ReviewLigand-specific receptor states: Implications for opiate receptor signalling and regulation
Introduction
Opiates are among the most effective analgesics known and elective in the treatment of severe pain. However, clinical use of opiates is limited because they also produce nausea, vomiting, constipation, respiratory depression, and their chronic administration is associated with tolerance, physical dependence and addiction. Not surprisingly then a major goal in opiate research has been the development of analgesics devoid of such detrimental actions. Traditionally, efforts to improve the side effect profile of drugs acting via G protein coupled receptors (GPCRs) have profited from distinct anatomical distribution and/or specific pharmacological properties of different receptor subtypes. For example, mu-opioid receptor (MOR) stimulation causes analgesia that cannot be dissociated from typical side effects of opiates [1]. On the other hand, delta opioid receptor (DOR) stimulation produces antinociceptive actions [2], [3] with reduced respiratory depression [4], low constipation [5] and minimal potential for physical dependence [6], properties that made DORs a target of choice for the development of better tolerated analgesics. However, DOR selective agonists generally display lower analgesic efficacy than MOR agonists, may produce seizures [7] and their concomitant activation with MORs could potentiate tolerance and dependence mediated by the latter [8], [9]. Consequently, alternative approaches for the development of novel analgesics are constantly being sought.
Strategies that are gaining considerable attention are those that take advantage of allosteric properties of GPCRs and their ability to adopt active conformations [10], [11] that differ in their pharmacological, signalling [12], [13] and regulatory properties [14]. This conformational diversity may be explained at least in part by organization of GPCRs into multiprotein arrays where the conformational state of the receptor is dictated by its interactions with different complex components. Not all signalling arrays harbouring a specific type of receptor are necessarily equal since their composition is influenced by levels of expression of the interacting partners, their membrane compartmentalization [15] and by the presence of scaffolding proteins that “glue” the complex together [16]. Thus, ligands that preferentially recognize a receptor within a particular type of signalling array have the potential for circumscribing pharmacological actions to a specific subpopulation of receptors. For example, drugs that specifically recognize MORs or DORs in signalling complexes that are confined to pain circuits, could provide a valid approach for the production of analgesic opiates with fewer side effects [17], [18]. In a similar line of thought stabilization of a conformational subgroup capable of stimulating signalling pathways preferentially involved in antinociception could constitute another alternative for the production of better tolerated analgesics. Ligands capable of stabilizing opioid receptors in conformations poorly recognized by inactivating proteins have also been proposed as a means of developing longer acting analgesics [18], [19], [20]. The purpose of this review is to summarize evidence supporting the existence of multiple active conformations for MORs and DORs, and analyze to which extent information available supports the idea that ligand-specific receptor states provide a viable solution for the production of longer lasting, better tolerated opiate analgesics.
Section snippets
Multiple active states and signal transduction by opioid receptors
G protein signalling. Spectroscopic studies using purified receptors have established that numerous GPCRs undergo ligand-specific conformational changes [21], [22], [23]. In particular, plasmon-waveguide resonance (PWR) spectroscopy has demonstrated that purified DORs are stabilized in different conformations by agonists, inverse agonists or neutral antagonists [24], and also that conformations stabilized by different agonists are not the same [25]. Three different observations led to this last
Multiple active conformations and opiate tolerance
Tolerance is the progressive decrease in responsiveness to opiates following their repeated administration. Changes responsible for this adaptive response occur at different organizational levels within the central nervous system starting at opioid receptors and progressing through neuronal networks to eventually modify circuital function [31]. At the molecular level tolerance has been associated with the process of homologous desensitization, and more recently with G protein inactivation by
Conclusion
The existence of multiple active states adds unprecedented diversity to opioid receptor function and provides a new perspective for development of longer acting, better tolerated analgesics. Molecular evidence in favour of conformational diversity for opioid receptors is quite strong and provides solid support to the idea that therapeutic agents that target different signalling complexes with distinct signalling and regulatory proteins could eventually be developed. The challenge that remains
Acknowledgements
This work was supported by grants from Natural Sciences and Engineering council of Canada (Grant number 311997), and from the Canadian Institutes of Health Research (Grant number MOP-79432). GP is the recipient of a “Chercheur Bousier" award from “Fonds de recherche en santé du Québec”. EAL was the recipient of an award from “Groupe de Recherche Universitaire sur le Médicament" (Montréal, Canada) and is presently the recipient of a postdoctoral award from “Fonds de recherche en santé du Québec”.
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