The role of hypothalamic mu opioid activity in the regulation of luteinizing hormone secretion.

Abstract

Studies in rats show that a decrease in opioid activity can trigger the preovulatory LH surge. Opioids have an acute inhibitory effect on LH secretion and blockade of opioid action on proestrus with naloxone advances the surge. Our work was aimed at determining whether this is the physiological mechanism by which an LH surge is triggered, or whether this is a pharmacological phenomenon. Also, as opioids are released in times of stress, we investigated whether opioid blockade would inhibit a stress response on the LH surge. We utilized a $\mu$-specific, long-lasting opioid antagonist, clocinnamox (CCAM) to determine if removing opioid tone prior to the LH surge would affect the timing of the LH surge. Studies were designed to validate that CCAM was an appropriate tool for assessing the effects of opioids at the $\mu$ receptor on reproductive function. CCAM was capable of blocking a $\mu$ effect, morphine analgesia. CCAM also reversed an effect of morphine on the reproductive neuroendocrine system, completely inhibiting morphine's ability to block the LH surge. CCAM also reduced $\mu$ receptor binding in in vivo binding assays. These effects persisted for periods exceeding 1 week. The administration of CCAM on the afternoon of diestrus II did not change the timing of the subsequent LH surge. LH levels were higher on proestrus, indicating that there is opioid tone on proestrus, but the surge was initiated at the same time as in control rats. CCAM given on the morning of proestrus caused an early initiation of the surge, similar to that seen in previous studies by others with naloxone, suggesting that opioid effects on LH are mediated by the $\mu$ receptor subtype. CCAM administration on days other than proestrus and in male rats showed no effect on plasma LH levels when LH levels were measured 1 day to 1 week after CCAM injection. These studies indicate no physiological role for $\mu$ opioid activity in the timing of the LH surge. In a stressful blood sampling paradigm, CCAM provided protection for the LH surge mechanism. While LH surges were blocked by the repeated sampling protocol in control rats, rats pretreated with CCAM showed normal LH surges. These data suggest that opioid activity at the $\mu$ receptor conveys information about the stress status to the reproductive system in the rat. These experiments together refute the hypothesis that a decrease in opioid tone is the trigger for the preovulatory surge, but support the hypothesis that opioids communicate stress status to the reproductive axis.