Center for Neuron and Disease, Frontier Institutes of Life Science and of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
Sci Signal. 2013 May 14;6(275):ra34. doi: 10.1126/scisignal.2003778.
Neurons in the insular cortex are activated by acute and chronic pain, and inhibition of neuronal activity in the insular cortex has analgesic effects. We found that in a mouse model in which peripheral nerve injury leads to the development of neuropathic pain, the insular cortex showed changes in synaptic plasticity, which were associated with a long-term increase in the amount of synaptic N-methyl-d-aspartate receptors (NMDARs), but not that of extrasynaptic NMDARs. Activation of cyclic adenosine monophosphate (cAMP)-dependent signaling enhanced the amount of synaptic NMDARs in acutely isolated insular cortical slices and increased the surface localization of NMDARs in cultured cortical neurons. We found that the increase in the amount of NMDARs required phosphorylation of the NMDAR subunit GluN2B at Tyr(1472) by a pathway involving adenylyl cyclase subtype 1 (AC1), protein kinase A (PKA), and Src family kinases. Finally, injecting NMDAR or GluN2B-specific antagonists into the insular cortex reduced behavioral responses to normally nonnoxious stimuli in the mouse model of neuropathic pain. Our results suggest that activity-dependent plasticity takes place in the insular cortex after nerve injury and that inhibiting the increase in NMDAR function may help to prevent or treat neuropathic pain.
岛叶皮层中的神经元被急性和慢性疼痛激活，抑制岛叶皮层中的神经元活动具有镇痛作用。我们发现，在一种外周神经损伤导致神经性疼痛发展的小鼠模型中，岛叶皮层显示出突触可塑性的变化，这与突触 N-甲基-D-天冬氨酸受体（NMDAR）数量的长期增加有关，但与突触外 NMDAR 无关。环磷酸腺苷（cAMP）依赖性信号的激活增强了急性分离的岛叶皮质切片中突触 NMDAR 的数量，并增加了培养的皮质神经元中 NMDAR 的表面定位。我们发现，NMDAR 数量的增加需要 NMDAR 亚基 GluN2B 在 Tyr(1472)处被依赖于腺苷酸环化酶亚型 1 (AC1)、蛋白激酶 A (PKA) 和 Src 家族激酶的途径磷酸化。最后，将 NMDAR 或 GluN2B 特异性拮抗剂注射到岛叶皮层中，可减少神经性疼痛小鼠模型中对正常非伤害性刺激的行为反应。我们的结果表明，神经损伤后岛叶皮层中发生了活性依赖性可塑性，抑制 NMDAR 功能的增加可能有助于预防或治疗神经性疼痛。
