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- Title
Ligand-Directed Trafficking of the δ-Opioid Receptor In Vivo: Two Paths Toward Analgesic Tolerance.
- Authors
Pradhan, Amynah A. A.; Walwyn, Wendy; Nozaki, Chihiro; Filliol, Dominique; Erbs, Eric; Matifas, Audrey; Evans, Christopher; Kieffer, Brigitte L.
- Abstract
α-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 α-opioid receptor, at both the cellular and behavioral level. We used agonists with similar binding and analgesic properties, but high [SNC8O ((+ )-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide)]or low [ARM39O (N,N-diethyl-4-(phenyl-piperidin-4-ylidenemethyl)benzamide)]-internalization potencies. As we found previously, a single SNC8O but not ARM39O -administration triggered acute desensitization of the analgesic response in mice. However, daily injections of either compound over 5 d produced full analgesic tolerance. SNC8O-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, ARM39Otolerant mice showed intact receptor expression, but α-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 α-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of biased agonism in vivo.
- Subjects
OPIOID receptors; LIGANDS (Biochemistry); BENZAMIDE; GANGLIA; LABORATORY mice
- Publication
Journal of Neuroscience, 2010, Vol 30, Issue 49, p16459
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3748-10.2010