Sialorphin potentiates effects of opioid peptide without toxicity as alosteric modulator

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08869
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55050:Anesthesiology-related
• Research Institution: Tokai University
• Principal Investigator: KAN Takugi 東海大学, 医学部, 助教 (60580256)
• Co-Investigator(Kenkyū-buntansha): 吉川 正信 東海大学, 医学部, 准教授 (90276791)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: シアロルフィン / オピオイド受容体 / 鎮痛 / アロステリックモデュレーター

Outline of Final Research Achievements

Differences were compared among combinations of three chemical peptidase inhibitors (amastatin, captopril, and phosphoramidon). The ratio of potencies of methionine enkephalin (ME) in mouse vas deferens pretreated with both sialorphin and a mixture of the three peptidase inhibitors (PIs) was higher than that with the mixture of peptidase inhibitors alone at any dose. Intrathecal administration both sialorphin and the mixture of three PIs produced an approximately 100-fold augmentation in ME-induced antinociception, but without signs of toxicity such as motor dysfunction in rats. Radioligand receptor binding assay revealed that sialorphin did not affect either binding affinity or maximal binding capacity of DAMGO. These results indicate that sialorphin potentiates the effects of ME without toxicity by a mechanism other than peptidase inhibition and with no effect on its affinity to mu-opioid receptors.

Free Research Field

麻酔科学

Academic Significance and Societal Importance of the Research Achievements

本研究結果よりシアロルフィンにはμオピオイド受容体の結合親和性に影響せずに、μオピオイド受容体の内活性を増強し、内因性オピオイオドペプチドの効力を増強する機能を有することが示唆された。 すなわち、シアロルフィンのようなオピオイド受容体アロステリックモジュレーターを用いることで、オピオイドの鎮痛効果増強→オピオイド使用量減量→オピオイドの有害作用を軽減→オピオイドを長期間安全に使用が可能、という新たな慢性疼痛治療法を創出できると考える。