Sex differences in the expression of calcitonin gene-related peptide receptor components in the spinal trigeminal nucleus.
Sex differences in the expression of calcitonin gene-related peptide receptor components in the spinal trigeminal nucleus.
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三叉神经脊髓核中降钙素基因相关肽受体成分表达的性别差异。
DOI：
10.1016/j.ynpai.2019.100031
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Masri,Radi
中科院分区：
文献类型：
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作者：
Ji,Yadong;Rizk,Alexandra;Voulalas,Pamela;Aljohani,Hanan;Akerman,Simon;Dussor,Gregory;Keller,Asaf;Masri,Radi
背景与目的降钙素基因相关肽（Calcitonin gene-related peptide，CGRP）在偏头痛的病理生理过程中起重要作用。CGRP主要通过激活由3种蛋白质组成的受体起作用：降钙素受体样受体（CGRP）、受体活性修饰蛋白1（RAMP 1）和受体组分蛋白（RCP）。我们测试的假设，性别差异存在于蛋白质水平的两个关键组成部分的CGRP receptor：RCPs和RCP.MethodsWe使用特定的抗体，以评估基线蛋白质水平的RCPs和RCP在三叉神经脊束核尾侧（SpVc）和上颈脊髓的雄性和雌性大鼠。我们还测试了是否操纵敲低RCP在SpVc中的表达，使用短发夹RNA（shRNA）的局部介导的基因转移，改善由脑膜的化学伤害性刺激诱导的颅内偏头痛样疼痛的动物模型中的疼痛。为了评估疼痛，我们使用的持续疼痛测试（大鼠面部鬼脸测试和冻结行为）和面部机械超敏反应和异常性疼痛的测试。ResultsThere是没有差异的SpVc和上颈髓的雄性和雌性动物（p > 0.11）之间的水平。然而，与雄性动物相比，雌性动物表现出更高的RCP基线水平（高达3倍）（p < 0.002）。敲低RCP的表达SpVc衰减化学伤害性刺激的脑膜引起的机械性面部异常性疼痛，但在女性和男性animes.ConclusionsRCP是CGRP受体的一个组成部分，并可能发挥关键作用，介导CGRP引起的中枢敏化后，脑膜伤害性刺激的持续疼痛行为的影响不大。RCP在SpVc和上颈髓中的表达具有性别二态性，在女性中表达水平较高。这种二态性可能与女性偏头痛发病率的增加有关，这一假设应该在未来得到验证。
Background and purposeCalcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology. CGRP acts primarily by activating a receptor composed of 3 proteins: calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP). We tested the hypothesis that sex differences exist in protein levels of two key components of this CGRP receptor: CLR and RCP.MethodsWe used specific antibodies to assess baseline protein levels of CLR and RCP in the spinal trigeminal nucleus caudalis (SpVc) and upper cervical spinal cord of both male and female rats. We also tested if manipulations that knock-down the expression of RCP in SpVc, using locally-mediated gene transfer of short hairpin RNA (shRNA), ameliorate pain in an animal model of intracranial migraine-like pain induced by chemical noxious stimulation of the meninges. To assess pain, we used tests of ongoing pain (rat face grimace test and freezing behavior) and tests of facial mechanical hypersensitivity and allodynia.ResultsThere was no difference in CLR levels between male and female animals (p > 0.11) in SpVc and the upper cervical cord. However, female animals exhibited greater baseline levels of RCP (up to 3-fold higher) compared to males (p < 0.002). The knock-down of RCP expression in SpVc attenuated mechanical facial allodynia induced by chemical noxious stimulation of the meninges, but had little effect on ongoing pain behaviors in female and male animals.ConclusionsRCP is an integral component of the CGRP receptor and may play a key role in mediating CGRP induced central sensitization after noxious stimulation of the meninges. RCP expression in the SpVc and upper cervical cord is sexually dimorphic, with higher levels of expression in females. This dimorphism may be related to the increased incidence of migraines in females–a hypothesis that should be tested in the future.