以防止细胞外谷氨酸的升高。2-甲基-6-（苯乙炔基）吡啶盐酸盐（mGluR5 的拮抗剂）可将 mEPSC 的频率降低至受伤前水平，表明存在一种正反馈机制，即在高细胞外谷氨酸存在下，mGluR5 的激活可促进递质释放。SNI 后，β-内酰胺抗生素头孢曲松治疗可增加背角中谷氨酸转运体 1（Glt1）的表达，提高递质摄取，降低细胞外谷氨酸。改善谷氨酸清除可防止 mGluR5 促进递质释放，并减轻神经性疼痛样行为。平衡神经损伤后的谷氨酸释放和摄取应该是慢性神经性疼痛治疗的一个重要目标。
