Dept. of Biology, Utah State University, 5305 Old Main Hill BNR117, Logan, UT 84322-5305, United States of America; Interdisciplinary Neuroscience Program, Utah State University, 5305 Old Main Hill BNR117, Logan, UT 84322-5305, United States of America.
Dept. of Biology, Utah State University, 5305 Old Main Hill BNR117, Logan, UT 84322-5305, United States of America.
Pharmacol Biochem Behav. 2023 Mar;224:173543. doi: 10.1016/j.pbb.2023.173543. Epub 2023 Mar 17.
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 and was evaluated 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. The results of a conditioned place preference experiment showed that treatment with MS15203 produced no place preference 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.
ProSAAS 是大脑中含量最丰富的蛋白质之一，可被加工成几种较小的肽。其中一种，BigLEN，是 G 蛋白偶联受体 GPR171 的内源性配体。最近在啮齿动物模型中的研究表明，GPR171 的小分子配体 MS15203 可增强吗啡的镇痛作用，并有效减轻慢性疼痛。虽然这些研究为 GPR171 作为潜在的疼痛靶点提供了证据，但它的滥用倾向尚未得到评估，本研究对此进行了评估。我们首先使用免疫组织化学方法绘制了整个大脑奖励回路中 GPR171 和 ProSAAS 的分布图谱，结果表明 GPR171 和 ProSAAS 定位于海马体、基底外侧杏仁核、伏隔核、前额叶皮层。在主要的多巴胺能结构中，腹侧被盖区（VTA）中，GPR171 似乎主要定位于多巴胺神经元，而 ProSAAS 则位于多巴胺神经元之外。接着，将 MS15203 给予有或没有吗啡的小鼠，并对 VTA 切片进行即时早期基因 c-Fos 的染色，作为神经元激活的标志物。对 c-Fos 阳性细胞的定量分析显示，MS15203 与生理盐水之间无统计学差异，表明 MS15203 不会增加 VTA 激活和多巴胺释放。条件性位置偏好实验的结果表明，MS15203 治疗并未产生位置偏好，表明其缺乏与奖励相关的行为。综合这些数据表明，新型疼痛治疗药物 MS15203 的奖赏相关性很小。因此，GPR171 作为疼痛靶点值得进一步探索。意义：先前研究表明，激活 GPR171 受体的药物 MS15203 可增加吗啡的镇痛作用。作者使用体内和组织学技术表明，它不能激活啮齿动物的奖励回路，为将 MS15203 作为新型疼痛药物和 GPR171 作为新型疼痛靶点继续探索提供了支持。
