Beijing Institute of Pharmacology and Toxicology, Beijing, China.
CNS Neurosci Ther. 2014 Mar;20(3):282-8. doi: 10.1111/cns.12210. Epub 2013 Dec 16.
It is considered that a long-acting therapy would be advantageous in the treatment of addiction. In a search for novel buprenorphine analogues, thienorphine was demonstrated to be an extremely long-acting orally active partial opioid agonist. This study explored the mechanisms underlying the long-lasting effects of thienorphine.
The binding kinetics of [(3) H]thienorphine were measured in membrane preparations expressing cloned rat opioid receptors. Flow cytometric analysis was used to determine the effect of thienorphine on the surface opioid receptor number. The long-lasting effects of thienorphine were also confirmed at the tissue level and in vivo.
At 37°C, [(3) H]thienorphine showed rapid association with μ- and κ-opioid receptors, while its dissociation was sluggish and biphasic (K-1 = 0.21 min(-1) , K-2 = 0.0078 min(-1) for the μ-receptor; K-1 = 0.17 min(-1) , K-2 = 0.0042 min(-1) for the κ-receptor). Treatment with thienorphine for 24, 48, and 72 h downregulated surface μ-receptor in a dose- and time-dependent manner. The inhibitory effect of thienorphine on guinea pig ileum persisted for more than 120 min after prolonged washing. In vivo, thienorphine exhibited significant antagonism of morphine-induced antinociception for more than 7 days.
These results indicate that multiple factors, including persistent receptor occupation and enhanced receptor downregulation, may contribute to the long-lasting effects of thienorphine that would be beneficial for its application in addiction treatment.
长效治疗被认为在成瘾治疗中具有优势。在寻找新型丁丙诺啡类似物的过程中，噻吩诺啡被证明是一种具有超长作用的口服活性部分阿片类激动剂。本研究探讨了噻吩诺啡长效作用的潜在机制。
使用表达克隆大鼠阿片受体的膜制剂测量[3H]噻吩诺啡的结合动力学。流式细胞术分析用于确定噻吩诺啡对表面阿片受体数量的影响。噻吩诺啡的长效作用也在组织水平和体内得到了证实。
在 37°C 下，[3H]噻吩诺啡与μ-和κ-阿片受体快速结合，而其解离缓慢且呈双相（μ-受体的 K-1=0.21 min-1，K-2=0.0078 min-1；κ-受体的 K-1=0.17 min-1，K-2=0.0042 min-1）。噻吩诺啡处理 24、48 和 72 小时以剂量和时间依赖的方式下调表面μ-受体。噻吩诺啡对豚鼠回肠的抑制作用在长时间洗涤后持续超过 120 分钟。在体内，噻吩诺啡对吗啡引起的镇痛作用表现出显著的拮抗作用，持续时间超过 7 天。
这些结果表明，多种因素，包括持续的受体占据和增强的受体下调，可能有助于噻吩诺啡的长效作用，这对其在成瘾治疗中的应用是有益的。
