Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2011; 108(49):19778-83. DOI: 10.1073/pnas.1115231108
Source: PubMed


Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.

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Available from: Ying-Xian Pan, Mar 26, 2014
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    • "Recently, iodobenzoylnaltrexamide (IBNtxA) has been shown to target MOR1G/NOP receptor heterodimers, displaying a full analgesic response without the side effects of opioids (Majumdar et al., 2011). MOR1G is a truncated, sixtransmembrane variant of the MOP receptor, which lacks exon 1, and is generated from a second, upstream promoter associated with exon 11. "
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    ABSTRACT: Despite high sequence similarity between NOP (nociceptin/orphaninFQ opioid peptide) and opioid receptors, marked differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization and trafficking have been identified; underscoring the evolutionary difference between NOP and opioid receptors. Activation of NOP receptors affects nociceptive transmission in a site-specific manner, with antinociceptive effects prevailing after peripheral and spinal activation, and pronociceptive effects after supraspinal activation in rodents. The net effect of systemically administered NOP receptor agonists on nociception is proposed to depend on the relative contribution of peripheral, spinal and supraspinal activation and this may depend on experimental conditions. Functional expression and regulation of NOP receptors at peripheral and central sites of the nociceptive pathway exhibits a high degree of plasticity under conditions of neuropathic and inflammatory pain. In rodents, systemically administered NOP receptor agonists exerted antihypersensitive effects in models of neuropathic and inflammatory pain. However they were largely ineffective in acute pain while concomitantly evoking severe motor side effects. In contrast, systemic administration of NOP receptor agonists to non-human primates (NHPs) exerted potent and efficacious antinociception in the absence of motor and sedative side effects. The reason for this species difference with respect to antinociceptive efficacy and tolerability is not clear. Moreover, co-activation of NOP and μ-opioid peptide (MOP) receptors synergistically produced antinociception in NHPs. Hence, both selective NOP receptor as well as NOP/MOP receptor agonists may hold potential for clinical use as analgesics effective in conditions of acute and chronic pain.
    British Journal of Pharmacology 08/2014; 171(16):3777-3800. DOI:10.1111/bph.12744 · 4.84 Impact Factor
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    • "Butorphanol is closely related, the difference being an N-methylcyclobutyl group and a 14-OH. They all display high affinity for mu receptors in binding assays, but these changes also lead to a loss of selectivity, with the compounds displaying high affinity for other receptor classes (Moulin et al., 1988; Tive et al., 1992; Inturrisi, 2002; Rowbotham et al., 2003; Majumdar et al., 2011). Their lack of selectivity for mu receptors may help explain their complex pharmacology, especially with evidence now showing a role for a truncated MOR-1 splice variant in their actions (see section VIII.C.3.b). "
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    ABSTRACT: Opiates are among the oldest medications available to manage a number of medical problems. Although pain is the current focus, early use initially focused upon the treatment of dysentery. Opium contains high concentrations of both morphine and codeine, along with thebaine, which is used in the synthesis of a number of semisynthetic opioid analgesics. Thus, it is not surprising that new agents were initially based upon the morphine scaffold. The concept of multiple opioid receptors was first suggested almost 50 years ago (Martin, 1967), opening the possibility of new classes of drugs, but the morphine-like agents have remained the mainstay in the medical management of pain. Termed mu, our understanding of these morphine-like agents and their receptors has undergone an evolution in thinking over the past 35 years. Early pharmacological studies identified three major classes of receptors, helped by the discovery of endogenous opioid peptides and receptor subtypes-primarily through the synthesis of novel agents. These chemical biologic approaches were then eclipsed by the molecular biology revolution, which now reveals a complexity of the morphine-like agents and their receptors that had not been previously appreciated.
    Pharmacological reviews 07/2013; 65(4):1257-1317. DOI:10.1124/pr.112.007138 · 17.10 Impact Factor
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    • "A 6TM μ-opioid receptor (MOR-1) variant in mice can identify ligands which lack the traditional side effects of classical opiates but maintain significant analgesic properties [6], and a 5TM somatostatin (sst2) receptor also retains functional activity and generates a receptor displaying an altered pharmacology [49]. A large series of splice variants of μ-OR (MOR) have been isolated from mice, rats, and humans with similar splicing patterns [6]. Most MOR-1 knock-out mice with a disruption of exon 1 were unresponsive to morphine, but mice with a series of MOR-1 variants generated from a second, upstream promoter associated with exon 11 had quite different pharmacology. "
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    ABSTRACT: Alternative splicing of G protein-coupled receptor (GPCR) genes greatly increases the total number of receptor isoforms which may be expressed in a cell-dependent and time-dependent manner. This increased diversity of cell signaling options caused by the generation of splice variants is further enhanced by receptor dimerization. When alternative splicing generates highly truncated GPCRs with less than seven transmembrane (TM) domains, the predominant effect in vitro is that of a dominant-negative mutation associated with the retention of the wild-type receptor in the endoplasmic reticulum (ER). For constitutively active (agonist-independent) GPCRs, their attenuated expression on the cell surface, and consequent decreased basal activity due to the dominant-negative effect of truncated splice variants, has pathological consequences. Truncated splice variants may conversely offer protection from disease when expression of co-receptors for binding of infectious agents to cells is attenuated due to ER retention of the wild-type co-receptor. In this review, we will see that GPCRs retained in the ER can still be functionally active but also that highly truncated GPCRs may also be functionally active. Although rare, some truncated splice variants still bind ligand and activate cell signaling responses. More importantly, by forming heterodimers with full-length GPCRs, some truncated splice variants also provide opportunities to generate receptor complexes with unique pharmacological properties. So, instead of assuming that highly truncated GPCRs are associated with faulty transcription processes, it is time to reassess their potential benefit to the host organism.
    Journal of Molecular Signaling 09/2012; 7(1):13. DOI:10.1186/1750-2187-7-13
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