Discriminative Stimulus and Low Abuse Liability Effects of Novel Endomorphin Analogs Suggest a Potential Treatment Indication for Opioid Use Disorder

Opioid dependence can be difficult to manage with existing pharmacotherapies. A long-acting opioid with low abuse liability that substitutes for a shorter acting opioid may improve treatment for opioid use disorders (OUD). We recently characterized an endomorphin (EM) analog (ZH853/analog 4) that produced a longer duration of antinociception compared to morphine, but did not produce self-administrations or several other adverse effects preclinically. Here, we further characterized this analog in tests of antinociception, abuse liability, and drug discrimination. A conditioned place preference (CPP) procedure that included a locomotor activity assessment was used to test abuse liability in rats. Subsequently, dopamine (DA) cell-somas located in the ventral tegmental area (VTA) from these rats were assessed by size using immunohistochemistry and Stereo Investigator software. A hot plate antinociception test in male and female mice confirmed central penetration. Morphine-substitution effects of several EM analogs were tested in a drug discrimination (DD) procedure in rats. Morphine produced dose-dependent CPP, locomotor sensitization, and reduced the size of DA cell somas in VTA, while analog 4 did not produce any of these effects relative to control. The antinociceptive effects of analog 4 were mu-receptor selective, since β-funaltrexamine antagonized these effects. Rats responded on a morphine-trained lever when injected with analogs 2 and 4 during DD experiments. The favorable morphine-substitution effects of these EM analogs relative to their low abuse liability indicate promising novel compounds that may improve treatment for OUD. SIGNIFICANCE STATEMENT The present experiment investigated the preclinical effects of novel endomorphin analogs for use as substitution therapies for opioid use disorder, a problem that has contributed to an opioid overdose epidemic. Several endomorphin analogs were shown to substitute for morphine without producing adverse effects including reward behaviors associated with abuse liability. These compounds have potential to become important additional tools to treat opioid use disorders.