Molecular mechanisms of Vitex agnus-castus L. in PMS

描述（由申请人提供）：牡荆（VAC）果实提取物自古以来就被用于缓解经前综合症（PMS）。最近的研究表明，多巴胺D2受体的激活和催乳素释放的抑制可能是部分原因。也有证据表明通过阿片受体起作用。经前症候群与内源性阿片肽的改变有关。这些多肽的水平在月经周期中波动，在黄体晚期降至最低，此时雌激素水平最低。与无症状的受试者相比，经前症候群的女性表现出更早和更大的阿片肽水平下降。事实上，一些人认为，阿片类药物水平的急剧下降可能会导致经前综合症中出现的轻度阿片类药物戒断综合征，包括头痛、情绪波动和水分潴留。高剂量的纳洛酮（一种非选择性阿片拮抗剂）可在健康志愿者中产生类似经前症候群的症状。阿片类药物对下丘脑-垂体-肾上腺轴产生强直性抑制，从而影响各种激素的水平。阿片类药物的活性可以缓解经前症候群中出现的背部和乳房疼痛以及情绪波动。Kappa受体的活性可能有助于减少水分潴留。在这个应用中，我们建议测试牡荆（Vitex agnus-castus L.）部分通过其对阿片受体的激动作用减轻经前症候群症状的假设。为了验证这一假设，我们将首先评估不同的VAC提取物对阿片受体的亲和力。通过测量G蛋白激活和腺苷酸环化酶抑制，进一步测试提取物对阿片受体的激活。最后，为了解决这些提取物对内源性阿片受体的影响，我们将评估提取物对脑阿片受体的结合和激活以及小鼠的行为后果。目前研究的数据将有助于改善或开发治疗经前症候群的新疗法。

DESCRIPTION (provided by applicant): Vitex agnus-castus L. (VAC) fruit extracts have been used since ancient times for the relief of premenstrual syndrome (PMS). Recent studies suggest that activation of dopamine D2 receptors and inhibition of prolactin release may account for part of the effect. Evidence also exists for the action through opiate receptors. PMS has been linked to alterations in endogenous opiate peptides. Levels of these peptides fluctuate during menstrual cycles, falling to the lowest in the late-luteal phase when estrogen is at its lowest level. When compared with symptom free subjects, women with PMS show an earlier and larger decrease in opiate peptide levels. In fact, some believe this sharp decrease in opiate levels may cause a mild opiate-withdrawal syndrome seen in PMS, including headache, mood swings, and water retention. High doses of naloxone, a nonselective opiate antagonist, can produce PMS-like symptoms in healthy volunteers. Opiates produce a tonic inhibition on the hypothalamus-pituitary-adrenal axis, thus affecting levels of various hormones. Opiate activity can relieve back and breast pain and mood swings seen in PMS. Activity at the Kappa receptor may help to lessen water retention. In this application, we propose to test the hypothesis that Vitex agnus-castus L. alleviates symptoms of PMS in part through its agonistic actions at the opiate receptors. To test this hypothesis, we will first evaluate the affinity of different VAC extracts for opiate receptors. The extracts will be further tested for their activation of opiate receptors by measuring G protein activation and adenylyl cyclase inhibition. Lastly, to address the effect of these extracts at endogenous opiate receptors, we will evaluate extracts' binding and activation of brain opiate receptors, and behavioral consequence in mice. Data from the current study will help to improve or develop novel therapies for the treatment of PMS.