期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 49, 页码 16459-16468出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3748-10.2010
关键词
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资金
- Centre National de la Recherche Scientifique, Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Strasbourg
- French Agence Nationale de la Recherche
- U.S. National Institutes of Health-National Institute on Drug Abuse [DA05010]
- Stefan and Shirley Hatos Research Foundation
- INSERM-Fonds de la Recherche en Sante Quebec
- Fondation pour la Recherche Medicale
delta-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 delta-opioid receptor, at both the cellular and behavioral level. We used delta agonists with similar binding and analgesic properties, but high [SNC80 ((+)-4-[(alpha R)-alpha-((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 either compound over 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 delta-opioid receptor coupling to Ca(2+) 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 delta-opioid receptor engages distinct adaptive responses, and this study reveals a novel aspect of biased agonism in vivo.
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