Emergence of Functional Spinal Delta Opioid Receptors After Chronic Ethanol Exposure

Abstract

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 naïve 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 naïve 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 naïve 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.

Identification of a selective small-molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties

“…We injected complete Freund’s adjuvant (CFA) into the hind paw of mice to induce inflammation and measured pain as hypersensitivity to touch by Von Frey filaments (24, 34). Intrathecal injections (into the spinal canal) with ST034307 at doses as low as 0.25 µg caused a significant relief of CFA-induced inflammatory pain, as indicated by the increase in the amount of pressure the mouse tolerated before removing the paw (Fig.…”

“…7). As a control pain reliever, we administered DAMGO at 50 ng per mouse (34), which provided a similar reduction in the hypersensitivity response (Fig. 7A).…”

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

“…These interactions persist in MOR-KO mice, suggesting that MOR is not required (Guo et al, 2003). However, the analgesic effects of DeltII have been attributed to MOR in some behavioral assays such as the tail-flick assay (Scherrer et al, 2004;van Rijn et al, 2012), raising the possibility that these synergistic interactions with a 2 AR agonists are MOR mediated rather than DOR mediated. In the current study, DeltII antinociception was absent in DOR-KO mice, validating the use of the SP behavioral assay as a tool to examine the role of DOR in synergistic interactions.…”

“…Thus, opioid-adrenergic interactions resulting in analgesic synergy are possible when activating DOR and can occur in the absence of MOR. However, reports that DeltII and DPDPE retain their antinociceptive action in DOR-KO mice and that MOR mediates this effect questions the selectivity of DOR agonists (Scherrer et al, 2004;van Rijn et al, 2012). This could mean that opioid-adrenergic synergistic interactions studied with DOR agonists are mediated by MOR and therefore justify further evaluation of the role of DOR in these interactions.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…However, considering that active lever pressing after forced abstinence is influenced by stress, such data may be confounded because NTI might exacerbate stress-induced relapse. Prolonged exposure to ethanol also promotes an upregulation of functional DOPr in the spinal cord in painmediating circuits (van Rijn et al, 2012). Similarly, chronic ethanol was also shown to modulate DOPr membrane translocation in the VTA.…”