Ligand-directed trafficking of the δ-opioid receptor in vivo: Two paths toward analgesic tolerance

Amynah A.A. Pradhan, Wendy Walwyn, Chihiro Nozaki, Dominique Filliol, Eric Erbs, Audrey Matifas, Christopher Evans, Brigitte L. Kieffer

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91 Citations (Scopus)

Abstract

δ-Opioid receptors are G-protein-coupled receptors that regulate nociceptive and emotional responses. It has been well established that distinct agonists acting at the same G-protein-coupled receptor can engage different signaling or regulatory responses. This concept, known as biased agonism, has important biological and therapeutic implications. Ligand-biased responses are well described in cellular models, however, demonstrating the physiological relevance of biased agonism in vivo remains a major challenge. The aim of this study was to investigate the long-term consequences of ligand-biased trafficking of the δ-opioid receptor, at both the cellular and behavioral level. We used δ agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)- 3-methoxybenzyl]-N,N-diethylbenzamide)]- or low [ARM390 (N,N-diethyl-4-(phenyl- piperidin-4-ylidenemethyl)-benzamide)]-internalization potencies. As we found previously, a single SNC80 - but not ARM390 - administration triggered acute desensitization of the analgesic response in mice. However, daily injections of eithercompoundover 5 d produced full analgesic tolerance. SNC80-tolerant animals showed widespread receptor downregulation, and tolerance to analgesic, locomotor and anxiolytic effects of the agonist. Hence, internalization- dependent tolerance developed, as a result of generalized receptor degradation. In contrast, ARM390-tolerant mice showed intact receptor expression, but δ-opioid receptor coupling to Ca2+ channels was abolished in dorsal root ganglia. Concomitantly, tolerance developed for agonist-induced analgesia, but not locomotor or anxiolytic responses. Therefore, internalization-independent tolerance was produced by anatomically restricted adaptations leading to pain-specific tolerance. Hence, ligand-directed receptor trafficking of the δ-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of biased agonism in vivo.

Original languageEnglish
Pages (from-to)16459-16468
Number of pages10
JournalJournal of Neuroscience
Volume30
Issue number49
DOIs
Publication statusPublished - 2010 Dec 8

ASJC Scopus subject areas

  • Neuroscience(all)

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    Pradhan, A. A. A., Walwyn, W., Nozaki, C., Filliol, D., Erbs, E., Matifas, A., Evans, C., & Kieffer, B. L. (2010). Ligand-directed trafficking of the δ-opioid receptor in vivo: Two paths toward analgesic tolerance. Journal of Neuroscience, 30(49), 16459-16468. https://doi.org/10.1523/JNEUROSCI.3748-10.2010