Emergence of Functional Spinal Delta Opioid Receptors after Chronic Ethanol Exposure

Background: The delta opioid receptor (DOR) is a promising target to treat multiple indications, including alcoholism, anxiety, and nonmalignant pain. The potential of the DORs has been underappreciated, in part, due to relatively low functional expression of these receptors in naive states. However, chronic exposure to stress, opioids, and inflammation can induce a redistribution of DORs to the cell surface where they can be activated. Previously, DORs were shown to be selectively/exclusively present in spinal cord circuits mediating mechanical sensitivity but not those mediating thermal nociception under naive conditions. Methods: We spinally administered DOR and mu opioid receptor (MOR) selective agonists ([D-Pen2,D-Pen5]-Enkephalin, deltorphin II, SNC80, and DAMGO) and antagonists (naltriben and CTAP) and determined thermal antinociception and mechanical sensitivity in wild-type mice or mice with a genetic disruption of DOR or MOR. Thermal antinociception was measured using a radiant heat tail-flick assay; mechanical sensitivity was measured using von Frey filaments. Dose response curves were generated in naive mice and mice exposed to ethanol in a model of voluntary consumption. Results: We show that prolonged exposure to ethanol can promote an upregulation of functional DORs in the spinal cord in thermal pain-mediating circuits but not in those mediating mechanical sensitivity. The upregulated DORs either modulate MOR-mediated analgesia through convergence of circuits or signal transduction pathways and/or interact directly with MORs to form a new functional (heteromeric) unit. Conclusions: Our findings suggest that DORs could be a novel target in conditions in which DORs are redistributed.