雌激素對偏頭痛影響的研究

王丹 于生元

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雌激素對偏頭痛影響的研究

王丹 于生元

偏頭痛(Migraine)是一種反復(fù)發(fā)作的、一側(cè)或雙側(cè)搏動性的劇烈頭痛, 發(fā)作時(shí)伴惡心、嘔吐、畏光和畏聲等癥狀［1］,此類疾病多發(fā)于中青年, 流行病學(xué)調(diào)查顯示中國偏頭痛的患病率為9.3％, 女性為男性的兩倍, 亞洲(除香港和韓國外)偏頭痛患病率女性為11.3％～14.4％, 男性為3.6％～6.7％［2,3］。由于偏頭痛高發(fā)病率和高致殘率, 使患者身心健康受到損害,工作效率降低, 生活質(zhì)量下降, 并且給家庭和社會帶來嚴(yán)重的經(jīng)濟(jì)負(fù)擔(dān), 因而深入了解及有效治療偏頭痛至關(guān)重要。

大量基礎(chǔ)和臨床研究均表明性激素在偏頭痛發(fā)作的病理生理過程中起到了重要作用, 性激素對偏頭痛影響目前研究比較多的是雌激素, 現(xiàn)就雌激素對偏頭痛影響的研究做簡要綜述。

1 臨床研究

雌激素對偏頭痛的作用與其血清濃度水平密切相關(guān), 雌激素水平在懷孕初期升高, 產(chǎn)后則急劇下降,60％的偏頭痛女性頭痛發(fā)生在圍月經(jīng)期(月經(jīng)期前2 d至月經(jīng)期后3 d)。大部分偏頭痛患者在妊娠期頭痛緩解。47例無先兆偏頭痛女性患者的調(diào)查顯示, 有80％的人妊娠期未出現(xiàn)偏頭痛, 而分娩以后, 幾乎所有的女性偏頭痛患者又恢復(fù)到以前的狀態(tài)［4］。臨床研究發(fā)現(xiàn),98例女性接受體外受精, 在卵巢過度刺激控制之前, 給予促性腺激素釋放激素, 下調(diào)雌激素水平,此時(shí), 有82％的女性發(fā)生了偏頭痛, 此研究結(jié)果提示雌激素水平下降可能誘發(fā)偏頭痛［5］。月經(jīng)前給予補(bǔ)充雌激素可以有效預(yù)防月經(jīng)性偏頭痛的發(fā)作［6］。中到高水平的雌激素可以預(yù)防某些無先兆偏頭痛發(fā)作, 但可能加重有先兆偏頭痛。

2 基礎(chǔ)研究

研究發(fā)現(xiàn), 雌激素影響神經(jīng)細(xì)胞形態(tài)發(fā)育, 在懷孕的第3個(gè)月, 中樞神經(jīng)系統(tǒng), 如大腦皮層、下丘腦、腦干、三叉神經(jīng)核等某些區(qū)域的性激素受體呈特定的分布。目前已知雌激素受體(estrogen receptor, ER)有兩種受體, ERα、ERβ［7,8］。在人類, ERα的mRNA在杏仁核及下丘腦的背內(nèi)側(cè)呈高表達(dá), 另外, ERα的mRNA在前額葉皮質(zhì)、額葉皮質(zhì)、扣帶回也有表達(dá)［8-10］；在大鼠及非人類種屬中, ER α的mRNA還在海馬表達(dá), 這是在人類沒有發(fā)現(xiàn)的。此外, 大鼠和猴子大腦的中縫核、三叉神經(jīng)核、中腦導(dǎo)水管周圍灰質(zhì)均發(fā)現(xiàn)了ERα, 而上述幾個(gè)區(qū)域均在偏頭痛的病理生理中起到重要的作用［11-13］。

雌激素影響神經(jīng)元興奮性, 目前認(rèn)為雌激素具有神經(jīng)興奮性, 雌激素可上調(diào)興奮性N-甲基-D-天冬氨酸(N-methyl-D-aspartate, NMDA) 受體的mRNA 水平, 增強(qiáng)NMDA介導(dǎo)的鈣離子內(nèi)流［8,14］, 降低谷氨酸脫羧酶的活性, 從而降低γ-氨基丁酸(gamma-aminobutyric acid, GABA)合成［15］。另外,雌激素可解開G蛋白激活內(nèi)向整流鉀離子通道, 可進(jìn)一步抑制GABA依賴的細(xì)胞膜超極化。因此, 雌激素在細(xì)胞膜水平可能通過直接與特異性受體結(jié)合產(chǎn)生神經(jīng)興奮作用［16］。雌激素的神經(jīng)興奮作用需要增加細(xì)胞代謝和能量, 已經(jīng)證實(shí)在細(xì)胞線粒體存在ERβ受體, 雌激素與其結(jié)合, 增加線粒體能量生成［17］。雌激素還可以使血管舒張和增加血流量, 不僅增加細(xì)胞增量還促進(jìn)一氧化氮(nitric oxide, NO)釋放［18,19］。同時(shí), 雌激素降低氧化應(yīng)激產(chǎn)物及興奮性毒性損傷。

雌激素通過影響不同的神經(jīng)遞質(zhì)和調(diào)節(jié)因子來影響神經(jīng)興奮性, 目前認(rèn)為參與偏頭痛發(fā)生的神經(jīng)遞質(zhì)主要有5羥色胺(5-hydroxytryptamine,5-HT)、谷氨酸(Glutamic acid, Glu)、GABA、阿片及去甲腎上腺素。

5-HT：在中樞神經(jīng)系統(tǒng),5-HT能神經(jīng)元主要分布在腦干的中縫核和腦橋。目前認(rèn)為其參與了偏頭痛病理生理過程并且可能是月經(jīng)性偏頭痛的一個(gè)重要因素。雌性嚙齒類動物的5-HT含量要高于雄性, 并且隨著卵巢周期變化［7］。5-HT可能對偏頭痛的發(fā)生和緩解起雙向作用,5-HT2A受體可促進(jìn)三叉神經(jīng)血管系統(tǒng)的NO釋放, 引起血管舒張, 痛覺受體敏化導(dǎo)致偏頭痛發(fā)生［20］；而5-HT1B/D受體使血管收縮, 緩解疼痛。雌激素通過影響5-羥色胺的合成, 再攝取, 降解從而影響偏頭痛。雖然雌激素對5-HT的作用多變, 總體來說, 雌激素對5-HT起到上調(diào)的作用, 主要通過是促進(jìn)其限速酶-色氨酸羥化酶-的活性, 并且降低其轉(zhuǎn)運(yùn)體和代謝酶的活性［21,22］。

Glu：雌激素可促進(jìn)興奮性Glu傳導(dǎo)。在中樞內(nèi)源性鎮(zhèn)痛系統(tǒng), 中腦導(dǎo)水管周圍灰質(zhì)(periaqueductal gray, PAG)含有大量Glu能神經(jīng)元, GABA能神經(jīng)元；神經(jīng)元興奮后, Glu可激活延腦頭端腹內(nèi)側(cè)(rostral ventromedial medulla, RVM)區(qū)內(nèi)的停止-神經(jīng)元(Off-cell)參與疼痛的抑制［23］。也有研究發(fā)現(xiàn),谷氨酸對RVM區(qū)神經(jīng)元有雙向作用, 低濃度谷氨酸(5 nmol)起到易化疼痛的作用, 高濃度谷氨酸(50 nmol)起到抑制疼痛的作用［24］。

GABA：GABA是中樞神經(jīng)系統(tǒng)重要的抑制性神經(jīng)遞質(zhì),皮層的GABA水平可能隨著月經(jīng)周期而變化。而PAG區(qū)的GABA能神經(jīng)元活化后, 可激活RVM區(qū)的on細(xì)胞, 使疼痛易化。Wagner等［25］報(bào)道雌二醇通過GABAB受體可調(diào)節(jié)下丘腦GABA能神經(jīng)元。相似的, RVM區(qū)的GABAB受體活化也產(chǎn)生雙向作用, 低劑量時(shí)抑制疼痛, 高劑量時(shí)易化疼痛［26］。

阿片：阿片系統(tǒng)在控制疼痛及調(diào)節(jié)生殖行為均起到重要作用, 阿片類神經(jīng)元主要分布在腹側(cè)被蓋區(qū)(ventral tegmental area, VTA), 阿片能神經(jīng)元與GABA能神經(jīng)元形成突觸, 活化后, 可抑制GABA釋放, 從而促進(jìn)中腦邊緣多巴胺能通路中的多巴胺釋放, 已有報(bào)道, 雌激素可上調(diào)內(nèi)啡肽、腦啡肽mRNA水平, 而患有月經(jīng)性偏頭痛的女性患者的內(nèi)啡肽水平要低于對照組［27,28］。

去甲腎上腺素：去甲腎上腺素是公認(rèn)的與偏頭痛有密切關(guān)系的神經(jīng)遞質(zhì)。雌二醇可以增加下丘腦去甲腎上腺素的釋放, 引起丘腦腹內(nèi)側(cè)興奮性提高。還可通過如下途徑影響腎上腺素受體的表達(dá)和功能：①下凋皮層α-腎上腺素受體的數(shù)量, 解開α2A-腎上腺素受體與G蛋白的耦聯(lián)作用。②減弱脊髓中α2-腎上腺受體介導(dǎo)的抗傷害作用［29］。

雌激素影響偏頭痛發(fā)作已經(jīng)得到大部分學(xué)者的認(rèn)同, 并且激素替代預(yù)防偏頭痛發(fā)作已試用于臨床, 多數(shù)患者收到了滿意療效, 但也有無效, 甚至癥狀加重的報(bào)道［30-32］。在研究雌激素對偏頭痛影響的作用時(shí), 也發(fā)現(xiàn)部分機(jī)制存在矛盾。因此, 雌激素在偏頭痛發(fā)作中的作用尚待進(jìn)一步研究。

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10.14164/j.cnki.cn11-5581/r.2015.05.192

2014-12-03］

100853 解放軍總醫(yī)院神經(jīng)內(nèi)科

于生元