Interferon-gamma potentiates NMDA receptor signaling in spinal dorsal horn neurons via microglia-neuron interaction.
Interferon-gamma potentiates NMDA receptor signaling in spinal dorsal horn neurons via microglia-neuron interaction.
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DOI：
10.1177/1744806916644927
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发表时间：
2016
期刊：
影响因子：
3.3
通讯作者：
Nakatsuka T
中科院分区：
文献类型：
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作者：
Sonekatsu M;Taniguchi W;Yamanaka M;Nishio N;Tsutsui S;Yamada H;Yoshida M;Nakatsuka T
神经胶质-神经元相互作用在神经病理性疼痛的发生发展中起着重要作用。周围神经损伤后，大鼠脊髓背角中促炎性神经递质→细胞因子IFNγ的表达上调，鞘内注射IFNγ可诱导大鼠机械性异常性疼痛。越来越多的证据表明IFNγ可能参与神经病理性疼痛的机制，但其对脊髓背角的影响尚不清楚。采用全细胞膜片钳技术，观察了IFNγ对大鼠脊髓胶状质神经元突触后谷氨酸诱导电流的影响。IFNγ灌流可显著增强NMDA诱导的胶状质神经元内向电流的幅度，但不影响AMPA诱导的电流。浴用IFNγ受体选择性拮抗剂可抑制IFNγ对NMDA诱导电流的促进作用。向移液器溶液中加入Janus活化激酶抑制剂托法替尼不影响IFNγ诱导的NMDA诱导电流易化。然而，IFNγ对NMDA诱导电流的易化作用被灌注小胶质细胞抑制剂米诺环素抑制。这些结果表明，IFNγ结合小胶质细胞IFNγ受体，并增强NMDA受体活性在胶状质神经元。接下来，为了鉴定从小胶质细胞到背角神经元的信号传递的效应器，我们向移液管溶液中加入G蛋白的抑制剂GDP-β-S。在含有GDP-β-S的移液器溶液中，IFNγ诱导的NMDA电流增强在30 min后被显著抑制。此外，IFNγ诱导的NMDA电流增强作用可被CCR 2的选择性拮抗剂阻断，其配体CCL 2可增加NMDA诱导的电流。我们的研究结果表明，IFNγ通过小胶质细胞IFNγ受体和CCL 2/CCR 2信号增强NMDA诱导的胶状质神经元内向电流的幅度。这种机制可能是持续性神经病理性疼痛的发展的部分原因。
Glia–neuron interactions play an important role in the development of neuropathic pain. Expression of the pro-inflammatory cytokne →cytokine Interferon-gamma (IFNγ) is upregulated in the dorsal horn after peripheral nerve injury, and intrathecal IFNγ administration induces mechanical allodynia in rats. A growing body of evidence suggests that IFNγ might be involved in the mechanisms of neuropathic pain, but its effects on the spinal dorsal horn are unclear. We performed blind whole-cell patch-clamp recording to investigate the effect of IFNγ on postsynaptic glutamate-induced currents in the substantia gelatinosa neurons of spinal cord slices from adult male rats. IFNγ perfusion significantly enhanced the amplitude of NMDA-induced inward currents in substantia gelatinosa neurons, but did not affect AMPA-induced currents. The facilitation of NMDA-induced current by IFNγ was inhibited by bath application of an IFNγ receptor-selective antagonist. Adding the Janus activated kinase inhibitor tofacitinib to the pipette solution did not affect the IFNγ-induced facilitation of NMDA-induced currents. However, the facilitatory effect of IFNγ on NMDA-induced currents was inhibited by perfusion of the microglial inhibitor minocycline. These results suggest that IFNγ binds the microglial IFNγ receptor and enhances NMDA receptor activity in substantia gelatinosa neurons. Next, to identify the effector of signal transmission from microglia to dorsal horn neurons, we added an inhibitor of G proteins, GDP-β-S, to the pipette solution. In a GDP-β-S–containing pipette solution, IFNγ-induced potentiation of the NMDA current was significantly suppressed after 30 min. In addition, IFNγ-induced potentiation of NMDA currents was blocked by application of a selective antagonist of CCR2, and its ligand CCL2 increased NMDA-induced currents. Our findings suggest that IFNγ enhance the amplitude of NMDA-induced inward currents in substantia gelatinosa neurons via microglial IFNγ receptors and CCL2/CCR2 signaling. This mechanism might be partially responsible for the development of persistent neuropathic pain.