TY - JOUR T1 - Plasticity of signaling by spinal estrogen receptor alpha, kappa-opioid receptor and mGluRs over the rat reproductive cycle regulates spinal endomorphin 2 antinociception: relevance of endogenous biased agonism JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.1927-17.2017 SP - 1927-17 AU - Nai-Jiang Liu AU - Vijaya Murugaiyan AU - Emiliya M. Storman AU - Stephen A. Schnell AU - Arjun Kumar AU - Martin W. Wessendorf AU - Alan R. Gintzler Y1 - 2017/10/12 UR - http://www.jneurosci.org/content/early/2017/10/12/JNEUROSCI.1927-17.2017.abstract N2 - We previously showed that intrathecal application of endomorphin 2 [EM2; the highly specific endogenous mu-opioid receptor (MOR) ligand] induces antinociception that varies with stage of the rat estrous cycle -- minimal during diestrus and prominent during proestrus. Earlier studies, however, did not identify proestrus-activated signaling strategies that enable spinal EM2 antinociception. We now report that in female rats, increased spinal dynorphin release and kappa-opioid receptor (KOR) signaling, as well as the emergence of glutamate-activated mGluR1 signaling, are critical to the transition from an EM2 non-responsive (during diestrus) to an analgesically responsive state (during proestrus). Differential signaling by mGluR1, depending on its activation by membrane estrogen receptor α (mERα) (during diestrus) vs. glutamate (during proestrus), concomitant with the ebb and flow of spinal dynorphin/KOR signaling, function as a switch, preventing or promoting, respectively, spinal EM2 antinociception. Importantly, EM2 and glutamate-containing varicosities appose spinal neurons that express MOR along with mGluRs and mERα, suggesting that signaling mechanisms regulating analgesic effectiveness of intrathecally applied EM2 also pertain to endogenous EM2. Regulation of spinal EM2 antinociception by both the nature of the endogenous mGluR1 activator (i.e., endogenous biased agonism at mGluR1) and changes in spinal dynorphin/KOR signaling represent a novel mechanism for modulating analgesic responsiveness to endogenous EM2 (and perhaps other opioids). This points the way for developing non-canonical pharmacological approaches to pain management by harnessing endogenous opioids for pain relief.SIGNIFICANCE STATEMENTThe current prescription opioid abuse epidemic underscores the urgency to develop alternative pharmacotherapies for managing pain. Our finding that the magnitude of spinal EM2 antinociception not only varies with stage of reproductive cycle, but is also differentially regulated during diestrus and proestrus, highlights the need for sex- and cycle-specific approaches to pain management. Additionally, our finding that spinal EM2 antinociception in female rats is regulated by both the ebb and flow of spinal dynorphin/KOR signaling over the estrous cycle as well as the nature of the endogenous mGluR1 activator could encourage non-canonical pharmacological approaches to pain management such as harnessing endogenous opioids for pain relief. ER -