Biased agonism at kappa opioid receptors: Implication in pain and mood disorders
Introduction
The G Protein Coupled Receptors (GPCRs) are the largest receptor class in the human genome (Allen and Roth, 2011), and known to modulate almost every human physiological function. Due to being involved in such diverse physiological processes, GPCRs are the most frequently targeted receptor class for therapeutic interventions (Ma and Zemmel, 2002). However, the development of GPCR selective drugs is challenging due to following reasons: 1—high degree of homology among many receptors which regulates diverse physiologic functions; 2—one GPCR may couple to more than one type of G proteins; 3—allosteric modulation of receptor signalling via biophysical interactions with small molecules and other proteins present in the microenvironment. Thus, the predominant signalling pattern of a GPCR may differ from cell to cell in various tissues and organs.
Classically, drug development programs targeting GPCRs have focused on the concepts of agonism and antagonism of one receptor target, in which a ligand (agonist or antagonist) upon binding the receptor, stabilizes it in one conformation and dictates the same nature of the downstream effector signalling, and thus ligand efficacy in most of the systems. However, over the last decade, the emerging concept of “biased agonism”, also called as “functional selectivity” have revealed that the nature of GPCR signalling is not so rigid (Kenakin, 1995) and that ligand structure can direct (bias) signal output by stabilizing active receptor states in different proportions than the endogenous ligand. Thus, a biased or a functionally selective ligand is a novel chemical entity that holds the unique ability to qualitatively guide GPCR signalling, leading to distinct efficacy profile determined by ligand structure. Actually, the classical models of allosterism had already predicted the existence of multiple conformational states in the absence of ligand as a fundamental characteristic of allosteric proteins (Monod et al., 1965). The recently solved GPCRs structure support this previous theoretical notion that GPCRs exist in several micro-conformations and different ligands can stabilize different conformations favouring distinct signalling profiles (Deupi and Kobilka, 2010, Wacker et al., 2013). Furthermore, receptor interacting proteins, such as β-arrestins and G proteins, can allosterically modulate agonist binding affinity and therefore receptor conformations (Nygaard et al., 2013). Thus, bidirectional modulation of receptor conformation from both the ligand and interacting proteins regulate final outcome-physiological/pharmacological response. Finally, the promise of “biased agonism” lies in its ability to produce therapeutically beneficial signals while minimizing adverse effects. Due to the prevailing notion in the field that “biased agonists” might have superior therapeutic benefits, effort for many GPCR targets for drug discovery and developments have been revitalized.
Opioids have been used since ancient times for the treatment of pain and other human ailments (Brownstein, 1993), and are still the most effective and widely used analgesics. Most of the opioid analgesics are agonists of the mu (µ), delta (δ) and kappa (κ) opioid receptors (also known as µ receptor, δ receptor, and k receptor, respectively). Opioid receptors are activated by a family of endogenous peptides to inhibit neuronal activity as they are coupled with inhibitory G proteins (Gαi/o) in physiological conditions. Although opioid receptors are the most widely known therapeutic targets for the treatment of acute as well as chronic pain conditions, their clinical use is constrained by adverse side effects, such as development of tolerance and addiction (Williams et al., 2013). Therefore, improving the side effect profile and reducing the development of analgesic tolerance have remained major goals in the opioid receptor field. The k receptor belongs to the opioid system, a neuromodulatory system that is widely expressed throughout the central and peripheral nervous systems. Among opioid peptides, dynorphins (encoded by the Pdyn gene) primarily activate the k receptor and have very low affinity for µ or δ receptor. On the other hand, the other opioid peptides—endorphin and enkephalins, exhibit very low affinity with k receptor. Therefore, the dynorphin/k receptor signalling pathway forms a distinct process within the opioid system (Chavkin et al., 1982, Goldstein et al., 1979). In contrast to µ receptor and δ receptor agonists, k receptor agonists have long been recognized to be analgesics with no addiction and tolerance liability. However, almost all k receptor agonists cause dysphoria, anhedonia, and hallucinations (Carlezon et al., 1998, Pfeiffer et al., 1986, Roth et al., 2002). The present review is mainly focused on various lines of evidence that indicate different ligands of k receptor as “biased”, and their potential implications in mood and pain disorders.
Section snippets
Biased agonism at k receptor
The dynorphin/k receptor system is implicated in several psychiatric conditions such as depression, anxiety, drug addiction and schizophrenia (Bruchas et al., 2011, Schindler et al., 2012, Tejeda et al., 2013). High levels of k receptor expression were observed using the human genomic sequence analysis and RT-PCR technology in almost all regions of the human and rodent brain (ventral tegmental area, prefrontal cortex, claustrum, hippocampus, striatum, amygdala, locus coeruleus, dorsal raphe,
Quantification of “Bias”: challenges and limitations
Even though biased agonism offers the potential of better therapeutics, there are several limitations for its detection, quantification and translation into various physiological responses. The observations of ligand-specific activation of different effector system or second messenger system, were originally made in the 1980s (Gee and Yamamura, 1983). However, only in the last one decade this has become an established dimension of GPCR signaling (Reiter et al., 2012). Most of the studies, until
Implication of k receptor biased agonism in mood disorders
Despite decades of extensive research, the molecular and cellular mechanisms of mood disorders remain unclear. Research on mood and affective states had mainly focused on the roles of brain systems containing monoamines, such as dopamine (DA), norepinephrine (NE), and serotonin (5-hydroxytryptamine [5HT]) (Di Chiara and Imperato, 1988, Koch et al., 2002, Ritz et al., 1987). Although, historically opioids have received far less interest than monoamine systems, essential role of endogenous opioid
Implication of k receptor biased agonism in pain disorders
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Peripheral nerve injury elicits abnormal pain characterized by allodynia, where generally non-noxious stimuli (mild warming, cooling or touch) induces pain, and hyperalgesia, where noxious stimuli (skin heating, cooling or strong mechanical stimuli) are perceived as more painful (Wang et al., 2001). Allodynia and hyperalgesia experienced in neuropathic
Concluding remarks
In the present review, we have highlighted the accumulating evidences supporting the role of k receptor/dynorphin system in mood and pain processing. We have also described how k receptor is perfectly positioned to effectively modulate several psychiatric and pain disorders. Previously, major aspirations in the GPCR field had been to identify distinct signalling pathways that may operate to control specific behavioural responses. Future studies using ¯ receptor ligands should combine
Acknowledgments
The authors thank Mrs Deepmala and Mrs. Swati N. Yadav for critically reading this manuscript and the Department of Science and Technology (Govt of India) for research grant (Ramanujan Fellowship to PNY) and University Grant commission of India for Fellowship (JRF and SRF to SD).
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