PT  - JOURNAL ARTICLE
AU  - Max V. McDermott
AU  - Akila Ram
AU  - Matt T. Mattoon
AU  - Emmaline E. Haderlie
AU  - Megan C. Raddatz
AU  - Madi K. Thomason
AU  - Erin N. Bobeck
TI  - A small molecule ligand for the novel pain target GPR171 produces minimal reward in mice
AID  - 10.1101/2022.07.05.498847
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.05.498847
4099  - http://biorxiv.org/content/early/2022/07/05/2022.07.05.498847.short
4100  - http://biorxiv.org/content/early/2022/07/05/2022.07.05.498847.full
AB  - ProSAAS is one of the most abundant proteins in the brain and is processed into several smaller peptides. One of which, BigLEN, is an endogenous ligand for the G protein-coupled receptor, GPR171. Recent work in rodent models has shown that a small-molecule ligand for GPR171, MS15203, increases morphine antinociception and is effective in lessening chronic pain. While these studies provide evidence for GPR171 as a possible pain target, its abuse liability has not yet been assessed which we evaluate in the current study. We first mapped the distribution of GPR171 and ProSAAS throughout the reward circuit of the brain using immunohistochemistry and showed that GPR171 and ProSAAS are localized in the hippocampus, basolateral amygdala, nucleus accumbens, prefrontal cortex. In the major dopaminergic structure, the ventral tegmental area (VTA), GPR171 appeared to be primarily localized in dopamine neurons while ProSAAS is outside of dopamine neurons. Next, MS15203 was administered to mice with or without morphine, and VTA slices were stained for the immediate early gene c-Fos as a marker of neuronal activation. Quantification of c-Fos-positive cells revealed no statistical difference between MS15203 and saline, suggesting that MS15203 does not increase VTA activation and dopamine release. Similarly, the results of a conditioned place preference experiment showed that treatment with MS15203 or MS15203 + Morphine produced no place preference compared to Saline indicating a lack of reward-related behavior. Taken together this data provides evidence that the novel pain therapeutic, MS15203, has minimal reward liability. Therefore, GPR171 deserves further exploration as a pain target.Significance Statement MS15203, a drug that activates the receptor GPR171, was previously shown to increase morphine analgesia. The authors use in vivo and histological techniques to show that it fails to activate the rodent reward circuitry, providing support for the continued exploration of MS15203 as a novel pain drug, and GPR171 a novel pain target.Competing Interest StatementThe authors have declared no competing interest.BLABasolateral AmygdalaCPPConditioned Place PreferenceHPCHippocampusNAcNucleus AccumbensPFCPrefrontal CortexTHTyrosine HydroxylaseVTAVentral Tegmental Area