European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Biased agonism at kappa opioid receptors: Implication in pain and mood disorders Shalini Dogra, Prem N. Yadav n Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India

art ic l e i nf o

a b s t r a c t

Article history: Received 9 February 2015 Received in revised form 18 June 2015 Accepted 7 July 2015

The kappa opioid receptor (k receptor) and its endogenous ligand dynorphin have received significant attention due to their involvement in pathophysiology of mood disorders, drug addiction, psychotic disorders and pain. Multiple lines of evidences suggest that the k receptor modulates overlapping neurocircuits connecting brainstem monoaminergic nuclei with forebrain limbic structures and thereby regulates neurobiological effects of stress and psychostimulants. The emerging concept of “biased agonism” (also known as functional selectivity) for G Protein Coupled Receptor (GPCR) ligands have provided new insights into overall response generated by a ligand, which could be exploited for drug discovery. According to this concept, every ligand possesses the unique ability (coded in its structure) that dictates distinct signalling pattern, and consequently beneficial or adverse response. Although still a long way to comprehend the clinical potential of biased GPCR ligands, such ligand could be vital pharmacological probes. This article highlights various lines of evidence, which indicates different ligands of k receptor as “biased”, and their potential implications in mood and pain disorders. & 2015 Published by Elsevier B.V.

Keywords: Biased agonism Opioid receptor Kappa opioid receptor Dynorphin Mood disorders

1. 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 n Correspondence to: Division of Pharmacology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, UP 226031, India. E-mail address: [email protected] (P.N. Yadav).

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 microconformations 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.

http://dx.doi.org/10.1016/j.ejphar.2015.07.018 0014-2999/& 2015 Published by Elsevier B.V.

Please cite this article as: Dogra, S., Yadav, P.N., Biased agonism at kappa opioid receptors: Implication in pain and mood disorders. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.07.018i

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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 (m), delta (δ) and kappa (κ) opioid receptors (also known as m 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 m 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 m 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.

2. 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, and hypothalamus) involved in the modulation of reward, mood, cognition, and perception (Arvidsson et al., 1995; Leitl et al., 2014; Simonin et al., 1995). Dysfunction of the reward circuitry is a well known cause of many psychiatric disorders, including depression and addiction (Navratilova and Porreca, 2014). Moreover, emerging evidence from the investigation of pain processing and reward (pleasure) processing circuitry suggests extensive similarities in the anatomical substrates of painful and pleasant sensations (Leknes and Tracey, 2008). Interestingly but not surprising (given the well recognized effects of opioids), opioid receptors are highly enriched in neurons that modulate reward and pain. Several groups have demonstrated that in contrast to other opioid receptors' agonists, k receptor agonists, including the endogenous ligand dynorphin A(1–17), inhibit dopamine efflux in mesolimbic system, and also block the rewarding effects of drugs of abuse like heroin and cocaine (Di Chiara and Imperato, 1988; Narita et al., 2001; Spanagel et al., 1990). Further, k receptor agonists have also been shown to inhibit hyperalgesia induced by chronic m receptor agonists (Meng et al., 2005). Therefore, identifying biased k receptor agonists with extreme signaling bias will help in characterizing a signaling pathway for therapeutic efficacy or adverse effects (Allen et al., 2011; White et al., 2015). Most of the k receptor agonists belong to five chemical classes: the endogenous peptides

(dynorphins), benzodiazepines (Diazepam, tifluadom), benzazociness (Bremazocines, Pentazocine), arylacetamides (Enadoline, U50488), and diterpenes (salvinorin A). The benzazocines, such as bremazocine, are not very selective k receptor agonists but show strong analgesic effects. However, these molecules were dropped from clinical development due to psychotomimetic and dysphoric effects (Dortch-Carnes and Potter, 2005), even though they had low potential for drug tolerance and dependence. Earlier, it was generally believed that k receptor agonists show adverse effects due to off-targets, and therefore new class of selective k receptor agonists, the arylacetamide derivatives (Enadolines, U69593, U50488), were developed to evade psychotomimetic and dysphoric effects. However, this class of compounds were also shown to produce hallucinations and aversion (Land et al., 2009; Robles et al., 2014). Salvinorin A, a highly potent and selective k receptor agonist with no considerable affinity for any other known receptor, is widely known for its psychedelic effects (Roth et al., 2002). Despite of such diverse structure/chemical scaffold and decades of research on mechanism of k receptor signaling, all k receptor agonists have more or less some psychotomimetic effects and therefore failed clinical development. Not surprising though, given the wide expression of k receptor in multiple brain regions (cortex, striatum, VTA, hippocampus, amygdala) and cell types (serotonergic neurons in raphe, dopaminergic neurons in VTA and nor-adrenergic neurons in locus coeruleus), simultaneous inhibition of multiple neurotransmitter systems by k receptor agonist could result in complex multidimensional effects such as hallucination, dysphoria and analgesia. The endogenous ligands of k receptor, dynorphins, are released during stress and produce behavioural correlates of dysphoria, depression and anxiety, effects that have been coupled to addiction and drug relapse (Bruchas et al., 2010). Moreover, agonist induced G protein receptor kinase 3 (GRK3) phosphorylation of k receptor (in C-terminal region) and consequent recruitment of βarrestins, which are scaffolding proteins (moonlighting proteins would be a more appropriate term as arrestins are emerging as multifunctional proteins), leads to p38 MAPK phosphorylation (Bruchas et al., 2006; McLaughlin et al., 2003). The identification of G-protein independent activation of p38 MAPK in serotonergic neurons of dorsal raphe by k receptor agonist U50488, thereby inducing dysphoria (Bruchas et al., 2007a, 2006 2011), was a major step towards elucidation of underlying mechanisms of k receptor mediated adverse effects. Interference of this signaling pathway in mice via receptor mutation (KORS369A) or GRK3 deletion or conditional deletion of p38-MAPK blocks the aversive effects of k receptor agonists without reducing their analgesic effects (Pradhan et al., 2012). These studies have important therapeutic implications because a selective partial k receptor agonist that does not efficiently activate arrestin-dependent signaling might produce analgesia without significant dysphoria (Schattauer et al., 2012). Such system bias (although purported as “Biased Agonism”, but no systematic analysis were made in these studies to support the notion of U50488 is a biased agonist), where one ligand preferentially activates one type of signaling pathway, has also been demonstrated for other receptor systems (Berg et al., 1998; Whistler et al., 1999), including m receptor. m receptor agonist fentanyl effectively causes receptor internalization, but morphine does not; even though both are potent analgesics (Keith et al., 1998). In addition, k receptor mediated activation of the p38 MAPK pathway in glia also appears to be important for the development of hyperalgesia following peripheral neuropathy (Xu et al., 2007). Clearly, these findings imply that the development of k receptor agonists that only activate G-protein-dependent signaling may produce analgesia without dysphoric effects. Although no such k receptor ligand existed until recently, where Roth and colleagues (White et al., 2015, 2014; Yan et al., 2009) performed elegant and

Please cite this article as: Dogra, S., Yadav, P.N., Biased agonism at kappa opioid receptors: Implication in pain and mood disorders. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.07.018i

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systematic pharmacological studies to discover a G protein-biased k receptor agonist, RB-64 (22-thiocyanatosalvinorin A). This study, using wild type and β-arrestin-2 KO mice, showed the evidence that RB-64 mediated G protein signalling induces analgesia and aversion, whereas β-arrestin-2 signalling mediates sedation, anhedonia and motor incoordination. This is a clear example of how the characterization of the signaling pathways, that mediate specific behaviors, may ultimately be used to tailor drug development. So far, almost all the studies for determining biased agonism at a given GPCR have investigated the biasness of a ligand for either G-protein or β-arrestin dependent downstream signaling only. However, it is quite possible that a ligand might stabilize a receptor conformation that favors receptor phosphorylation more by protein kinase C isoforms than GRK isoforms, which could ultimately affect overall salutary and adverse effects. Thus, to determine the true biasness of a ligand, several proximal signaling readouts (e.g., PKC or GRKs dependent receptor phosphorylation) are a prerequisite (this aspect is further discussed in more detail in the following section).

3. 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 recently, on biased agonism have used largely qualitative observations, such as reversals in agonist potency orders or maximal agonist response between two different pathways, as indicators of biased agonism. However, such approaches are flawed. The observed response of an agonist in a given pathway is not only the result of a unique ligand-induced receptor conformation, rather it is affected by microenvironment or “system bias”, which reflects the differing coupling efficiencies of the receptor to a given signaling pathway, and also by biased observations arising from differing assay setup and sensitivity (Kenakin and Christopoulos, 2013b). One should objectively measure the bias imposed only by the ligand on the receptor, which can then be chemically optimized to improve the therapeutic profile of a drug. Therefore, it is imperative to quantify signaling bias in such a way that it eliminates system and observation bias, in order to reveal the unique signaling profile that is induced by the ligand. The potency of a ligand is determined by its affinity for the receptor state coupled to that particular pathway as well as its intrinsic efficacy for generating a response in that pathway (Kenakin et al., 2014). However, the maximal response of a ligand at saturating concentrations is determined only by intrinsic efficacy. Furthermore, contributors to system bias, such as signal amplification and degree of over-expression in heterologous systems, need to be considered carefully as they have different effects on potencies and efficacies of differently efficacious ligands. Therefore, a meticulous and practical analysis of bias should consider both potency and maximal effect of a ligand, eliminate effects of system and observation bias, and should be broadly applicable to routinely derived concentration–response data. Thus, a rigorous and multidimensional approach to characterize a ligand’s properties across variety of controlled assay system would also significantly aid medicinal chemistry efforts in the discovery of biased ligands. Several analytical approaches have been described to quantify biased agonism (Kenakin and Christopoulos, 2013a). Of these, the

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relative transduction ratio (ΔΔlog(τ/KA)) is one of the most robust and widely applicable method for bias quantification. This method applies the operational model of agonism, first derived by Black and Leff (1983). Application of this model to concentration– response curves estimates a “transduction coefficient” log(τ/KA), which is comprised of the functional equilibrium dissociation constant (operational affinity, KA), a measure of the affinity for the receptor coupled to a particular effector protein or signalling pathway, which is different to the affinity of the ligand for the bare receptor determined in radioligand binding assay; and τ, which encompasses both the intrinsic efficacy of the agonist in activating a particular signalling response and receptor density. The log(τ/ KA) is thus an overall measure of the relative ‘power’ of an agonist to induce a response. In order to eliminate the effects of system and observation bias, the log(τ/KA) is normalised to a reference agonist, yielding values of Δlog(τ/KA). Finally, these values can be compared across two signalling pathways for a given agonist to obtain the relative transduction ratio ΔΔlog(τ/KA) as measures of agonist bias (Kenakin, 2014; Kenakin and Williams, 2014; Thompson et al., 2015). Since the contents of signalling effectors across various cell types/tissues/organs are not identical, the degree of “biased agonism” in different systems changes. For example, the effect of a given ligand in primary cells isolated from two different tissues can result in opposite bias (Thompson et al., 2015). The over expression of GRK2 has very often been used as a strategy to increase the sensitivity of β-arrestin2 recruitment detection for several GPCRs (Allen et al., 2011; Frolich et al., 2011; Hoffmann et al., 2008). However, there is evidence which demonstrates that receptor phosphorylation is also subject to bias (ligand-dependent), leading to varying downstream consequences such as differential engagement of signalling kinases or differential receptor regulation (Butcher et al., 2011; Doll et al., 2011; Just et al., 2013). Therefore, over expressing a kinase might affect efficacy differently for different ligands, consequently changing the bias profile of a set of ligands and ultimately leading to “System Bias”. One way of eliminating such artificial bias is to obtain all signalling readouts in exactly the same cellular conditions. However, the issue of differential contents of effectors and receptor interacting proteins in different tissues still remains, for example, high levels of GRK2 are found in brain, leukocytes, heart and spleen, followed by lungs and kidney (Aragay et al., 1998). Once a signalling bias is observed in a heterologous system, it is very important to identify ligands with unique signalling profiles. Ligands must therefore be evaluated in vivo to determine the consequences of biased agonism. Thus, it is important to adopt universal perspective on the concept of bias that can ultimately translate to development of safe and efficacious therapeutics.

4. 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 systems in mood regulation is widely accepted. Some of the reward-related effects of opiates, such as morphine, appear to depend upon their ability to activate DA systems (Leone et al., 1991) via inhibition of GABAergic neurons that regulate the activity of midbrain dopaminergic neurons (Johnson and North, 1992). Considering that endogenous opioid systems are interwoven with monoamine

Please cite this article as: Dogra, S., Yadav, P.N., Biased agonism at kappa opioid receptors: Implication in pain and mood disorders. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.07.018i

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Fig. 1. Kappa opioid receptor/Dynorphin system modulates neurocircuitry of mood. k Receptor modulates monoamine and catecholamine neurotransmitter system in different brain regions by inhibiting serotonergic neurons (in DRN), dopaminergic neurons (in VTA and SN) and noradrenergic neurons (in LC). Upon ligand binding, the βγ subunits dissociate from trimeric complex (Gαiβγ) leaving Gαi free to inhibit adenylyl cyclase activity. The βγ subunits in turn activate GIRKs (G-protein gated inwardly rectifying potassium channels) to increase membrane hyperpolarisation and inhibit voltage gated calcium ion channels and consequently hyperpolarization of neurons. Agonist treatment also causes phosphorylation in the carboxyl-terminal/intracellular domains of the k receptor via GRK3 and thereby β-arrestin recruitment to the receptor. Like other GPCRs, k receptor activation also leads to phosphorylation of ERK and JNK in both G protein dependent and independent (or arrestin dependent) pathways. The G protein mediated responses are proposed to be responsible for analgesic response and aversion in CPA, while arrestin dependent signalling is proposed to cause sedation, anhedonia and motor incoordination. CP¼ caudate putamen, CPA ¼ conditioned place aversion, HIPPO¼ hippocampus, HYPO ¼ hypothalamus, DRN¼ dorsal raphe nucleus, KOR ¼ kappa opioid receptor, LC ¼ locus coeruleus, NAC ¼nucleus accumbens, PFC ¼ prefrontal cortex, SN¼ substantia nigra, VTA ¼ ventral tegmental area.

systems in the brain (Snyder and Pasternak, 2003), it should not be surprising that various effects of opioid receptor stimulation involve monoamine neurotransmitters. The fact that both endogenous and exogenous opioids can affect mood, raises the possibility that drugs targeting endogenous opioid systems could be utilized in the treatment of debilitating psychiatric conditions. The k receptor/dynorphin systems are enriched in the ventral tegmental area, nucleus accumbens (NAc), amygdala and prefrontal cortex; brain regions that regulate mood and motivation (depicted in Fig. 1). Significantly, neurochemical and electrophysiological studies have demonstrated that k receptor activation in these regions decreases DA transmission. Further, k receptor deletion or blockade in the NAc increases basal DA release, indicating the existence of a tonically active k receptor/dynorphin system that inhibits basal mesoaccumbal neurotransmission (Shippenberg, 2009; Shippenberg et al., 2007). Given the inhibitory effects of k receptor agonists on DA transmission, these findings suggest that up regulation of k receptor/dynorphin systems might lead to depression. Reverberating with this concept,

various groups demonstrated that k receptor agonists and CREBmediated induction of dynorphin in NAc produce depression-like symptoms in rodents, and k receptor antagonists produce antidepressant-like effects (Beardsley et al., 2005; Carr et al., 2010; Mague et al., 2003; Shirayama et al., 2004). Based on these results, several pharmaceutical companies are developing k receptor antagonists with short-acting properties that might work extremely well for the treatment of major depression (for example, ALKS 5461 from Alkermes in phase II (Harrison, 2013) and LY2456302 from Eli Lilly in phase II clinical trial (NCT01913535). Although, most of the k receptor antagonists have not been systematically evaluated for “biased” factor (at least, not as per above mentioned criterions), recent evidences do suggest that 6-GNTI produces “biased agonism” (Rives et al., 2012; Schmid et al., 2013). Unlike m receptor and δ receptor antagonists, certain k receptor antagonists have an extremely long duration of action. For example, a single injection of the k receptor selective antagonists norBNI, GNTI and JDTic maintain continual blockade of k receptor for up to 3 weeks (Bruchas et al., 2007b; Carroll et al.,

Please cite this article as: Dogra, S., Yadav, P.N., Biased agonism at kappa opioid receptors: Implication in pain and mood disorders. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.07.018i

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2004; Horan et al., 1992). Such a long duration of action is in sharp contrast to the pan-opioid receptor antagonist naloxone, which is effective only for few hours. Recent work has shown that such sustained activity is mediated by activation of c-Jun N-terminal kinases (JNK). Surprisingly, norBNI and JdTic, both long lasting antagonists, have been found to activate JNK (increase pJNK levels) via k receptor in the brain and spinal cord of wild-type mice but not of k receptor—KO mice (Bruchas et al., 2007b; Melief et al., 2011). Although it is quite complex to understand mechanistically, JNK1 appears to play a critical role in mediating long-term antagonism caused by norBNI and JdTic (Melief et al., 2010, 2011). Clearly, this is a case where a ligand is a classical antagonist in one assay (blocking agonist binding) and a “biased agonist” for the other (JNK mediated signal transduction). Therapeutically, k receptor antagonists are being developed for the treatment of stress, anxiety, depression and addiction. Therefore, understanding the underlying mechanisms of the unique pharmacokinetics of some k receptor antagonists might have significant implications for drug development.

5. 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 pain state is associated with neuroplastic alterations including changes in the spinal level of substance P, cholecystokinin and dynorphin. Hence, identification of a precise mechanism underlying the development and maintenance of allodynia and hyperalgesia appears essential for the development of effective strategies for pharmacological treatment of neuropathic pain state. Similar to other opioids, k receptor agonists have also been shown to attenuate pain pathways in the central nervous system, whereas brain impermeable k receptor agonists have been developed to target k receptor located on visceral and somatic afferent nerves for relief of inflammatory, visceral, and neuropathic chronic pain (Vanderah et al., 1996). This analgesic action of k receptor agonists is attributed to their ability to activate inhibitory Gi/o proteins (Taussig et al., 1993) that inhibit cAMP production (Schoffelmeer et al., 1988) and calcium channels (Tallent et al., 1994), but activate inward rectifier potassium channels, which ultimately hyperpolarize neurons. Substantial evidence suggests that neuropathic pain states are associated with elevated spinal dynorphin level (Bian et al., 1999; Kajander et al., 1990; Malan et al., 2000), and increased expression of endogenous dynorphin and prodynorphin mRNA (Cox et al., 1985; Przewlocki et al., 1988). Dynorphin is located primarily in the intrinsic neurons of layers I, II and V of the spinal cord dorsal horn (Ruda et al., 1988), which overlaps with the areas of occurrence of neurons responding to noxious input. Furthermore, dynorphin has been shown to play a beneficial physiological role (antinociceptive action) via the opioid receptor, as well as induces pathological effects (pronociceptive action) by activating NMDA and B2 bradykinin receptor (Lai et al., 2006; Laughlin et al., 1997; Lee et al., 1995; Vanderah et al., 1996). The recruitment of arrestins to k receptor have been demonstrated to regulate antinociceptive tolerance (McLaughlin et al., 2004). Hence, it is imperative to obtain a G protein-biased agonist in order to achieve analgesic efficacy without the adverse effects triggered by arrestin (Chavkin, 2011). Although 6-guanidinonaltrindol (6-GNTI) was originally proposed as a δ receptor–k

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receptor heteromer-selective ligand (Sharma et al., 2001; Waldhoer et al., 2005), later this ligand clearly exhibited “biased agonism” as demonstrated by antagonistic activity on arrestin recruitment and agonistic activity on G protein dependent cAMP inhibition (Rives et al., 2012). However, 6′-GNTI has been shown to produce analgesia only when administered intrathecally, but not in the brain (Waldhoer et al., 2005). Thus, it is difficult to clearly define the biasness of 6-GNTI as this ligand exhibits varying effects in different tissues.

6. 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 κ receptor ligands should combine behavioural studies and multiple intracellular signalling cascades, in addition to those activated by G proteins with biased ligands, to elucidate activation of which signalling cascade contributes to which behavioural effect. Finally, quick evolving structural and dynamic information of GPCRs, and understanding of biased agonism have raised our expectation for designing more selective therapies with fewer side effects for several disorders.

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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Please cite this article as: Dogra, S., Yadav, P.N., Biased agonism at kappa opioid receptors: Implication in pain and mood disorders. Eur J Pharmacol (2015), http://dx.doi.org/10.1016/j.ejphar.2015.07.018i