Cutrer F M, Moskowitz M A
Department of Neurology, Massachusetts General Hospital, Boston 02129, USA.
Headache. 1996 Nov-Dec;36(10):579-85. doi: 10.1046/j.1526-4610.1996.3610579.x.
Gamma-aminobutyric acid (GABA) receptors are ubiquitous inhibitory receptors in the central and peripheral nervous systems. Valproic acid (2-propylpentanoic acid), which enhances GABA synthesis and blocks degradation, is useful in migraine treatment and may act through activation of GABA receptors to modulate trigeminal nociceptive neurons innervating the meninges. To investigate this possibility, we tested the effect of valproate and allopregnanolone, a metabolite of progesterone, which binds and modulates the GABA receptor in an animal model of cephalic pain. One hundred ten Hartley guinea pigs were pretreated with either valproate or allopregnanolone 30 minutes prior to activation of trigeminal afferent fibers via intracisternal injection of the irritant, capsaicin. The effects of valproic acid and allopregnanolone were examined on c-fos expression within the trigeminal nucleus caudalis (lamina I, II), the termination site for small unmyelinated C fibers projecting from the meninges. C-fos positive cells were counted at three representative levels (rostral, middle, and caudal) by an observer naive to the treatment group. We found that valproate (> or = 10 mg/kg, IP) reduced labeled cells by 52% (P < 0.05) and allopregnanolone (> or = 100 mg/kg, IP) reduced labeled cells by 42% (P < 0.01). Bicuculline (GABAA antagonist), but not phaclofen (GABAB antagonist), blocked the valproate effect, thereby documenting the importance of GABAA receptors. We conclude that the attenuation of c-fos-LI by valproate and allopregnanolone is mediated via GABAA receptors. These studies complement prior experiments showing that valproic acid and allopregnanolone block neurogenic inflammation within the meninges via GABAA receptor-mediated mechanisms. The findings suggest a potential strategy for discovering new antimigraine drugs with high affinity for the GABAA receptor and its modulatory sites.
γ-氨基丁酸（GABA）受体是中枢和外周神经系统中普遍存在的抑制性受体。丙戊酸（2-丙基戊酸）可增强GABA合成并阻断其降解，在偏头痛治疗中有用，可能通过激活GABA受体来调节支配脑膜的三叉神经伤害性神经元。为了研究这种可能性，我们在一种头痛动物模型中测试了丙戊酸盐和别孕烯醇酮（孕酮的一种代谢产物，可结合并调节GABA受体）的作用。110只哈特利豚鼠在通过脑池内注射刺激物辣椒素激活三叉神经传入纤维前30分钟，分别用丙戊酸盐或别孕烯醇酮进行预处理。研究了丙戊酸和别孕烯醇酮对三叉神经尾侧核（I层、II层）内c-fos表达的影响，三叉神经尾侧核是从脑膜投射来的无髓鞘小C纤维的终止部位。由对治疗组不知情的观察者在三个代表性水平（吻侧、中间和尾侧）对c-fos阳性细胞进行计数。我们发现丙戊酸盐（≥10mg/kg，腹腔注射）使标记细胞减少了52%（P<0.05），别孕烯醇酮（≥100mg/kg，腹腔注射）使标记细胞减少了42%（P<0.01）。荷包牡丹碱（GABAA拮抗剂）而非巴氯芬（GABAB拮抗剂）阻断了丙戊酸盐的作用，从而证明了GABAA受体的重要性。我们得出结论，丙戊酸盐和别孕烯醇酮对c-fos免疫反应性的减弱是通过GABAA受体介导的。这些研究补充了先前的实验，表明丙戊酸和别孕烯醇酮通过GABAA受体介导的机制阻断脑膜内的神经源性炎症。这些发现提示了一种潜在策略，用于发现对GABAA受体及其调节位点具有高亲和力的新型抗偏头痛药物。
