老化相关的阿片类药物增敏增加了其副反应的发生风险，限制了其在老年患者疼痛治疗中的应用，但具体机制不明。我们前期研究发现血脑屏障OATP1A2转运芬太尼，老化大鼠血脑屏障Oatp1a4表达上调，ALK5表达和血清TGF-β1水平下降。基于前期结果，结合某些病理条件下TGF-β1/ALK5信号可调控Oatp1a4表达，我们推测老化通过TGF-β1/ALK5信号上调血脑屏障Oatp1a4表达，导致老年脑对芬太尼敏感性增加。为此，本项目拟通过细胞和动物实验探索：血脑屏障Oatp1a4在芬太尼中枢转运和分布中的作用；老化对血脑屏障Oatp1a4表达和活性的影响及其与芬太尼增敏的关系；TGF-β1/ALK5通路调控老化中Oatp1a4表达的机制。阐明老年患者芬太尼增敏的生物学机制有助于老年患者芬太尼的精准用药。

Aging-related increased sensitivity to opioids raises the risk for adverse drug reaction and limits the use of opioids in pain treatment for elderly patients, but the mechanism of increased sensitivity to opioids remains unclear. Our previous studies have found that OATP1A2 expressed at the blood-brain barrier (BBB) was responsible for fentanyl transmembrane transportation. We also found increased Oatp1a4 expression at the BBB, a significant decrease in serum TGF-β1 level and decreased expression of ALK5 receptor at the BBB in aged rats. Based on above, and according to recent reports that TGF-β1/ALK5 could modulate the expression of Oatp1a4 under multiple pathological conditions, we hypothesize that aging up-regulates Oatp1a4 expression at the BBB via TGF-β1/ALK5 signal pathway, which leads to fentanyl increased sensitivity in aged brain. Through cell experiments and animal studies, the main research design in our program include: to investigate the role of Oatp1a4 in the transportation and distribution of fentanyl; to explore the effects of aging on the expression and activity of Oatp1a4 at the BBB and its relationship with increased sensitivity to fentanyl in aged brain; to make clear the role of TGF-β1/ALK5 signaling in Oatp1a4 expression during aging. Our study is supposed to shed light on the mechanism of increased fentanyl sensitivity in the elderly and facilitate the precision use of fentanyl in elderly patients.

本项目检测了OATP1A2对芬太尼的转运作用及其与芬太尼剂量个体差异的关系；探索了抑制RIPK1对慢性应激诱导的脑功能损伤的防治及其机制。发现：①在体外细胞中OATP1A2能直接转运芬太尼，其表达与芬太尼浓度正相关；②SLCO1A2 G550A和G553A基因（OATP1A2编码基因）在中国中西部人群中突变率很低，芬太尼镇痛剂量的个体差异可能与其无关；③抑制RIPK1显著减轻了慢性应激导致的认知功能损伤，同时抑制了脑内炎症和RIP1、NF-κB的表达，增加了神经元新生和AMPA受体表达。这些结果表明：OATP1A2能转运芬太尼，但与芬太尼剂量的个体差异关系不明显；RIPK1可能是慢性应激导致的认知功能损伤的防治靶点。