Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord
Pain after Discontinuation of Morphine Treatment Is Associated with Synaptic Increase of GluA4-Containing AMPAR in the Dorsal Horn of the Spinal Cord
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DOI：
10.1038/npp.2013.46
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发表时间：
2013-07-01
影响因子：
7.6
通讯作者：
Moron, Jose A.
中科院分区：
文献类型：
--
作者：
Cabanero, David;Baker, Alyssa;Moron, Jose A.
停用处方阿片类药物会导致疼痛敏感性增加，从而延长治疗时间。这种疼痛敏感性归因于汇聚于脊髓背角的神经可塑性改变。我们最近报道了反复给药吗啡会触发海马体中缺乏glua2 （Ca2+渗透性）α -氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的插入。这一发现与AMPAR参与炎症性疼痛机制的报道一起，使我们假设脊髓AMPAR在阿片类药物诱导的疼痛行为中起作用。用递增剂量吗啡治疗的小鼠对机械刺激表现出超敏反应。鞘内给药Ca2+渗透性AMPAR选择性阻滞剂破坏吗啡诱导的机械敏感性。对脊髓背角匀浆和突触后密度组织中AMPAR亚基（GluA1/2/3/4）的表达和磷酸化水平的分析显示，吗啡后突触后密度中GluA4的表达和磷酸化水平升高。免疫共沉淀分析表明，GluA4同质体（Ca2+渗透性AMPAR）增加，免疫组织化学染色定位了III-V层中GluA4水平的增加。在吗啡处理的小鼠中，III-V层记录的兴奋性突触后电流（EPSCs）显示对Ca2+渗透性AMPAR阻断剂的敏感性增强。此外，AMPAR介导的EPSCs的电流-电压关系表明，吗啡处理的小鼠的纠正指数（Ca2+渗透性AMPAR贡献的指标）增加，而盐处理的小鼠则没有。通过膜片移液管输注GluA4抗体可逆转上述作用。这是第一个直接证据表明含有glua4 - AMPAR在吗啡诱导的疼痛中起作用，并强调了含有glua4 - AMPAR的脊柱作为阻止吗啡诱导的疼痛敏感性的靶点。
Withdrawal from prescribed opioids results in increased pain sensitivity, which prolongs the treatment. This pain sensitivity is attributed to neuroplastic changes that converge at the spinal cord dorsal horn. We have recently reported that repeated morphine administration triggers an insertion of GluA2-lacking (Ca2+-permeable) alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) in the hippocampus. This finding together with the reported involvement of AMPAR in the mechanisms underlying inflammatory pain led us to hypothesize a role for spinal AMPAR in opioid-induced pain behavior. Mice treated with escalating doses of morphine showed hypersensitivity to mechanical stimulation. Intrathecal administration of a Ca2+-permeable AMPAR selective blocker disrupted morphine-induced mechanical sensitivity. Analysis of the expression and phosphorylation levels of AMPAR subunits (GluA1/2/3/4) in homogenates and in postsynaptic density fractions from spinal cord dorsal horns showed an increase in GluA4 expression and phosphorylation in the postsynaptic density after morphine. Co-immunoprecipitation analyses suggested an increase in GluA4 homomers (Ca2+-permeable AMPAR) and immunohistochemical staining localized the increase in GluA4 levels in laminae III-V. The excitatory postsynaptic currents (EPSCs) recorded in laminae III-V showed enhanced sensitivity to Ca2+-permeable AMPAR blockers in morphine-treated mice. Furthermore, current-voltage relationships of AMPAR-mediated EPSCs showed that rectification index (an indicator of Ca2+-permeable AMPAR contribution) is increased in morphine-treated but not in saline-treated mice. These effects could be reversed by infusion of GluA4 antibody through patch pipette. This is the first direct evidence for a role of GluA4-containing AMPAR in morphine-induced pain and highlights spinal GluA4-containing AMPAR as targets to prevent the morphine-induced pain sensitivity.