Positive allosteric modulation of the delta opioid receptor attenuates depression-like and pain-like behaviors but does not promote convulsions.

The delta opioid receptor (DOR) has been a focus of research for the treatment of depression and certain pain disorders. Unfortunately, clinical translation of delta opioid agonists to humans has proved challenging partly because of their propensity to cause convulsions at higher doses. The discovery that the DOR can be allosterically modulated has opened the possibility of developing compounds that may be able to produce some of the positive therapeutic effects, either as standalone treatments to enhance the action of endogenous opioid peptides or as sparing agents allowing the use of lower doses of DOR agonists, which could reduce the chance of inducing convulsions. BMS-986187 is a positive allosteric modulator of DOR. The behavioral effects of BMS-986187 related to depression and pain have not been investigated. In this study, we examined the impact of BMS-986187 on DOR-mediated antidepressant-like effects in the forced swim test, antinociceptive and antiallodynic actions and propensity to cause convulsions. BMS-986187 (1 mg/kg) showed antidepressant-like effects when administered alone, but did not produce convulsions. BMS-986187 (10 mg/kg) also enhanced the antinociceptive and antiallodynic effects of the standard DOR agonist SNC80, with only a very minor effect on SNC80-mediated convulsions. The results suggest the development of positive modulators of DOR for the management of pain and/or depression. SIGNIFICANCE STATEMENT: The delta opioid receptor (DOR) has been suggested as a target to treat depression and pain. However, agonists at this receptor can cause convulsions. This study demonstrates that a positive allosteric modulator of DOR administered alone reduces depression-like behaviors and, in combination with a DOR agonist, shows robust pain-relieving actions, without convulsive effects. This suggests a novel and safe treatment for depression and/or pain.