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首页> 外文期刊>Experimental Neurology >Dynamic genotype-selective 'phenotypic switching' of CGRP expression contributes to differential neuropathic pain phenotype
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Dynamic genotype-selective 'phenotypic switching' of CGRP expression contributes to differential neuropathic pain phenotype

机译：CGRP表达的动态基因型选择性“表型转换”有助于差异性神经性疼痛表型

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摘要

Using a genetic model we demonstrate the role played by "phenotypic switching" of calcitonin gene related peptide (CGRP) expression in axotomized large Aβ afferents in the development of neuropathic pain behavior in rats. After nerve injury both substance P and CGRP are upregulated in Aβ afferents in the corresponding DRGs. It has been proposed that intraspinal release of these neurotransmitters upon gentle stroking of skin drives ascending pain signaling pathways resulting in tactile allodynia. We reported previously that in rat lines genetically selected for high (HA) vs. low (LA) pain phenotype, SP is upregulated equally in both strains, but that CGRP is upregulated exclusively in the pain prone HA line (Nitzan-Luques et al., 2011). This implicates CGRP as the principal driver of tactile allodynia. Here we confirm this conclusion by showing: 1) that the time of emergence of CGRP-IR in DRG Aβ neurons and their central terminals in HA rats matches that of pain behavior, 2) that following spinal nerve lesion (SNL) selective activation of low threshold afferents indeed drives postsynaptic pain-signaling neurons and induces central sensitization in HA rats, as monitored using c-Fos as a marker. These changes are much less prominent in LA rats, 3) that intrathecal (i.t.) administration of CGRP induces tactile allodynia in na?ve rats and 4) that i.t. administration of the CGRP-receptor antagonist BIBN4096BS (Olcegepant) attenuates SNL-evoked tactile allodynia, without blocking baseline nociception. Together, these observations support the hypothesis that genotype-selective phenotypic switching of CGRP expression in Aβ afferents following nerve injury is a fundamental mechanism of neuropathic tactile allodynia.
机译：使用遗传模型，我们证明了降钙素基因相关肽（CGRP）表达在大鼠神经病理性疼痛行为发展过程中的降钙素基因相关肽（CGRP）表达的“表型转换”所起的作用。神经损伤后，相应DRGs中Aβ传入的P物质和CGRP均上调。已经提出，当轻柔地抚摸皮肤时，这些神经递质的脊髓内释放驱动上升的疼痛信号传导途径，从而导致触觉性异常性疼痛。我们以前曾报道过，在遗传选择为高（HA）与低（LA）疼痛表型的大鼠品系中，两种品系中SP均上调，但CGRP仅在易痛HA品系中上调（Nitzan-Luques等。 ，2011）。这暗示CGRP是触觉异常性疼痛的主要驱动力。在这里，我们通过证明以下结论来证实这一结论：1）HA大鼠中DRGAβ神经元及其中枢末端的CGRP-IR出现时间与疼痛行为相匹配; 2）脊髓神经病变（SNL）选择性激活低如使用c-Fos作为标记所监测的，阈值传入确实驱动了突触后疼痛信号神经元并诱导了HA大鼠的中枢敏化。这些变化在LA大鼠中不那么明显，3）鞘内（i.t.）给予CGRP在幼稚大鼠中引起触觉异常性疼痛，以及4）i.t.小鼠。 CGRP受体拮抗剂BIBN4096BS（Olcegepant）的给药可减轻SNL诱发的触觉异常性疼痛，而不会阻止基线伤害感受。总之，这些观察结果支持以下假设：神经损伤后Aβ传入中CGRP表达的基因型选择性表型转换是神经性触觉异常性疼痛的基本机制。

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