Multiple Mechanisms Underlying the Long Duration of Action of Thienorphine, A Novel Partial Opioid Agonist for the Treatment of Addiction

摘要

Summary Aims 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. Methods The binding kinetics of [3H]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 . Results At 37°C, [3H]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. Conclusions 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.