In vivo characterization of the novel delta opioid receptor positive allosteric modulator BMS‐986187

The delta opioid receptor (DOPr) is a member of the opioid receptor family of G protein‐coupled receptors (GPCR). Activation of DOPr induces antinociception, antihyperalgesia, and antidepressant‐like effects in animal models. However, some DOPr agonists cause convulsions, hindering their development as therapeutics in humans. Positive allosteric modulators (PAMs) bind to a receptor site distinct from the orthosteric binding site of a GPCR and may have several advantages over orthosteric agonists including greater selectivity, a larger safety margin and preservation of the spatiotemporal integrity of the endogenous system. Therefore, a PAM could be an effective strategy for eliciting DOPr‐mediated therapeutic effects without convulsions. To evaluate this hypothesis, we investigated the ability of the DOPr PAM BMS‐986187 to elicit DOPr‐mediated behaviors in mice alone or in combination with the DOPr orthosteric agonist SNC80. DOPr‐mediated antinociception was assessed in the acetic acid‐induced stretch assay. Antihyperalgesia was evaluated using a nitroglycerin‐induced thermal hyperalgesia assay. Antidepressant‐like effects were measured using the forced swim test. BMS‐986187 enhanced the potency of SNC80 to induce antinociception and antihyperalgesia without altering SNC80‐induced convulsions. BMS‐986187 alone produced antidepressant‐like effects without convulsions. These antidepressant‐like effects were blocked by the DOPr antagonist naltrindole and absent in DOPr knockout mice, indicating a DOPr‐mediated effect. Pretreatment with the enkephalinase inhibitor RB101 produced a synergistic effect in the forced swim test with BMS‐986187 but not SNC80 suggesting that BMS‐986187 exerts it antidepressant‐like effects by enhancing the actions of endogenous enkephalins. Overall, these findings suggest that BMS‐986187 functionally increases the therapeutic index of SNC80 and that a DOPr PAM could be a safer alternative to an orthosteric agonist as a novel treatment for depression. Support or Funding Information This project was partially funded by a PhRMA Foundation Starter Grant to EMJ and by NIH Grant DA035316 to JRT.