Furthering GPR171 as a novel pain target by assessing its abuse liability

Previous work from our lab showed a small-molecule ligand for the G protein-coupled receptor, GPR171, is capable of modulating morphine antinociception in mice. This suggests possible clinical use as a combination therapeutic with opioids, but side effects, such as reward modulation, must be assessed. Here we investigated this ligand, MS15203, further by asking whether it alters morphine reward. To investigate this question, we used in vivo conditioned place preference and ex vivo immunohistochemistry. For conditioned place preference (CPP), animals were injected with MS15203 alone or in combination with morphine on Days 2-9 and placed in an isolated compartment of a three-chamber CPP apparatus. On Day 1 and 10 animals were allowed to roam freely through the entirety of apparatus, time spent in each chamber was quantified using motion tracking software. CPP results show MS15203 alone does not cause aversion or preference for the drug-paired chamber. MS15203 when combined with morphine decreases time spent in the drug-paired chamber compared to morphine alone, but is not significant. To test whether MS15203 alters dopamine neuron function, neuronal activity was assessed within the ventral tegmental area of animals treated with MS15203 alone or with morphine. Thirty minutes following injection of the drugs, animals were transcardially perfused and brains were sliced coronally (50 µm). Slices of ventral tegmental area (VTA) were stained for cfos and tyrosine hydroxylase, and colocalization of the two antibodies were subsequently visualized and quantified. IHC results corroborate in vivo CPP results by showing similar cfos activation in the VTA for controls and MS15203 groups. Taken together, these results further the potential of GPR171 as an opioid antinociceptive enhancer that does not increase the abuse liabilities of opioids. NARSAD Young Investigator Award Brain and Behavior Research Foundation, 2017 – 2019.