Article

Ligand-directed signalling within the opioid receptor family

Semel Institute for Neuropsychiatry & Human Behavior, University of California Los Angeles, Los Angeles, CA, USA Shirley and Stefan Hatos Center for Neuropharmacology, UCLA, Los Angeles, CA, USA Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université de Strasbourg, Illkirch, France.
British Journal of Pharmacology (Impact Factor: 4.84). 06/2012; 167(5):960-9. DOI: 10.1111/j.1476-5381.2012.02075.x
Source: PubMed

ABSTRACT

The classic model of GPCR activation proposed that all agonists induce the same active receptor conformation. However, research over the last decade has shown that GPCRs exist in multiple conformations, and that agonists can stabilize different active states. The distinct receptor conformations induced by ligands result in distinct receptor-effector complexes, which produce varying levels of activation or inhibition of subsequent signalling cascades. This concept, referred to as ligand-directed signalling or biased agonism has important biological and therapeutic implications. Opioid receptors are G(i/o) GPCRs and regulate a number of important physiological functions, including pain, reward, mood, stress, gastrointestinal transport and respiration. A number of in vitro studies have shown biased agonism at the three opioid receptors (µ, δ and κ); however, in vivo consequences of this phenomenon have only recently been demonstrated. For the µ and δ opioid receptors, the majority of reported ligand selective behavioural effects are observed as differential adaptations to repeated drug administration. In terms of the κ opioid receptor, clear links between ligand-selective signalling events and specific in vivo responses have been recently characterized. Drugs for all three receptors are either already used or are being developed for clinical applications. There is clearly a need to better characterize the specific events that occur following agonist stimulation and how these relate to in vivo responses. This understanding could eventually lead to the development of tailor-made pharmacotherapies where advantageous drug effects can be selectively targeted over adverse effects.

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Available from: Monique Leana Smith, Apr 25, 2014
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    • "Biased agonism has been described in all three classical opioid receptors and has been reviewed recently (Pradhan et al. 2012). Opioid receptor biased agonist have been proven to be potential therapeutic drugs, for instance µ biased agonists are better analgesics with reduced abused liabilities, while δ and κ biased agonists are promising candidates for the treatment of pain and mood disorders (Pradhan et al. 2012). "
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    • "Receptor localization within the lipid rafts after agonist binding can promote G protein coupling or recruitment of other intracellular regulatory proteins [40,41]. Over the past years, increased attention has been drawn to the understanding of intracellular signaling pathways that mediate the therapeutic and/or adverse effects of opioid agonists acting at the MOP receptor [42-44]. In vitro and in vivo studies demonstrate that different opioids can initiate distinct cellular and physiological responses downstream of receptor activation [40,42]. "
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    • "However, a common feature of GPCRs is that a single receptor can interact with multiple endogenous and exogenous ligands, each of which may activate the receptor in different ways. For example, a large number of endogenous opioid neuropeptides as well as many different opiate drugs interact with opioid receptors, and different opioids and opiates result in divergent processes of receptor activation and regulation (9). Thus, the simplistic view of receptor activation and regulation has been revised by the appreciation that different agonists of the same receptor can result in distinct patterns of signaling and regulation. "
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