Translational research : the journal of laboratory and clinical medicine
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Nociception and opioid antinociception in females are pliable processes, varying qualitatively and quantitatively over the reproductive cycle. Spinal estrogenic signaling via membrane estrogen receptors (mERs), in combination with multiple other signaling molecules [spinal dynorphin, kappa-opioid receptors (KOR), glutamate and metabotropic glutamate receptor 1 (mGluR1)], appears to function as a master coordinator, parsing functionality between pronociception and antinociception. This provides a window into pharmacologically accessing intrinsic opioid analgesic/anti-allodynic systems. ⋯ Aromatase-mERα oligomers are also plentiful, in a central nervous system region-specific fashion. These can be independently regulated and allow estrogens to act intracellularly within the same signaling complex in which they are synthesized, explaining asynchronous relationships between circulating estrogens and central nervous system estrogen functionalities. Observations with EM2 highlight the translational relevance of extensively characterizing exogenous responsiveness to endogenous opioids and the neuronal circuits that mediate them along with the multiplicity of estrogenic systems that concomitantly function in phase and out-of-phase with the reproductive cycle.