Puri Veena, Cui Lisa, Liverman Christopher S, Roby Kathy F, Klein Robert M, Welch K Michael A, Berman Nancy E J
Department of Anatomy and Cell Biology, University Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 3038, Kansas City, KS 66160, USA.
Neuropeptides. 2005 Aug;39(4):409-17. doi: 10.1016/j.npep.2005.04.002.
Women are more than three times as likely as men to experience migraine headaches and temporomandibular joint pain, and painful episodes are often linked to the menstrual cycle. To understand how hormone levels may influence head and face pain, we assessed expression of pain-associated neuropeptides and estrogen receptor alpha (ERalpha) during the natural estrous cycle in mice. Gene expression was analyzed in the trigeminal ganglia of cycling female mice at proestrus, estrus and diestrus using RT-PCR. Peptide/protein expression in trigeminal neurons was analyzed using immunohistochemistry. ERalpha mRNA was present at all stages and highest at estrus. ERalpha protein was present in the cytoplasm of medium-sized and small trigeminal neurons. ERalpha immunoreactive neurons were most common at diestrus. CGRP and ANP mRNAs did not change across the estrous cycle, while expression of galanin and NPY mRNAs were strongly linked to the estrous cycle. Galanin mRNA levels peaked at proestrus, when expression was 8.7-fold higher than the diestrus levels. Galanin immunoreactivity also peaked at proestrus. At proestrus, 7.5% of trigeminal neurons contained galanin, while at estrus, 6.2% of trigeminal neurons contained galanin, and at diestrus, 4.9% of trigeminal neurons contained galanin. NPY mRNA peaked at estrus, when levels were 4.7-fold higher than at diestrus. Our findings suggest that estrogen receptors in trigeminal neurons modulate nociceptive responses through effects on galanin and NPY. Variations in neuropeptide content in trigeminal neurons across the natural estrous cycle may contribute to increases in painful episodes at particular phases of the menstrual cycle.
女性患偏头痛和颞下颌关节疼痛的可能性是男性的三倍多，且疼痛发作往往与月经周期有关。为了了解激素水平如何影响头部和面部疼痛，我们评估了小鼠自然发情周期中疼痛相关神经肽和雌激素受体α（ERα）的表达。使用逆转录聚合酶链反应（RT-PCR）分析了处于动情前期、发情期和动情后期的周期性雌性小鼠三叉神经节中的基因表达。使用免疫组织化学分析三叉神经节神经元中的肽/蛋白质表达。ERα mRNA在所有阶段均存在，且在发情期最高。ERα蛋白存在于中小型三叉神经节神经元的细胞质中。ERα免疫反应性神经元在动情后期最为常见。降钙素基因相关肽（CGRP）和心钠素（ANP）mRNA在整个发情周期中没有变化，而甘丙肽和神经肽Y（NPY）mRNA的表达与发情周期密切相关。甘丙肽mRNA水平在动情前期达到峰值，此时表达比动情后期水平高8.7倍。甘丙肽免疫反应性也在动情前期达到峰值。在动情前期，7.5%的三叉神经节神经元含有甘丙肽，而在发情期，6.2%的三叉神经节神经元含有甘丙肽，在动情后期，4.9%的三叉神经节神经元含有甘丙肽。NPY mRNA在发情期达到峰值，此时水平比动情后期高4.7倍。我们的研究结果表明，三叉神经节神经元中的雌激素受体通过对甘丙肽和NPY的作用来调节伤害性反应。在自然发情周期中，三叉神经节神经元中神经肽含量的变化可能导致月经周期特定阶段疼痛发作增加。
