Multiple mechanisms underlying the long duration of action of thienorphine, a novel partial opioid agonist for the treatment of addiction.
CNS Neurosci Ther
; 20(3): 282-8, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24330593
ABSTRACT
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 [(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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Buprenorfina
/
Dependência de Morfina
/
Antagonistas de Entorpecentes
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
CNS Neurosci Ther
Assunto da revista:
NEUROLOGIA
/
TERAPEUTICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
China