Abstract
Nowadays, the delta opioid receptor (DOPr) represents a promising target for the treatment of chronic pain and emotional disorders. Despite the fact that they produce limited antinociceptive effects in healthy animals and in most acute pain models, DOPr agonists have shown efficacy in various chronic pain models. In this chapter, we review the progresses that have been made over the last decades in understanding the role played by DOPr in the control of pain. More specifically, the distribution of DOPr within the central nervous system and along pain pathways is presented. We also summarize the literature supporting a role for DOPr in acute, tonic, and chronic pain models, as well as the mechanisms regulating its activity under specific conditions. Finally, novel compounds that have make their way to clinical trials are discussed.
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1 The Opioid System
While opium has been used for centuries, the endogenous opioid system was only discovered in the mid-1970s. Two pentapeptides named methionine- and leucine-enkephalin were first identified and characterized by Hughes and colleagues in 1975 (Hughes et al. 1975). Rapidly thereafter, endorphin (Li and Chung 1976; Loh et al. 1976) and dynorphin (Goldstein et al. 1979) were also discovered. More recently, an opioid-like peptide named nociceptin/orphanin was also identified (Meunier et al. 1995; Reinscheid et al. 1995). The endogenous opioid/opioid-like ligands are derived from four distinct precursors, namely proenkephalin, proopiomelanocortin (POMC), prodynorphin, and pronociceptin/orphanin. The synthesis of the opioid peptides therefore depends on the activity of endo- or carboxypeptidases (for more details on the discovery of the opioid peptides, see Akil et al. 1998; Darland et al. 1998; Snyder and Pasternak 2003).
Opioid peptides bind to three major receptor subtypes, namely mu (MOPr), delta (DOPr), and kappa (KOPr) opioid receptors. These receptors are, respectively, encoded by the oprm1, oprd1, and oprk1 genes. The opioid-like peptide nociceptin/orphanin rather binds to the opioid-like receptor called Orphanin FQ/nociceptin receptor (NOPr). All four receptors belong to the superfamily of G protein-coupled receptors (GPCRs) and exhibit a high sequence homology in their protein structure and genomic organization (Kieffer and Gaveriaux-Ruff 2002; Stevens 2009).
Opioids (and opioid receptors) are particularly well known for their important effects in controlling pain. However, opioids are also involved in reward, addiction, neuroprotection, and many other physiological processes such as respiration, gastrointestinal motility, as well as in the endocrine and the immune systems (for reviews, see Kieffer and Gaveriaux-Ruff 2002; Kieffer and Evans 2009; Pradhan et al. 2011; Sauriyal et al. 2011; Chu Sin Chung and Kieffer 2013; Lutz and Kieffer 2013; Gendron et al. 2015). Indeed, MOPr agonists are widely prescribed for the management of pain, although their pronounced unwanted effects (constipation, respiratory depression, sedation, tolerance) often limit their usage (McQuay 1999; Al-Hasani and Bruchas 2011). By contrast, DOPr agonists also produce pain relief but they were shown to have fewer unwanted effects than MOPr agonists (Dondio et al. 2001; Petrillo et al. 2003; Gallantine and Meert 2005) and do not induce tolerance in various animal models (Dondio et al. 2001; Mika et al. 2001; Beaudry et al. 2009). DOPr agonists therefore appear as a good and promising alternative for the treatment of chronic pain (Pradhan et al. 2011). It is worth noting that DOPr agonists also have anxiolytic, anti-depressive, analgesic, and cardio- and neuroprotective effects (Pradhan et al. 2011; Headrick et al. 2015).
In this chapter, we will discuss the role and the functions of DOPr in pain control. In particular, we will describe the distribution of DOPr along the pain pathways and summarize the literature supporting a role for DOPr in the treatment of pain. An overview of novel compounds and their effects in clinical trials will also be provided.
2 The Delta Opioid Receptor: A One-of-a-Kind
2.1 Cloning of DOPr
In 1992, two distinct groups successfully identified an opioid binding site from NG108-15 cells (Evans et al. 1992; Kieffer et al. 1992). Using similar approaches, both groups concomitantly cloned the mouse DOPr by creating a random cDNA library from the RNA of these cells. The cloning of MOPr and KOPr followed soon afterward (Chen et al. 1993; Meng et al. 1993; Minami et al. 1993; Wang et al. 1993).
Oprd1, the gene encoding DOPr, was identified and its chromosomal localization determined. In humans, oprd1 is located in the distal part of the short arm of chromosome 1. Interestingly, although they share a similar genomic structure and a high sequence homology (Zaki et al. 1996; Chaturvedi et al. 2000), genes encoding MOPr and KOPr are found on different chromosomes, namely in the long arm of chromosomes 6 and 8, respectively (Befort et al. 1994; Wang et al. 1994; Yasuda et al. 1994). The detailed structure of oprd1 and its translational and epigenetic regulation have been recently reviewed elsewhere (Wei and Loh 2011; Gendron et al. 2016).
2.2 DOPr Structure and Signaling
As a member of the GPCR superfamily, DOPr contains seven hydrophobic transmembrane domains connected by intra- and extracellular loops. DOPr also possesses N- and C-terminal tails, respectively, at its extra- and intracellular ends. The crystal structures of all three opioid receptors have been recently resolved (Granier et al. 2012; Manglik et al. 2012; Wu et al. 2012). The structures revealed a well-conserved amino acid backbone among the three receptors in the lower part of the binding pocket, a region important for the recognition of the morphinan group. This portion of the binding pocket interacts with the “message segment” of the ligand which is responsible for its efficacy. The upper part of the binding pocket is, however, divergent among the three receptors and its interaction with the distinct “address” segment of the ligand is responsible for receptor selectivity (Granier et al. 2012). DOPr was also found to contain a sodium allosteric binding site regulating biased signaling and constitutive activity (Fenalti et al. 2014).
As MOPr and KOPr, DOPr interacts with numerous proteins and signaling partners (Gendron et al. 2016). When activated, conformational changes within the receptor and its transmembrane domains are leading to the activation of multiple signaling pathways. In particular, the G protein subunits Gαi/o and Gβγ dissociate from each other and act on various intracellular effectors. The activation of the G protein modifies the activity of calcium (P/Q-, N- and L-type) and potassium channels (G protein gated inwardly rectifying potassium, Kir3) and inhibits adenylyl cyclase activity (reducing the level of intracellular cAMP). These events produce a decrease in neuronal excitability and modifications of gene expression (Kieffer and Evans 2009; Al-Hasani and Bruchas 2011; Gendron et al. 2016). Following agonist stimulation, DOPr also undergoes rapid phosphorylation by G protein-regulated kinases (GRKs). Phosphorylation of DOPr on its C-terminal tail by GRKs is followed by the recruitment of β-arrestins and internalization of the receptor via clathrin-coated vesicles (endocytosis). After internalization, GPCRs are either recycled back to the plasma membrane or undergo degradation (Bie and Pan 2007). While MOPr is mainly recycled back to the plasma membrane, DOPr was shown to be primarily degraded through the lysosomal pathway (Tsao and von Zastrow 2000; Finn and Whistler 2001; Whistler et al. 2002). Several motifs within the receptor are involved in controlling this process. In particular, specific interactions with distinct sorting proteins are routing DOPr either to the degradation or to the recycling pathways. As an example, the Na+/H+ exchanger regulatory factor (NHERF), also called ERM-binding phosphoprotein 50 (EBP50), and the N-ethylmaleimide sensitive factor (NSF) were found to be important for the recycling of DOPr (Heydorn et al. 2004; Bie et al. 2010). By contrast, GPCR associated sorting protein (GASP) and sorting nexin-1 (SNX-1) were shown to sort the receptor to the degradation pathway. The C-terminal tail of DOPr seems to have a high affinity for GASP and SNX-1 (Whistler et al. 2002; Heydorn et al. 2004; Simonin et al. 2004). Indeed, swapping the C-terminal tail of DOPr with that of MOPr was shown to shift the fate of the receptor from the degradation toward the recycling pathway (Whistler et al. 2002). Similarly, GASP inactivation was shown to reduce the amount of DOPr in lysosomal compartments and to inhibit its downregulation following agonist stimulation (Whistler et al. 2002).
2.3 DOPr Expression and Distribution
The expression of DOPrs in the mammalian central nervous system has been widely investigated. Precisely, the distribution of DOPr mRNA and binding sites was studied by in situ hybridization, autoradiography, and/or immunohistochemistry (Mansour et al. 1987, 1993, 1994; Sharif and Hughes 1989; George et al. 1994; Cahill et al. 2001a; Pradhan and Clarke 2005; Peng et al. 2012). In mice, the expression of the opioid receptors begins at early developmental stages in the CNS and in peripheral tissues (Zhu et al. 1998). MOPr and KOPr mRNA were, respectively, detected in basal ganglia and midbrain as early as at embryonic stage E11.5. By contrast, the expression of DOPr mRNA only begins at E13.5 in the pons and the hypothalamus. Compared to MOPr and KOPr, DOPr remains restricted within a few brain regions including the caudate–putamen, the olfactory tubercle, and the parabrachial nucleus until late in the development. In dorsal root ganglia (DRGs), DOPr mRNA was detected as early as the embryonic stage E12.5 while it only appears at E15.5 in the ventral part of the spinal cord. Surprisingly, the expression of DOPr mRNA in the mouse dorsal horn of the spinal cord only appears at E17.5 (Zhu et al. 1998).
Although opioid binding sites have been observed by autoradiography in the developing embryo (Kent et al. 1981), specific binding for DOPr has not been observed in rodents before the second week after birth (McDowell and Kitchen 1986; Negri et al. 1997). However, DPDPE-induced GTPγS binding was reported in the caudate–putamen at E12.5 and at E17.5 in the pons and the hypothalamus, suggesting the existence of functional DOPrs at these stages, at least in mice (Nitsche and Pintar 2003).
In the adults, the three opioid receptors are not evenly distributed throughout the CNS, suggesting that they have distinct physiological roles (for reviews see Mansour et al. 1995; Le Merrer et al. 2009). Whereas MOPrs are widely distributed in the brain with an enrichment in the thalamus, striatum, interpeduncular complex, habenula, cortex, superior and inferior colliculi, DOPrs are mainly expressed in distinct areas of the forebrain, predominantly in the olfactory tubercle, cerebral cortex, amygdala, nucleus accumbens, and striatum (Fig. 1a, b). KOPrs are mainly found in the cortex, olfactory tubercle, striatum, nucleus accumbens, hypothalamus, amygdala, and periaqueductal gray (PAG) (Mansour et al. 1987; Sharif and Hughes 1989; Slowe et al. 1999). Interestingly, in the areas where the three receptors were found, their cellular distribution often differs. This is exemplified in the striatum, where DOPr and KOPr are diffusely distributed while MOPrs are expressed in patch-like clusters (Mansour et al. 1987).
DOPr distribution and functions in the central nervous system. (a) Schematic representation of DOPr binding sites and presumed functions in the central nervous system (CNS). DOPrs are highly expressed in the rostral part of the brain (black squares), especially in the olfactory bulb, cortex, striatum, and amygdala suggesting a role in pain processing and awareness, in emotional disorders (depression and anxiety), in addiction and impulsivity. Moderate (grey squares) to weak (open squares) expression of DOPr is also observed throughout the caudal part of the brain, including the spinal cord and the DRGs. (b, c) Representative photomicrographs showing a similar pattern of expression between DOPr binding sites labeled with [3H]-Deltorphin II and DOPr immunofluorescence from DOPr-GFP knock-in mice (modified with permission from Pradhan et al. 2011; Bardoni et al. 2014)
Of a particular interest for this chapter, DOPrs are known to be largely expressed along the pain pathways in all animal species studied to date, including humans. DOPrs are indeed present in primary afferents (i.e., DRGs), in the spinal cord, as well as in important structures along the ascending and descending pain pathways (Fig. 1). Among these structures, it is worth noting that DOPr is expressed in the PAG, the rostro-ventral medulla (RVM), the cerebral cortex, and the amygdala (Mansour et al. 1994, 1995; Cahill et al. 2001a; Mennicken et al. 2003; Poulin et al. 2006; Peng et al. 2012). Interestingly, the distribution of DOPr in the spinal cord – and possibly in other structures as well – significantly differs among species. In the rodent spinal cord (mice and rats), DOPr is diffusely distributed in the gray matter (Sharif and Hughes 1989; Arvidsson et al. 1995; Mennicken et al. 2003) (Fig. 2). In monkeys, although DOPr binding sites are also found in all lamina of the spinal cord, a higher density of binding could be observed in the superficial lamina. Most interestingly, DOPr binding sites are restricted to the superficial lamina as well as in the Clark’s column in the human spinal cord (Mennicken et al. 2003) (Fig. 2). The fact that the DOPr transcript is virtually absent in the human spinal cord (Fig. 2) suggests that DOPr binding sites are exclusively present on presynaptic primary afferent axon terminals. These observations strongly advise for a specialization of DOPr toward the pain pathways in higher species. For instance, the intrathecal injection of DOPr agonists in various acute and chronic pain models has been shown to produce antinociception, supporting a role for DOPr in pain.
Phylogenetic changes in DOPr expression in spinal cord and DRGs. Representative photomicrographs illustrating (A) DOPr mRNA expression (in situ hybridization) and (B) [125I]-Deltorphin labeled DOPr binding sites in spinal cord and DRGs of mice, rats, monkeys, and humans (modified with permission from Mennicken et al. 2003)
The exact distribution of DOPr in primary afferents remains a matter of controversy and most certainly differs among species. While DOPr was commonly shown to be expressed in all three types of DRG neurons (Dado et al. 1993; Mansour et al. 1994; Ji et al. 1995; Minami et al. 1995; Zhang et al. 1998; Wang and Wessendorf 2001; Mennicken et al. 2003; Gendron et al. 2006), in DOPr-GFP knock-in mice DOPr was rather found to be primarily expressed in large myelinated nonpeptidergic neurons and around hair follicles supporting a role in the perception of mechanical stimuli and light touch (Bardoni et al. 2014). These observations support the fact that MOPr and DOPr were, respectively, shown to specifically inhibit thermal and mechanical pain (Scherrer et al. 2009). This is, however, in sharp contrast with the work of others. Firstly, DOPr has often been found in substance P-containing neurons by a number of independent groups, and with different experimental approaches (Guan et al. 2005; Zhang et al. 2006, 2010; Riedl et al. 2009; Wang et al. 2010; Zhao et al. 2011). In particular, a role for an interaction between DOPr and preprotachykinin A (the precursor for substance P) in the targeting of DOPr to the cell surface through the regulated secretory pathway has been described (Guan et al. 2005). DOPr was indeed found to be present in large dense core vesicles (LDCV) containing substance P (Guan et al. 2005; Zhao et al. 2011). The presence of DOPr in substance P-containing neurons was also confirmed by single-cell RT-PCR (Wang et al. 2010). Also contrasting with the work cited above is the fact that the activation of DOPr by various agonists and in different animal models of pain was not only found to inhibit noxious mechanical stimuli but also heat-induced pain (Tables 1 and 2).
For a GPCR, DOPr was found to have an uncommon subcellular location. Indeed, under normal conditions DOPr was found to be retained in the cytoplasm, in association with intracellular compartments (Pasquini et al. 1992; Arvidsson et al. 1995; Cheng et al. 1995, 1997; Zhang et al. 1998; Cahill et al. 2001a; Commons et al. 2001; Wang and Pickel 2001) (Fig. 3a). Interestingly, it was observed that the density of cell surface DOPr can be increased under certain conditions such as in chronic pain models, or following prolonged morphine treatment (Cahill et al. 2001a, 2003; Commons 2003; Morinville et al. 2003, 2004; Lucido et al. 2005; Gendron et al. 2006) (Fig. 3b, c). Since it is not the purpose of this chapter, the distinct mechanisms involved in the regulation of DOPr trafficking will not be discussed here. This topic has, however, recently been extensively reviewed elsewhere (Gendron et al. 2016). Simply, it should be kept in mind that the subcellular localization of DOPr and the possibility to increase its density at the cell surface could explain why DOPr agonists are more potent under certain conditions than in control/naïve animals.
Enhancement of DOPr expression at the plasma membrane of neurons under inflammatory or chronic morphine conditions. (a) Intracellular localization of DOPr in the neostriatum labeled with [125I]-Azido-DTLET (a DOPr selective agonist, left panel) or by a DOPr antibody directed against the 3–17 segment (left panel) in untreated animals. (b, c) Electron microscopy of immunolabeled DOPr in the superficial laminae of lumbar spinal cord dorsal horn in animals treated with morphine (b, right panel) or in the CFA pain model (c, right panel) showing an increase in immunogold particles associated with the plasma membrane (adapted with permission from Pasquini et al. 1992; Cahill et al. 2001b, 2003, Lucido et al. 2005)
3 DOPr and Pain Modulation
The analgesic efficacy of DOPr agonists was widely investigated using pharmacological and genetic approaches. Before describing the effects of DOPr agonists in acute and chronic pain models, it is worth noting that mice deficient for DOPr (DOPr knockout mice) did not show any significant change in pain perception following acute noxious stimuli (thermal, mechanical, or chemical stimuli) (Zhu et al. 1999; Filliol et al. 2000). However, sensitivity to thermal and mechanical stimuli is increased in inflammatory and neuropathic pain models in DOPr knockout mice (Nadal et al. 2006; Gaveriaux-Ruff et al. 2008). These observations therefore suggest that a constitutive tone of endogenous opioid release acting on DOPr would prevent exacerbation of chronic pain. This hypothesis is supported by the fact that the selective ablation of DOPr in NaV1.8 sensory neurons increases chronic pain (Gaveriaux-Ruff et al. 2011).
3.1 DOPr-Mediated Analgesia in Acute Pain Models
Agonists acting at DOPr are known to produce antinociception (Gaveriaux-Ruff and Kieffer 2011). Although first evidence for DOPr-mediated antinociception was provided in the early 1980s (Brantl et al. 1982), the lack of highly selective DOPr ligands prevented a clear demonstration of the physiological effects of this receptor. A pioneer study used [2-d-penicillamine, 5-d-penicillamine]enkephalin (DPDPE), a highly selective DOPr agonist (Mosberg et al. 1983), and confirmed that DOPr could mediate antinociception in the hot plate test (Porreca et al. 1984). Although their antinociceptive effects have been commonly reported thereafter, it is generally accepted that DOPr agonists, no matter the route of administration, only have weak or no antinociceptive effects when healthy animals are tested with routinely used acute pain tests (e.g., tail flick and hot plate tests). Indeed, DOPr agonists seem to have only modest antinociceptive effects in acute pain models when compared to MOPr agonists. As an example, the i.c.v. administration of [d-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAMGO; a selective MOPr agonist) produced a more profound analgesia than DPDPE in the hot plate test (Porreca et al. 1984). Similarly, DAMGO was also shown to reduce mechanical nociception by 80% at a dose of 0.2 nmol (i.c.v.) in the paw pressure test while doses of 60 and 400 nmol of the DOPr agonists Deltorphin II and SNC80, respectively, were needed to produce similar effects (Fraser et al. 2000b). Table 1 summarizes the DOPr-mediated antinociceptive effects in acute pain tests.
3.1.1 Regulation of DOPr by MOPr in Healthy Animals
As described above, the antinociceptive effects of centrally administered DOPr agonists are generally weak. However, it was demonstrated that morphine or other MOPr agonists can potentiate the analgesic effects of spinally administered DOPr agonists (Cahill et al. 2001b; Morinville et al. 2003; Gendron et al. 2007a). The cellular mechanisms involved in the potentiation of DOPr functions are unclear. However, it was noted that the administration of morphine induces a translocation of DOPr to the plasma membrane in DRG (Gendron et al. 2006), spinal cord (Cahill et al. 2001b; Morinville et al. 2003; Gendron et al. 2007a), and central gray neurons (Lucido et al. 2005; see also Fig. 3b). As of to date, the exact mechanisms involved in this process have not been totally unveiled. We do know, however, that it involves MOPr as these effects are completely abolished in MOPr knockout animals (Morinville et al. 2003). In the PAG, morphine also increases the DOPr-mediated presynaptic inhibition of GABAergic synaptic currents (Hack et al. 2005). Both MOPr and β-arrestin 2 have been shown to be important for the upregulation of DOPr functions in the PAG (Hack et al. 2005). A more recent study also suggests that morphine induces a cdk5-mediated phosphorylation of the threonine 161 residue located in the second intracellular loop of DOPr (Xie et al. 2009). Phosphorylation of this residue by cdk5 would indeed increase the membrane expression of DOPr and, ultimately, enhance the antinociceptive effects of DOPr agonists in morphine-treated animals (Beaudry et al. 2015b). The phosphorylation of DOPr by cdk5 was further hypothesized to disrupt the formation of the MOPr-DOPr heterodimer (Xie et al. 2009). This is consistent with the observations made by others who show that chronic morphine treatment potentiates MOPr and DOPr heterodimerization throughout the CNS including areas involved in pain processing and in the DRGs (Gupta et al. 2010). It was further demonstrated that a mixture of the MOPr agonist methadone and the DOPr antagonist naltriben can stabilize DOPr at the cell surface in a heterodimer form preventing its endocytosis and therefore avoiding degradation (Milan-Lobo and Whistler 2011; Milan-Lobo et al. 2013).
3.2 DOPr-Mediated Analgesia in Acute Inflammatory Pain Models
By contrast to their minor effects in acute pain tests, DOPr agonists were found to be more efficient at alleviating acute inflammatory pain. Formalin- and capsaicin-induced pain behaviors are indeed efficiently inhibited following DOPr activation (Bilsky et al. 1996b; Cahill et al. 2001b; Morinville et al. 2003; Pradhan et al. 2006; Beaudry et al. 2011). As an example, the intrathecal administration of Deltorphin II was shown to significantly reduce the typical biphasic nociceptive response induced by formalin as well as the spontaneous pain-like behaviors – licking, biting, and flinching – induced by capsaicin. These effects were completely antagonized by the DOPr selective antagonist naltrindole, therefore supporting a role for DOPr (Bilsky et al. 1996b; Cahill et al. 2001b; Morinville et al. 2003; Pradhan et al. 2006; Beaudry et al. 2011). At the spinal level, DOPr-mediated analgesia was shown to involve an inhibition of substance P release (Beaudry et al. 2011; Kouchek et al. 2013). Substance P is produced in peptidergic C fibers and released upon activation of these neurons by peripheral noxious stimuli (Cao et al. 1998). As revealed by an inhibition of c-fos expression, the intrathecal administration of Deltorphin II or SNC80 reduces the activation of spinal neurons (Beaudry et al. 2011; Kouchek et al. 2013). Activation of DOPr in the spinal cord also prevents substance P release and blocks NK1 internalization in the superficial lamina of the lumbar dorsal horn induced by intraplantar formalin and capsaicin (Beaudry et al. 2011; Kouchek et al. 2013).
The systemic administration of DOPr agonists also produces antinociception in response to chemical stimuli (Barn et al. 2001; Brandt et al. 2001; Saitoh et al. 2011; Saloman et al. 2011). In primates, thermal hypersensitivity induced by capsaicin and prostaglandin E2 was completely reversed following subcutaneous administration of SNC80 (Brandt et al. 2001). KNT127 and SNC80 were also found to inhibit the biphasic nociceptive response induced by formalin as well as the acetic acid induced abdominal constrictions in mice (Barn et al. 2001; Saitoh et al. 2011).
Beside their central mechanism of actions, DOPr agonists also produce analgesia via receptors expressed in the periphery (Stein et al. 2001). The intraplantar administration of Deltorphin II, SNC80, and DSLET was shown to effectively suppress formalin-induced pain behaviors in rodents (Bilsky et al. 1996b; Kabli and Cahill 2007; Obara et al. 2009). This antinociceptive effect was completely reversed by intraplantar treatment with the DOPr antagonist naltrindole or by a pretreatment with DOPr antisense oligodeoxynucleotides (Bilsky et al. 1996a, b). Again, DOPr agonists had no significant effect on thermal or mechanical nociceptive thresholds under normal conditions (Bilsky et al. 1996b; Kabli and Cahill 2007; Obara et al. 2009).
3.2.1 Regulation of DOPr in Acute Inflammatory Pain
A recent study by Doyle Brackley and collaborators has provided mechanistic insights for the lack of efficacy of peripheral DOPr agonists in naïve animals. They indeed observed that peripheral DOPr expressed on sensory nerves is constitutively desensitized by a GRK2-dependent mechanism. They found that under basal conditions GRK2 is constitutively associated with DOPr, therefore preventing its coupling to G proteins or other signaling partners. The knockdown of GRK2 was found to be sufficient to increase peripheral DOPr-mediated analgesia. Interestingly, in inflamed tissues PKC activation leads to RKIP phosphorylation which in turn sequesters GRK2. In this model, the sequestering of GRK2 “awakens” DOPr in sensory neurons and increases the analgesic effects of peripheral DOPr agonists (Brackley et al. 2016).
3.3 DOPr-Mediated Analgesia in Chronic Pain Models
The antinociceptive effects of various DOPr agonists in animal models of chronic pain are summarized in Table 2. In general, the efficacy and the potency of DOPr agonists at producing antinociception in chronic pain models are more important, when compared to acute pain models. Overall, the observations made in preclinical models of chronic pain suggest that DOPr agonists efficiently inhibit inflammatory, neuropathic, diabetic, as well as cancer pain. Interestingly, recent observations also support a role for DOPr in the treatment of migraine.
3.3.1 DOPr in Inflammatory Pain Models
Complete Freund’s adjuvant (CFA) and carrageenan are commonly used to induce inflammation or as rodent models of arthritis (Klareskog 1989; Hansra et al. 2000). In these inflammatory pain models, spinal DOPr activation was shown to alleviate hyperalgesia (Hylden et al. 1991; Stewart and Hammond 1994; Qiu et al. 2000). In the CFA model of inflammation, Deltorphin II is effective at reducing both thermal hyperalgesia and mechanical allodynia in a dose-dependent manner (Cahill et al. 2003; Gendron et al. 2007a, b; Beaudry et al. 2009, 2015a; Dubois and Gendron 2010; Otis et al. 2011). The effects of Deltorphin II are DOPr-mediated since they are completely antagonized by DOPr selective antagonists. Interestingly, Deltorphin II has no analgesic effect on the uninflamed paw, supporting a lack of effects in healthy tissues (Cahill et al. 2003; Gendron et al. 2007a; Beaudry et al. 2009; Dubois and Gendron 2010; Otis et al. 2011). Indeed, in these chronic pain models, DOPr agonists commonly display a leftward shift of their dose-response effects when compared to dose-response curves in healthy animals.
The enhancement of DOPr analgesic potency in inflammatory pain models is thought to be the result of an increase in DOPr expression at the plasma membrane of spinal neurons. As stated above, the subcellular distribution of DOPr in the lumbar dorsal horn, as assessed by electron microscopy, revealed a predominant localization of the receptor within the intracellular compartments of neurons (Fig. 3b, c). However, following some inflammatory/pain state, an increase in DOPr distribution at the plasma membrane was seen in the ipsilateral lumbar spinal cord and the DRG neurons (Cahill et al. 2003; Gendron et al. 2006) (see also Fig. 3c). Studies based on fluorescent ligand internalization (used as a tool to evaluate the density of membrane receptors) further revealed an increased level of internalization in the lumbar spinal cord and in small and medium DRG neurons in inflamed animals, thus supporting an upregulation of DOPr at the neuronal plasmalemma (Gendron et al. 2006, 2007a). Again, the mechanisms involved in this process are still unclear. As for the morphine-induced regulation of DOPr, CFA-induced inflammation requires MOPr to increase the membrane density of DOPr and the antinociceptive effects of DOPr agonists (Cahill et al. 2003; Gendron et al. 2007b). Similarly, the inhibition of cdk5-induced phosphorylation of DOPr prevents the enhancement of DOPr-mediated analgesia (Beaudry et al. 2015b). However, if an interaction between DOPr and preprotachykinin A appears to be essential for the membrane expression of DOPr in non-treated mice, the upregulation of DOPr function in the CFA model was shown to be independent of substance P (Dubois and Gendron 2010).
Centrally administered (i.c.v.) DOPr agonists also produce analgesia in the CFA model of inflammatory pain. SNC-80 and Deltorphin II were shown to increase the time to paw withdrawal in response to a thermal stimulus (Hargreaves test) (Fraser et al. 2000a). The potency of centrally administered DOPr agonists was also found to be improved in animals with persistent inflammation when compared to healthy animals. Indeed, the effective i.c.v. dose of SNC80 and Deltorphin II required to produce antihyperalgesic effect in the rat CFA model of inflammation is three times lower than that needed to induce analgesia to thermal stimulus in acute pain models (Fraser et al. 2000a). Other groups have also demonstrated an involvement of DOPr in the descending pain pathways. In fact, DOPr activation in supraspinal sites such as the RVM and PAG was found to produce analgesia in various animal models of chronic pain (for review, see Bie and Pan 2007). As an example, microinjection of Deltorphin II into the RVM was shown to dose-dependently reverse thermal hyperalgesia in CFA-treated rats (Hurley and Hammond 2000).
Activation of peripheral DOPr produces antinociception under pathological pain conditions. DPDPE, when administered in the periphery, produces antinociception in CFA and neuropathic pain models (Zhou et al. 1998; Hervera et al. 2009; Obara et al. 2009). Following inflammation, opioid receptors were shown to be upregulated in primary afferents in which they are highly transported toward the free nerve endings in the periphery. As a consequence, the potency of peripheral opioid agonists in mediating analgesia is enhanced. The low pH in the inflamed tissues is also thought to facilitating ligand/receptor coupling (for reviews, see Stein et al. 2001; Stein and Lang 2009). The local administration of the DOPr agonist SNC80 was also shown to dose-dependently reduce the mechanical hyperalgesia induced by the subcutaneous injection of prostaglandin E2 in the hindpaw (Pacheco and Duarte 2005). DOPr-induced analgesia in the periphery is thought to be mediated by the nitric oxide/cGMP pathway. Indeed, in the CFA model of inflammation the nitric oxide donor NOC-18 potentiates the antihyperalgesic effect of DPDPE (Hervera et al. 2009). Nitric oxide synthase or guanylate cyclase inhibitors also prevent the SNC80-mediated analgesia in the prostaglandin E2 pain model (Pacheco and Duarte 2005). Interestingly, the intraplantar administration of glibenclamide and tolbutamide, two ATP-sensitive K+ channel blockers, was shown to reduce the analgesia produced by the local administration of SNC80, suggesting that the antinociceptive effect of this compound is specifically mediated by ATP-sensitive K+ channels (Pacheco and Duarte 2005).
3.3.2 DOPr in Neuropathic Pain Models
As reported in Table 2, DOPr agonists are also efficient at alleviating neuropathic pain in various preclinical models. The intrathecal administration of DPDPE or Deltorphin II was shown to significantly relieve allodynia and hyperalgesia in the sciatic nerve ligation model (Mika et al. 2001; Holdridge and Cahill 2007). DPDPE injected into the ventral PAG also effectively reduces mechanical and thermal allodynia in a neuropathic pain model where both the tibial and sural nerves are completely cut (Sohn et al. 2000). In other nerve injury models, peripherally administered DOPr agonists also produce anti-allodynic effects (Kabli and Cahill 2007; Obara et al. 2009). In the peripheral nerve injury model, the increased analgesic effects of DOPr agonists may be the consequence of a higher level of DOPr expression or as a relocalization of DOPr at the cell surface (Kabli and Cahill 2007; Obara et al. 2009).
3.3.3 DOPr in Diabetic Neuropathy
Diabetic neuropathy represents another disease in which DOPr agonists may be used to reduce pain. For instance, the non-peptide TAN-67 was found to produce a dose-dependent antinociception in the mouse tail flick assay when administered i.c.v. (Kamei et al. 1997b). In diabetic mice, an increase in the endogenous tone of the spinal DOPr system was demonstrated. Indeed, in these mice, the inflammatory phase of the formalin test is greatly reduced, an effect reversed by naltrindole (Kamei et al. 1997a).
3.3.4 DOPr in Bone Cancer Pain
Although it has a unique set of characteristics, bone cancer-induced pain includes an important neuropathic component (Honore et al. 2000). It is therefore not surprising to see that DOPr agonists are effective in bone cancer models. In a rat model of metastatic bone cancer-induced pain (Dore-Savard et al. 2010), the intrathecal administration of Deltorphin II was shown to dose-dependently reverse mechanical allodynia, an effect completely blocked by a pretreatment with the DOPr antagonist naltrindole (Otis et al. 2011). The intraperitoneal administration of [dVal(L)2,Ala(L)5]E, another selective DOPr agonist, also produces analgesia in a mouse model of bone cancer-induced pain (Brainin-Mattos et al. 2006). The analgesic effect of DOPr was also demonstrated in mice bearing a tibial osteosarcoma (Baamonde et al. 2005). In this model the peritumoral injection of DPDPE induced a naltrindole-sensitive increase in the paw thermal withdrawal latencies (Baamonde et al. 2005). Similarly, DOPr activation alleviates mechanical hypersensitivity in an orthotopic mouse oral cancer model (Ye et al. 2012). In humans coping with cancer pain, intrathecally administered DADLE, a DOPr-preferred agonist, has also been shown to produce analgesia, even in patients who had developed tolerance to morphine (Onofrio and Yaksh 1983; Moulin et al. 1985; Krames et al. 1986).
3.3.5 DOPr Agonists in Trigeminal and Migraine Pain Models
DOPr appears to play a crucial role in the modulation of trigeminal pain. In rodents and humans, DOPr mRNA can be found in small-, medium-, and large-sized trigeminal ganglia neurons (Mennicken et al. 2003). In the trigeminal nucleus caudalis (Sp5C), a structure involved in modulating and processing somatosensory and nociceptive inputs originating from the orofacial region, DOPr binding sites have a more widespread distribution in rodents than humans. In humans, DOPr binding sites are confined to the superficial laminae of the Sp5C (Mennicken et al. 2003; Ichikawa et al. 2005). Supporting a role for DOPr in trigeminal pain, the activation of peripheral DOPrs was found to attenuate the capsaicin-induced mechanical hypersensitivity in the masseter muscle via the activation of GIRK channels in rats (Saloman et al. 2011; Chung et al. 2014). The activation of DOPr with low doses of DPDPE was also found to reduce substance P release from Sp5C slices, a hallmark of opioid-mediated analgesia (Suarez-Roca and Maixner 1992). Yet, the systemic administration of Deltorphin II produces a pronounced inhibition of C fiber-evoked responses in wide dynamic range neurons of the Sp5C (Wang et al. 1996). Under inflammatory conditions, DOPr-mediated trigeminal analgesia is also enhanced. As measured by a reduction in CGRP release and adenylate cyclase activity, a pretreatment with bradykinin increases the potency of DPDPE to inhibit the activity of trigeminal nociceptors (Patwardhan et al. 2005). In trigeminal nociceptors, this effect is concomitant to an increase of cell surface DOPr (Patwardhan et al. 2005).
In patients unresponsive to classical treatments, opioids acting on MOPrs are often prescribed to treat severe cases of migraine headachesFootnote 1 (for review see Becker 2015). In some cases, however, extensive treatments with opioids can lead to an exacerbation of the frequency and the intensity of migraine episodes in addition to interfere with other migraine therapies (Bigal and Lipton 2008; Bigal et al. 2008; Ansari and Kouti 2016). Recent reports revealed a promising therapeutic potential for DOPr in alleviating migraine headaches (Charles and Pradhan 2016). In an animal model of migraine induced by nitroglycerine (NTG), DOPr activation efficiently reduces thermal hyperalgesia and mechanical allodynia, two symptoms often observed in humans coping with migraine (Pradhan et al. 2014). In this model, the antinociceptive effect of SNC80 is similar to that obtained with sumatriptan, a classical serotonergic receptor (5-HT1B and 5-HT1D) agonist used to treat migraine headaches. SNC80 was also found to be efficient in reducing the aversive state evoked by NTG in the conditioned place preference test, further supporting a role for DOPr in alleviating migraine headaches (Pradhan et al. 2014). These observations are supported by the fact that cortical spreading depression events (CSD; a phenomenon thought to be responsible for the occurrence of migraine with aura, Charles and Baca 2013) evoked by KCl were reduced by the systemic administration of SNC80 (Pradhan et al. 2014).
4 Novel Compounds and Clinical Trials
DOPr is commonly considered as a potential target for the development of novel therapies for the management of chronic pain and emotional disorders (Pradhan et al. 2011). One of the major challenges in the development of novel DOPr agonists for the clinic is the propensity of such ligands to induce nonlethal convulsions at analgesic doses (Comer et al. 1993; Dykstra et al. 1993; Pakarinen et al. 1995; Broom et al. 2002a, b; Chung et al. 2015). Still, a few drugs targeting DOPr have been moved to clinical trials. ADL5747 and ADL5859 are two orally bioavailable compounds (Le Bourdonnec et al. 2008, 2009) that were tested in small cohorts of patients. These compounds, which are devoid of pro-convulsive actions in preclinical models, have indeed been tested for acute (NCT00993863) and chronic (NCT00979953) pain management in Phase 2 clinical trials. Unfortunately, none of the compounds were more effective than the placebo in patients suffering from osteoarthritic pain.
More recently, it was proposed that DOPr-induced seizures are mediated by the activation of the β-arrestin 2 pathway. Exploiting the concept of biased ligands, Trevena, Inc. has developed a novel orally available DOPr-selective compound with a robust bias toward the G protein signaling pathway. This is to say that the compound has virtually no ability to recruit β-arrestin 2 but still activates G proteins with high efficiency. The preclinical evaluation of TRV250 is promising for the treatment of migraine headaches. TRV250 was found to preserve the analgesic properties of common DOPr agonists without producing seizures (http://www.trevenainc.com/TRV250.php).
Although this was not thoroughly covered in this chapter, one should note that DOPr can form dimers or interact with other GPCRs (reviewed in Gendron et al. 2016). Because of their unique pharmacology, GPCR dimers represent a novel class of targets for the development of new drugs and/or therapies (Fujita et al. 2014, 2015). One such target is the MOPr-DOPr heteromer (Fujita et al. 2015). A library screening for this target led to the identification of CYM51010, a selective MOPr-DOPr agonist (Gomes et al. 2013). In the tail flick test, CYM51010 was found to produce antinociception without inducing tolerance (Gomes et al. 2013). This target is thought to induce analgesia without causing the common unwanted effects associated with opioids (Fujita et al. 2015). Bivalent ligands designed to have a high affinity for MOPr and DOPr or KOPr and DOPr were found to exhibit good analgesic properties. Compounds targeting MOPr and DOPr such as L2, L4 (Harvey et al. 2012), MDAN (Daniels et al. 2005b), or RV-JIM-C3 (Podolsky et al. 2013) as well as compounds targeting KOPr and DOPr such as KDAN-18 (Daniels et al. 2005a) and KDN-21 (Bhushan et al. 2004) were found to produce robust analgesia with no apparent signs of tolerance, physical dependence, or sedation (Daniels et al. 2005b; Ansonoff et al. 2010; Podolsky et al. 2013). Two such bivalent ligands targeting MOPr and DOPr are currently in clinical trials. Compound 51 and MuDelta (both acting as MOPr agonist and DOPr antagonist) completed clinical trials in patients suffering from irritable bowel syndrome (Breslin et al. 2012; Wade et al. 2012). The MuDelta was approved recently by the US authorities to be commercialized under the name of Eluxadoline (Garnock-Jones 2015). This compound proved to be efficient in relieving abdominal pain symptoms and diarrhea (Garnock-Jones 2015; Lembo et al. 2016).
5 Conclusion
DOPr represents a promising therapeutic target for the treatment of chronic pain and emotional disorders. Although DOPr agonists produce only weak analgesic effects in healthy animals and in acute pain models, numerous groups have previously described an increase in their analgesic potency in chronic pain models (e.g., inflammatory, neuropathic, and bone cancer-induced pain models). Interestingly, the increased analgesic effects of DOPr agonists are paralleled by a translocation of DOPr from the intracellular compartments to the plasma membrane of spinal cord and DRG neurons.
Notes
- 1.
Migraine is the most common and disabling neurological disorder that occurs as recurrent, pulsatile, episodic headaches with or without aura. It is thought to be the result of trigeminal nerve activation leading to distension in cerebral and meningeal blood vessels. The cortical spreading depression (CSD) is defined as a slowly propagated wave of depolarization originating from the occipital to the frontal part of the brain which is followed by a suppression of brain activity (Goadsby et al. 2009; Olesen et al. 2009).
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Acknowledgments
This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada [RGPIN-2015-05213] and the Canadian Institutes of Health Research (CIHR) [MOP 123399] to L.G. L.G. is the recipient of a Chercheur-boursier Senior from the Fonds de la Recherche du Québec-Santé. The authors are grateful to Véronique Blais for her help in editing the manuscript.
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Abdallah, K., Gendron, L. (2017). The Delta Opioid Receptor in Pain Control. In: Jutkiewicz, E. (eds) Delta Opioid Receptor Pharmacology and Therapeutic Applications. Handbook of Experimental Pharmacology, vol 247. Springer, Cham. https://doi.org/10.1007/164_2017_32
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