美国斯克里普斯生物医学研究所Kirill A. Martemyanov和美国华盛顿大学医学院Brock Grill研究团队合作发现，Ptchd1通过胆固醇依赖的μ-阿片受体转运作用介导阿片耐受。该研究于2022年8月18日发表于国际一流学术期刊《自然—神经科学》杂志上。
他们在秀丽隐杆线虫中使用前向遗传筛选来无偏地鉴定调节阿片类药物耐受性的基因，并揭示了 PTR-25/Ptchd1 的作用。他们发现 PTR-25/Ptchd1 控制 μ-阿片受体转运，并且这些作用是由 PTR-25/Ptchd1 控制膜胆固醇含量的能力介导的。
电生理学研究表明，小鼠中 Ptchd1 的缺失降低了阿片类药物诱导的几个大脑区域和周围神经系统神经元的脱敏。缺乏 Ptchd1/PTR-25 的小鼠和秀丽隐杆线虫对阿片类药物的反应同样增强。Ptchd1 基因敲除小鼠无法产生镇痛耐受性，并大大减少了体细胞戒断。因此，他们提出 Ptchd1 在保护 μ-阿片受体免受过度刺激方面起着进化上保守的作用。
研究人员表示，反复接触阿片类药物会导致耐受性，这限制了它们的镇痛效用并造成过量和滥用。然而，支撑耐受性的分子机制尚不清楚。
附：英文原文
Title: Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking
Author: Maza, Nycole, Wang, Dandan, Kowalski, Cody, Stoveken, Hannah M., Dao, Maria, Sial, Omar K., Giles, Andrew C., Grill, Brock, Martemyanov, Kirill A.
Issue&Volume: 2022-08-18
Abstract: Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms underpinning tolerance are not well understood. Here, we used a forward genetic screen in Caenorhabditis elegans for unbiased identification of genes regulating opioid tolerance which revealed a role for PTR-25/Ptchd1. We found that PTR-25/Ptchd1 controls μ-opioid receptor trafficking and that these effects were mediated by the ability of PTR-25/Ptchd1 to control membrane cholesterol content. Electrophysiological studies showed that loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system. Mice and C. elegans lacking Ptchd1/PTR-25 display similarly augmented responses to opioids. Ptchd1 knockout mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal. Thus, we propose that Ptchd1 plays an evolutionarily conserved role in protecting the μ-opioid receptor against overstimulation.
DOI: 10.1038/s41593-022-01135-0
Source: https://www.nature.com/articles/s41593-022-01135-0
Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex
本期文章：《自然—神经科学》：Online/在线发表
