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.