Generation of a pain memory in the primary afferent nociceptor triggered by PKCε activation of CPEB.
Generation of a pain memory in the primary afferent nociceptor triggered by PKCε activation of CPEB.
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DOI：
10.1523/jneurosci.5138-11.2012
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发表时间：
2012-02-08
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影响因子：
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通讯作者：
Levine JD
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文献类型：
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作者：
Bogen O;Alessandri-Haber N;Chu C;Gear RW;Levine JD
用炎症或神经性损伤激发的Isolectin B4阳性[IB 4（+）]初级传入伤害感受器对促炎细胞因子前列腺素E2（PGE 2）的后续激发产生蛋白激酶C ε（PKCε）依赖性持久痛觉过敏反应，这种现象称为痛觉过敏引发。在这里，我们证明，神经可塑性潜在的伤害性感受器启动需要72小时才能建立;大鼠已被激发与炎症介质TNFα 24小时或48小时前的PGE 2没有表现出增强和延长的痛觉过敏反应的IB 4（+）-伤害性感受器的特点。此外，由于潜在的可塑性可以通过外周给予蛋白质翻译抑制剂茴香霉素来中断，因此其通过外周蛋白质表达模式的变化来反映。最后，选择性PKCε激动剂激活的c激酶的psi ε受体（psi εRACK）诱导的引发可以通过鞘内注射胞质多聚腺苷酸化元件结合蛋白（CPEB）mRNA的反义寡核苷酸来预防，但不能逆转，CPEB是一种与PKCε共免疫沉淀的蛋白质翻译的主要调节因子，几乎只由IB 4（+）-伤害感受器表达。我们的研究结果表明，CPEB是PKCε在细胞信号级联反应的下游，负责诱导启动，提高了有趣的可能性，朊病毒样错误折叠可能是一个负责任的机制慢性疼痛。
Isolectin B4 positive [IB4(+)] primary afferent nociceptors challenged with an inflammatory or neuropathic insult develop a protein kinase C epsilon (PKCε)-dependent long-lasting hyperalgesic response to a subsequent challenge by the pro-inflammatory cytokine prostaglandin E2 (PGE2), a phenomenon known as hyperalgesic priming. Here we demonstrate that the neuroplasticity underlying nociceptor priming requires 72 hrs to be established; rats that have been challenged with the inflammatory mediator TNFα 24 hrs or 48 hrs ahead of PGE2 do not show the enhanced and prolonged hyperalgesic response by which primed IB4(+)-nociceptors are being characterized. Moreover, as the underlying plasticity can be interrupted by the peripheral administration of the protein translation inhibitor anisomycin it is reflected by changes in the peripheral protein expression pattern. Finally, the induction of priming by the selective PKCε agonist, psi epsilon receptor for activated c kinase (ψεRACK) can be prevented, but not reversed by intrathecal injections of antisense oligodeoxynucleotides for the cytoplasmic polyadenylation element binding protein (CPEB) mRNA, a master regulator of protein translation that co-immunoprecipitated with PKCε and is almost exclusively expressed by IB4(+)-nociceptors. Our results suggest that CPEB is downstream of PKCε in the cellular signaling cascade responsible for the induction of priming, raising the intriguing possiblity that prion-like misfolding could be a responsible mechanism for the chronification of pain.