Streptozotocin-Induced Diabetic Neuropathic Pain Is Associated with Potentiated Calcium-Permeable AMPA Receptor Activity in the Spinal Cord
Streptozotocin-Induced Diabetic Neuropathic Pain Is Associated with Potentiated Calcium-Permeable AMPA Receptor Activity in the Spinal Cord
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DOI：
10.1124/jpet.119.261339
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发表时间：
2019-11-01
影响因子：
3.5
通讯作者：
Pan, Hui-Lin
中科院分区：
文献类型：
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作者：
Chen, Shao-Rui;Zhang, Jixiang;Pan, Hui-Lin
在糖尿病神经病理性疼痛中，脊髓背角神经元的过度活动可以放大伤害性输入。谷氨酸-N-甲基-D-天冬氨酸和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(分别为NMDA受体和AMPA受体)参与了脊髓伤害性信息传递。然而，目前尚不清楚痛性糖尿病神经病变是否与脊髓背角神经元突触NMDA受体和AMPA受体活性的变化有关。缺乏GluA2的AMPA受体是钙离子通透性的(CP-AMPA受体)，其电流表现出内向整流的特征。在本研究中，我们发现由链脲佐菌素诱发的兴奋性突触后电流(EPSCs)在糖尿病大鼠脊髓背侧神经元呈现内向整流。糖尿病大鼠和对照组大鼠脊髓背角突触前和突触后NMDA受体活性相似。在脊髓背侧，糖尿病大鼠脊髓胞膜GluA2蛋白水平明显低于对照组，而胞浆GluA2蛋白水平高于对照组。相反，质膜和胞浆中的GluA1亚单位水平在两组之间没有差异。阻断CP-AMPA受体可显著降低糖尿病大鼠背角神经元的波幅，但对对照组无明显影响。此外，阻断脊髓CP-AMPA受体可降低糖尿病大鼠的疼痛过敏性，但对对照组大鼠的伤害性没有影响。我们的研究表明，糖尿病神经病变通过导致细胞内GluA2滞留和损害GluA2膜运输而增强脊髓背角Cp-AMPA受体的活性。研究表明，脊髓背角突触膜钙通透性AMPA受体的表达增加，介导了糖尿病神经病变的疼痛超敏反应。因此，钙通透性AMPA受体在痛性糖尿病神经病变的脊髓谷氨酸能突触可塑性中起重要作用。这一新的知识提高了我们对与糖尿病神经病理性疼痛相关的中枢敏化机制的理解，并表明钙通透性AMPA受体是治疗这种慢性疼痛的替代治疗靶点。
Neuronal hyperactivity in the spinal dorsal horn can amplify nociceptive input in diabetic neuropathic pain. The glutamate N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDA receptors and AMPA receptors, respectively) are involved in spinal nociceptive transmission. It is unclear, however, whether painful diabetic neuropathy is associated with changes in the activity of synaptic NMDA receptors and AMPA receptors in spinal dorsal horn neurons. AMPA receptors lacking GluA2 are Ca2+-permeable (CP-AMPA receptors), and their currents display characteristic inward rectification. In this study, we showed that evoked excitatory postsynaptic currents (EPSCs), induced by streptozotocin, exhibited inward rectification in spinal dorsal neurons in diabetic rats. Presynaptic and postsynaptic NMDA receptor activity in the spinal dorsal horn was similar in diabetic and control rats. In the dorsal spinal cord, the membrane GluA2 protein level was significantly lower in diabetic than in control rats, whereas the cytosolic GluA2 level was greater in diabetic than in control rats. In contrast, the GluA1 subunit levels in the plasma membrane and cytosol did not differ between the two groups. Blocking CP-AMPA receptors significantly reduced the amplitude of dorsal horn neurons in diabetic but not in control rats. Furthermore, blocking spinal CP-AMPA receptors reduced pain hypersensitivity in diabetic rats but had no effect on nociception in control rats. Our study suggests that diabetic neuropathy augments CP-AMPA receptor activity in the spinal dorsal horn by causing intracellular retention of GluA2 and impairing GluA2 membrane trafficking. Increased prevalence of spinal CP-AMPA receptors sustains diabetic neuropathic pain.SIGNIFICANCE STATEMENTThis study demonstrates that the prevalence of synaptic calcium-permeable AMPA receptors is increased in the spinal dorsal horn, which mediates pain hypersensitivity in diabetic neuropathy. Thus, calcium-permeable AMPA receptors play an important role in glutamatergic synaptic plasticity in the spinal cord in painful diabetic neuropathy. This new knowledge improves our understanding of the mechanisms involved in central sensitization associated with diabetic neuropathic pain and suggests that calcium-permeable AMPA receptors are an alternative therapeutic target for treating this chronic pain condition.