In vitro and in vivo pharmacological profile of UFP-512, a novel selective δ-opioid receptor agonist; correlations between desensitization and tolerance

B. Aguila, L. Coulbault, M. Boulouard, F. Liveilli, A. Davis, G. Toth, A. Borsodi, G. Balboni, S. Salvadori, P. Jauzac, S. Allouche

Research output: Article

25 Citations (Scopus)

Abstract

Background and purpose: δ-Opioid receptors (DOP receptors) could represent a novel target in the treatment of depressive disorders. To explore this new field of interest, the development of highly selective DOP receptor agonists is essential. UFP-512 [H-Dmt-Tic-NH-CH(CH 2-COOH)-Bid], was recently shown to behave in vitro as a selective and potent DOP receptor agonist and to promote antidepressant- and anxiolytic-like effects in vivo (Vergura et al., 2007). Here, we have characterized the pharmacological properties of UFP-512 and established a link between desensitization and tolerance. Experimental approach: Studies were performed in the human neuroblastoma SK-N-BE cells to establish i) binding parameters for UFP-512 ii) signalling pathways activated after acute and chronic treatment iii) regulation (phosphorylation and trafficking) of human DOP (hDOP) receptors after sustained activation by UFP-512. In vivo, we studied UFP-512-induced antidepressant-like effects after acute or chronic treatment in the mouse forced swimming test. Key results: In vitro, UFP-512 was a high affinity agonist for DOP receptors. While UFP-512 induced marked phosphorylation of DOP receptors on Ser 363, we observed a low desensitization of the cAMP pathway, associated with receptor endocytosis and recycling without any reduction on extracellular signal-regulated protein kinase 1/2 activation. In vivo, acute administration of UFP-512 produced an antidepressant-like effect, without any sign of tolerance after chronic administration. Conclusions and implications: There was a correlation between weak desensitization, significant internalization and recycling of the human DOP receptors and lack of tolerance to UFP-512. This suggests that this compound would be a promising drug prototype for exploring innovative treatments for mood disorders.

Original languageEnglish
Pages (from-to)1312-1324
Number of pages13
JournalBritish journal of pharmacology
Volume152
Issue number8
DOIs
Publication statusPublished - dec. 1 2007

ASJC Scopus subject areas

  • Pharmacology

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    Aguila, B., Coulbault, L., Boulouard, M., Liveilli, F., Davis, A., Toth, G., Borsodi, A., Balboni, G., Salvadori, S., Jauzac, P., & Allouche, S. (2007). In vitro and in vivo pharmacological profile of UFP-512, a novel selective δ-opioid receptor agonist; correlations between desensitization and tolerance. British journal of pharmacology, 152(8), 1312-1324. https://doi.org/10.1038/sj.bjp.0707497