title: Multiple mechanisms underlying the long duration of action of thienorphine, a novel partial opioid agonist for the treatment of addiction.
abstract: OBJECTIVE
  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 [(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.
  
  
  RESULTS
  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.
  
  
  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.
authors: Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors: Gang
authors: G
authors: Yu
authors: Shu-Hui
authors: SH
authors: Li
authors: Meng-Xun
authors: MX
authors: Cui
authors: Ling-Di
authors: LD
authors: Yan
authors: Zheng
authors: Z
authors: Yong
authors: Pei-Lan
authors: PL
authors: Zhou
authors: Rui-Bin
authors: RB
authors: Su
authors: Ze-Hui
authors: ZH
authors: Gong
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009021:Morphine Dependence / Q000188:drug therapy*; D009119:Muscle Contraction / Q000187:drug effects; D009292:Narcotic Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D009292:Narcotic Antagonists; D011957:Receptors, Opioid; C512397:thienorphine; D014316:Tritium; D002047:Buprenorphine; D000109:Acetylcholine
keywords: Kinetics; Long duration of action; Opioid receptor; Surface receptor number; Thienorphine