Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA.
Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
Life Sci. 2024 May 15;345:122580. doi: 10.1016/j.lfs.2024.122580. Epub 2024 Mar 19.
Substance use disorder (SUD) affects over 48 million Americans aged 12 and over. Thus, identifying novel chemicals contributing to SUD will be critical for developing efficient prevention and mitigation strategies. Considering the complexity of the actions and effects of these substances on human behavior, a high-throughput platform using a living organism is ideal. We developed a quick and easy screening assay using Caenorhabditis elegans. C. elegans prefers high-quality food (Escherichia coli HB101) over low-quality food (Bacillus megaterium), with a food preference index of approximately 0.2, defined as the difference in the number of worms at E. coli HB101 and B. megaterium over the total worm number. The food preference index was significantly increased by loperamide, a μ-opioid receptor (MOPR) agonist, and decreased by naloxone, a MOPR antagonist. These changes depended on npr-17, a C. elegans homolog of opioid receptors. In addition, the food preference index was significantly increased by arachidonyl-2'-chloroethylamide, a cannabinoid 1 receptor (CB1R) agonist, and decreased by rimonabant, a CB1R inverse agonist. These changes depended on npr-19, a homolog of CB1R. These results suggest that the conserved opioid and endocannabinoid systems modulate the food preference behaviors of C. elegans. Finally, the humanoid C. elegans strains where npr-17 was replaced with human MOPR and where npr-19 was replaced with human CB1R phenocopied the changes in food preference by the drug treatment. Together, the current results show that this method can be used to rapidly screen the potential effectors of MOPR and CB1R to yield results highly translatable to humans.
物质使用障碍（SUD）影响着超过 4800 万 12 岁及以上的美国人。因此，鉴定导致 SUD 的新型化学物质对于开发有效的预防和缓解策略至关重要。考虑到这些物质对人类行为的作用和影响的复杂性，使用活体生物的高通量平台是理想的。我们使用秀丽隐杆线虫（C. elegans）开发了一种快速简便的筛选测定法。秀丽隐杆线虫更喜欢高质量的食物（大肠杆菌 HB101）而不是低质量的食物（巨大芽孢杆菌），食物偏好指数约为 0.2，定义为大肠杆菌 HB101 和巨大芽孢杆菌的线虫数量与总线虫数量之差。洛哌丁胺（一种 μ-阿片受体（MOPR）激动剂）显著增加了食物偏好指数，纳洛酮（一种 MOPR 拮抗剂）则降低了食物偏好指数。这些变化取决于秀丽隐杆线虫阿片受体的同源物 npr-17。此外，花生四烯酰-2'-氯乙酰胺（一种大麻素 1 型受体（CB1R）激动剂）显著增加了食物偏好指数，利莫那班（一种 CB1R 反向激动剂）则降低了食物偏好指数。这些变化取决于 CB1R 的同源物 npr-19。这些结果表明，保守的阿片类和内源性大麻素系统调节秀丽隐杆线虫的食物偏好行为。最后，将 npr-17 替换为人 MOPR 的类人秀丽隐杆线虫菌株和将 npr-19 替换为人 CB1R 的类人秀丽隐杆线虫菌株复制了药物处理引起的食物偏好变化。总之，目前的结果表明，该方法可用于快速筛选 MOPR 和 CB1R 的潜在效应物，从而获得高度可转化为人类的结果。
