Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level
Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level
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DOI：
10.1186/1744-8069-5-27
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发表时间：
2009-06-07
期刊：
影响因子：
3.3
通讯作者：
Dickenson, Anthony H.
中科院分区：
文献类型：
--
作者：
Asante, Curtis O.;Wallace, Victoria C.;Dickenson, Anthony H.
背景：雷帕霉素的哺乳动物靶标（MTOR）是mRNA翻译的关键调节剂，其作用可以被药物雷帕霉素抑制。长期可塑性的形式需要蛋白质合成，证据表明树突，轴突末端和细胞体中的mRNA对于长期突触可塑性至关重要。特定于疼痛，疼痛阈值的转移和反应性是神经元可塑性的表达，这可能导致持续的疼痛。我们通过抑制雷帕霉素在脊柱水平上抑制MTOR的活性，对接受福尔马林测试的大鼠的活性，同时使用行为和电生理技术进行。溶液：用于体内电生理学，Sprague Dawley大鼠已完全麻醉，并进行了单次和单调的大鼠细胞外记录是从Lamina V宽动态范围（WDR）背角脊柱获得的从后爪收到输入的区域的神经元。幼稚大鼠的神经元反应表明，雷帕霉素敏感的途径在伤害性特异性的C纤维介导的WDR神经元的传播以及机械诱发的反应中很重要，因为雷帕霉素有效地减弱了这些措施。将福尔马林溶液注入后爪中，然后将雷帕霉素或车辆直接施加到裸露的脊髓上。当雷帕霉素在后爪福尔马林注射前将雷帕霉素应用于脊髓时，福尔马林测试的延长延长的第二阶段显着衰减，这包括对脊髓的持续传入输入，神经元过度过度刺激性和激活的降降疗法。作用于脊柱神经元的脑干。根据电生理数据，行为研究表明，雷帕霉素减弱了福尔马林注射到后爪中引起的行为超敏反应。结论：我们得出结论，MTOR在通过mRNA翻译和蛋白质合成中通过mRNA转换维持持续性疼痛状态具有作用。我们假设可以通过作用于感觉传入末端以及背角脊柱神经元的兴奋性神经递质释放来激活MTOR，这可以通过源自大脑中高等中心的下降促进系统进一步扩大。
Background: The mammalian target of rapamycin ( mTOR) is a key regulator of mRNA translation whose action can be inhibited by the drug rapamycin. Forms of long-term plasticity require protein synthesis and evidence indicates that mRNA in dendrites, axon terminals and cell bodies is essential for long-term synaptic plasticity. Specific to pain, shifts in pain thresholds and responsiveness are an expression of neuronal plasticity and this likely contributes to persistent pain. We investigated this by inhibiting the activity of mTOR with rapamycin at the spinal level, of rats that were subjected to the formalin test, using both behavioural and electrophysiological techniques.Results: For in vivo electrophysiology, Sprague Dawley rats were fully anaesthetised and single-unit extracellular recordings were obtained from lamina V wide dynamic range (WDR) dorsal horn spinal neurones at the region where input is received from the hind paw. Neuronal responses from naive rats showed that rapamycin-sensitive pathways were important in nociceptive-specific C-fibre mediated transmission onto WDR neurones as well mechanically-evoked responses since rapamycin was effective in attenuating these measures. Formalin solution was injected into the hind paw prior to which, rapamycin or vehicle was applied directly onto the exposed spinal cord. When rapamycin was applied to the spinal cord prior to hind paw formalin injection, there was a significant attenuation of the prolonged second phase of the formalin test, which comprises continuing afferent input to the spinal cord, neuronal hyperexcitability and an activated descending facilitatory drive from the brainstem acting on spinal neurones. In accordance with electrophysiological data, behavioural studies showed that rapamycin attenuated behavioural hypersensitivity elicited by formalin injection into the hind paw.Conclusion: We conclude that mTOR has a role in maintaining persistent pain states via mRNA translation and thus protein synthesis. We hypothesise that mTOR may be activated by excitatory neurotransmitter release acting on sensory afferent terminals as well as dorsal horn spinal neurones, which may be further amplified by descending facilitatory systems originating from higher centres in the brain.