Chen Yishen, Derkach Victor A, Smith Peter A
Department of Pharmacology and Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA 98195-7350, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7350, USA.
Exp Neurol. 2016 May;279:168-177. doi: 10.1016/j.expneurol.2016.03.001. Epub 2016 Mar 3.
Synapses transmitting nociceptive information in the spinal dorsal horn undergo enduring changes following peripheral nerve injury. Indeed, such injury alters the expression of the GluA2 subunit of glutamatergic AMPA receptors (AMPARs) in the substantia gelatinosa and this predicts altered channel conductance and calcium permeability, leading to an altered function of excitatory synapses. We therefore investigated the functional properties of synaptic AMPA receptors in rat substantia gelatinosa neurons following 10-20d chronic constriction injury (CCI) of the sciatic nerve; a model of neuropathic pain. We measured their single-channel conductance and sensitivity to a blocker of calcium permeable AMPA receptors (CP-AMPARs), IEM1460 (50μM). In putative inhibitory, tonic firing neurons, CCI reduced the average single-channel conductance of synaptic AMPAR from 14.4±3.5pS (n=12) to 9.2±1.0pS (n=10, p<0.05). IEM1460 also more effectively antagonized evoked, spontaneous and miniature EPSCs in tonic neurons from sham operated animals than in those from animals that had been subjected to CCI. By contrast, CCI did not change the effectiveness of IEM1460 in delay firing neurons although average single channel conductance was increased from 7.6±1.2pS (n=11) to 12.2±1.5pS (n=10, p<0.01). CCI thus elicits plastic changes in a specific set of glutamatergic synapses of substantia gelatinosa due to subunit recomposition and loss of GluA2-lacking CP-AMPAR. These insights reveal a molecular mechanism of nerve injury acting at synapses of inhibitory neurons to reduce their drive and therefore inhibitory tone in the spinal cord, therefore contributing to the central sensitization associated with neuropathic pain.
在周围神经损伤后，脊髓背角中传递伤害性信息的突触会发生持久变化。实际上，这种损伤会改变脊髓背角胶状质中谷氨酸能α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）的GluA2亚基的表达，这预示着通道电导和钙通透性的改变，从而导致兴奋性突触功能改变。因此，我们研究了坐骨神经10 - 20天慢性压迫损伤（CCI）（一种神经性疼痛模型）后大鼠脊髓背角胶状质神经元中突触性AMPA受体的功能特性。我们测量了它们的单通道电导以及对钙通透性AMPA受体（CP - AMPARs）阻滞剂IEM1460（50μM）的敏感性。在假定的抑制性紧张性放电神经元中，CCI使突触性AMPA受体的平均单通道电导从14.4±3.5 pS（n = 12）降低至9.2±1.0 pS（n = 10，p < 0.05）。与假手术动物相比IEM1460也更有效地拮抗了假手术动物的紧张性神经元中诱发的、自发的和微小的兴奋性突触后电流（EPSCs）。相比之下，尽管平均单通道电导从7.6±1.2 pS（n = 11）增加至12.2±1.5 pS（n = 10，p < 0.01），但CCI并未改变IEM1460对延迟放电神经元的作用效果。因此，由于亚基重组和缺乏GluA2的CP - AMPAR的丢失，CCI在脊髓背角胶状质的一组特定谷氨酸能突触中引发了可塑性变化。这些见解揭示了神经损伤在抑制性神经元突触处起作用以降低其驱动从而降低脊髓抑制张力的分子机制，因此促成了与神经性疼痛相关的中枢敏化。
