Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, Athens, GA 30602, USA.
J Physiol. 2013 Apr 1;591(7):2001-19. doi: 10.1113/jphysiol.2012.250522. Epub 2013 Jan 28.
Activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs) is a crucial mechanism underlying the development and maintenance of pain. Traditionally, the role of NMDARs in the pathogenesis of pain is ascribed to their activation and signalling cascades in postsynaptic neurons. In this study, we determined if presynaptic NMDARs in the primary afferent central terminals play a role in synaptic plasticity of the spinal first sensory synapse in a rat model of neuropathic pain induced by spinal nerve ligation. Excitatory postsynaptic currents (EPSCs) were recorded from superficial dorsal horn neurons of spinal slices taken from young adult rats. We showed that increased glutamate release from the primary afferents contributed to the enhanced amplitudes of EPSCs evoked by input from the primary afferents in neuropathic rats. Endogenous activation of presynaptic NMDARs increased glutamate release from the primary afferents in neuropathic rats. Presynaptic NMDARs in neuropathic rats were mainly composed of NR2B receptors. The action of presynaptic NMDARs in neuropathic rats was enhanced by exogenous D-serine and/or NMDA and dependent on activation of protein kinase C. In contrast, glutamate release from the primary afferents in sham-operated rats was not regulated by presynaptic NMDARs. We demonstrated that the lack of NMDAR-mediated regulation of glutamate release in sham-operated rats was not attributable to low extracellular levels of the NMDAR agonist and/or coagonist (D-serine), but rather was due to the insufficient function and/or number of presynaptic NMDARs. This was supported by an increase of NR2B receptor protein expression in both the dorsal root ganglion and spinal dorsal horn ipsilateral to the injury site in neuropathic rats. Hence, suppression of the presynaptic NMDAR activity in the primary sensory afferents is an effective approach to attenuate the enhanced glutamatergic response in the spinal first sensory synapse induced by peripheral nerve injury, and presynaptic NMDARs might be a novel target for the development of analgesics.
N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）的激活是疼痛发生和维持的关键机制。传统上，NMDAR 在疼痛发病机制中的作用归因于它们在突触后神经元中的激活和信号级联。在这项研究中，我们确定了在脊神经结扎诱导的神经病理性疼痛大鼠模型中，初级传入中枢末端的突触前 NMDAR 是否在脊髓第一感觉突触的突触可塑性中发挥作用。从幼年大鼠的脊髓切片中记录到浅层背角神经元的兴奋性突触后电流（EPSC）。我们表明，神经病理性大鼠初级传入中谷氨酸释放的增加导致初级传入诱发的 EPSC 幅度增强。神经病理性大鼠中内源性激活突触前 NMDAR 增加了初级传入的谷氨酸释放。神经病理性大鼠中的突触前 NMDAR 主要由 NR2B 受体组成。神经病理性大鼠中突触前 NMDAR 的作用通过外源性 D-丝氨酸和/或 NMDA 增强，并依赖于蛋白激酶 C 的激活。相比之下，假手术大鼠初级传入的谷氨酸释放不受突触前 NMDAR 的调节。我们证明，假手术大鼠中谷氨酸释放不受突触前 NMDAR 调节的原因不是由于 NMDAR 激动剂和/或共激动剂（D-丝氨酸）的细胞外水平低，而是由于突触前 NMDAR 的功能和/或数量不足。这得到了神经病理性大鼠损伤侧背根神经节和脊髓背角中 NR2B 受体蛋白表达增加的支持。因此，抑制初级感觉传入中的突触前 NMDAR 活性是减轻周围神经损伤诱导的脊髓第一感觉突触中增强的谷氨酸反应的有效方法，突触前 NMDAR 可能是开发镇痛药的新靶点。
