Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Opioid Receptor

  • Vladana Vukojević
  • Yu Ming
  • Tijana Jovanović-Talisman
  • Lars Terenius
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_596

Synonyms

From http://www.genome.jp/kegg/genes.html

 μ-opioid receptor (MOP): OPRM1, KIAA0403, LMOR, MOR, MOR1, OPRM

 δ-opioid receptor (DOP): OPRD1, OPRD

 κ-opioid receptor (KOP): OPRK1, KOR, OPRK

 Nociceptin opioid receptor (NOP): OPRL1, KOR-3, MGC34578, NOCIR, OOR, ORL1

Historical Background

The existence of opioid receptors (OR) was postulated in 1954 (Beckett and Casy 1954), at a time when evidence for specific drug-responsive substances was evasive and the concept of biochemical receptors was still in its infancy. Unequivocal confirmation of specific binding sites for opioids in the brain was first reported in 1973 (Pert and Snyder 1973; Simon et al. 1973; Terenius 1973). This breakthrough was shortly followed by evidence that opioid ligands bind specifically to different anatomical locations and show different pharmacological activity, suggesting that several types of opioid receptors exist (Martin et al. 1976; Lord et al. 1977). Based on extensive pharmacological and animal model studies that followed, opioid receptors were originally classified into four types: mu (μ), kappa (κ), sigma (σ), and delta (δ). The first three variants were named after specific ligands used for their characterization: μ after morphine, κ after ketocyclazocine, and σ after SKF-10047, whereas the δ-opioid receptor was identified in mice and named after the thick-walled tube in the male reproductive system (called the vas deferens) from which it was characterized (Lord et al. 1977). The ultimate proof for the existence of opioid receptor subtypes was provided by the isolation of mouse δ-opioid receptor mRNA, leading to cDNA synthesis and receptor cloning (Kieffer et al. 1992; Evans et al. 1992). Subsequent studies have led to the identification of receptor sequences for the μ- and κ-opioid receptors, dismissed the σ-opioid receptor as an opioid receptor family member, and revealed the existence of a receptor with a sequence similar to opioid receptors but with distinct pharmacology. This “opioid receptor-like” (ORL), or nociceptin/orphanin (N/OFQ) protein, remained an “orphan” receptor until its corresponding endogenous peptide ligand nociceptin/orphanin FQ was identified in 1995 (Meunier et al. 1995; Reinscheid et al. 1995). It is nowadays commonly regarded that the opioid receptor family contains four types, the classical opioid receptors μ, δ, and κ, and the nonclassical nociceptin opioid receptor. The Committee on Receptor Nomenclature and Drug Classification of the International Union of Basic and Clinical Pharmacology (IUPHAR) has recommended that μ, δ, κ, and nociceptin opioid receptors should be denoted as MOP, DOP, KOP, and NOP, respectively.

Opioid Receptor Relevance

Opioid receptors MOP, DOP, KOP, and NOP, and their respective peptide ligands: endorphins, enkephalins, dynorphins, and nociceptin/orphanin, constitute the endogenous opioid neuromodulatory system. This system plays a critical role in regulating sensory and cognitive system functions and is intricately implicated in emotional self-regulation (Bodnar 2010). For example, the opioid system controls the nociceptive pathways (response to noxious and painful stimuli) and plays a decisive role in substance and behavioral addiction, mental disorders, memory, learning, and response to stress. In addition, the opioid system is implicated in the regulation of neuroendocrine, cardiovascular, gastrointestinal, renal and hepatic functions, hormonal activity, respiration, thermoregulation, and immunological responses.

Opioid receptors are also very important pharmacological targets – natural alkaloid opiates like morphine or synthetic opiates like methadone are potent pain-killers but also highly addictive drugs. Opioid antagonists, such as naltrexone, are clinically used to reduce craving in substance addiction (heroin, alcohol, and amphetamine), food abuse in obesity, and the hedonic responses in nonsubstance-related, i.e., behavioral addictions (gambling and gaming).

Opioid Receptor Evolution

The opioid system is an ancient neuromodulatory system. Chromosomal phylogeny studies suggest that the opioid system with four receptor types and four opioid peptide precursors was already present approximately 450 million years ago (Dreborg et al. 2008). These studies imply that the ancestral opioid peptide precursor and opioid receptor gene were located on the same chromosome and concomitantly duplicated in two whole genome duplication events. The first genome duplication incident yielded two genes DOP/MOP and NOP/KOP and their precursors. A second genome duplication event has led to the development of four opioid receptor types and three opioid precursor molecules. The fourth opioid peptide precursor gene appeared to be created later on, through local gene duplication (Dreborg et al. 2008).

The opioid system, with four types of receptors and opioid peptide precursors, has been identified in all vertebrate organisms. In humans, opioid receptors are encoded by opioid receptor (OPR) genes: OPRM1 encoding MOP, OPRD1 encoding DOP, OPRK1 encoding KOP, and OPRL1 encoding NOP. They are located on four different chromosomes: OPRD1 on chromosome 1, OPRM1 on chromosome 6, OPRK1 on chromosome 8, and OPRL1 on chromosome 20 (Fig. 1, green). Opioid peptides are derived from four prepropeptide genes: the proopiomelanocortin (POMC), proenkephalin (PENK), prodynorphin (PDYN), and prepronociceptin (PNOC), encoding the precursors of endorphins, enkephalins, dynorphins, and nociceptin/orphanin, respectively (Fig. 1, red).
Opioid Receptor, Fig. 1

Chromosomal mapping of human opioid system genes. Opioid receptors genes (green): OPRM1 encoding MOP, OPRD1 encoding DOP, OPRK1 encoding KOP, and OPRL1 encoding NOP sequences are located on four different chromosomes: 6, 1, 8, and 20, respectively. Opioid peptide precursor genes (red): proopiomelanocortin (POMC), proenkephalin (PENK), prodynorphin (PDYN), and prepronociceptin (PNOC) are located on three different chromosomes: 2, 8, 8, and 20, respectively. Chromosomal phylogeny studies suggest that the ancestral opioid peptide precursor and opioid receptor genes were located on the same chromosome and suggest that the current system with four opioid receptor types and four opioid peptide precursors had evolved through two whole genome duplication events, where the ancestral opioid receptor and opioid peptide precursor genes were concomitantly duplicated. Through this process, all four opioid receptor genes and three opioid peptide precursor genes were derived, whereas the fourth opioid peptide precursor gene was suggested to evolve through a local duplication event (Dreborg et al. 2008) (Image adapted using the Ensembl genome databases for vertebrates and other eukaryotic species as a template (http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00500000269674))

Opioid Receptor Cellular Dynamics and Function

Opioid receptors transmit chemical signals across the cellular plasma membrane. Opioid receptors and/or opioid peptide precursors are expressed in neuronal and nonneuronal cells. The cellular physiology of opioid receptor and opioid peptide production is complex. In brief, the opioid receptors and opioid peptide precursor molecules are assembled by ribosomes, transferred to the endoplasmic reticulum (ER), the Golgi complex, and the trans-Golgi network (TGN) and sorted into transport vesicles. During this process, opioid receptor molecules undergo several posttranslational modifications such as disulfide bond formation, palmitoylation, acetylation, phosphorylation, and glycosylation, whereas the peptide precursor molecules are subjected to proteolytic cleavage by prohormone convertases (PC). At the cell termini, opioid receptors are inserted into the plasma membrane, whereas opioid peptides are secreted by transport vesicles fusing with the cell membrane.

Opioid peptides secreted by presynaptic neurons bind to opioid receptors on the postsynaptic neurons and activate the secondary messenger system (Fig. 2a). Opioid receptors make no direct links with effector proteins. Instead, their “message” is generally relayed via the heterotrimeric guanine nucleotide-binding proteins – opioid receptors are therefore classified as G protein-coupled receptors (GPCR). It has been demonstrated that activation of opioid receptors may lead to the closing of voltage sensitive calcium channels (VSCC), stimulation of potassium efflux, or reduced cyclic adenosine monophosphate (cAMP) production via the inhibition of adenylyl cyclase. In this way, opioid ligands cause a range of physiological and behavioral effects that can last several seconds to several days at the organism level (Dean et al. 2009).
Opioid Receptor, Fig. 2

Schematic presentation of a synaptic cleft with opioid receptor signaling and intracellular trafficking. (a) Endogenous opioid ligand molecules (green spheres) secreted from the presynaptic neuron (on top) bind to an opioid receptor (red, bottom) located at the postsynaptic neuron. The agonist-bound receptor canonically initiates cellular signaling by activating the heterotrimeric G protein and causing its dissociation into α- and βγ-subunits. The subunits can activate a number of cellular responses, such as protein kinase C (PKC) mediated enhancement of KATP channel activity (green arrows). The agonist-bound opioid receptor devoid of the G proteins can rapidly undergo phosphorylation by GPCR kinases (GRK) (black arrows). Selective phosphorylation of the activated receptor and subsequent binding of β-arrestin prevent further interactions of the activated receptor with G proteins and enables receptor sorting to clathrin-coated pits for receptor endocytosis, thereby effectively terminating the G protein-mediated signaling. Further sorting of endocytosed opioid receptors between divergent downstream pathways may produce additional distinct effects on cellular signaling. For example, sorting of internalized receptors to lysosomes promotes proteolytic degradation of receptors (red arrow), preventing receptors from signaling again and resulting in a prolonged attenuation of cellular signaling. In contrast, sorting of internalized receptors into a rapid recycling pathway, promotes the return of intact receptors to the plasma membrane and effectively resensitizes cells to respond again to the extracellular ligand (blue arrow). While this mechanism has been inferred from numerous studies, however, quantitative information on the cellular dynamics of opioid receptors and the kinetics of the underlying interactions is still limited (Image adapted and reprinted with permission from (Hanyaloglu and von Zastrow 2008)) (b) Dual-color Confocal Laser Scanning Microscopy (CLSM) image of live PC12 cells stably transformed to express the kappa-opioid receptor fused with the enhanced Green Fluorescent Protein (KOP-eGFP; green) recorded 15 min after stimulation with 150 nM Dynorphin A fluorescently tagged with carboxytetramethylrhodamine (Dyn A-TAMRA; red). CLSM shows ligand-receptor colocalization in the plasma membrane (yellow) and inward moving trafficking vesicles that contain ligand-receptor complexes and/or both the ligand and the receptor (yellow). Outward moving trafficking vesicles transport newly synthesized KOP-eGFP receptors to the plasma membrane (green). In lysosomes (red vesicles), eGFP is degraded and TAMRA, which is not biodegradable, is accumulated

Increasing experimental evidence supports the notion that opioid receptor cellular dynamics and localization in the plasma membrane are central to opioid receptor signaling. Cellular dynamics of surface receptors is a critical factor in determining receptor availability at the plasma membrane (Hanyaloglu and von Zastrow 2008). A number of factors and highly regulated processes are involved in opioid receptor cellular dynamics. For example, endocytic membrane trafficking is an important regulator of opioid receptor density at the membrane surface (Fig. 2b). Through this dynamic process, the surface density of opioid receptors and their availability for ligand activation can be controlled without modifying the overall number of receptors through receptor synthesis (up- or downregulation). Opioid receptor ligands differ in their ability to induce receptor trafficking. For example, opioid peptides such as DAMGO cause internalization of MOP, whereas the alkaloid morphine produces little MOP internalization.

Opioid Receptor Structure

The crystal structures of opioid receptors were determined in 2012 (Manglik et al. 2012; Wu et al. 2012; Thompson et al. 2012; Granier et al. 2012), revealing information on intramolecular geometry, low energy conformations, hydrogen bonds, and intra- and intermolecular interactions. Previously, opioid receptor structures and structural requirements for ligand binding and selectivity were assessed indirectly, using methods such as site-directed mutagenesis, affinity labeling, and chimeric receptor design. In addition, computational techniques enabling homology modeling were used in order to predict the three-dimensional (3D) receptor structure and the possible binding sites for different ligands (docking studies). Over the years, these methods have been successfully used to build realistic models of primary, secondary, and tertiary structures of opioid receptors in their native environment, the plasma membrane, and identify key contacts in ligand recognition sites (Kane et al. 2006). Cumulatively, these studies have shown that opioid receptors are integral, rhodopsin-like proteins that span the plasma membrane by seven helical transmembrane (TM) domains (Fig. 3). Opioid receptor types show a high sequence identity in their transmembrane (TM) domains (about 75%) and the cytoplasmic loops (about 65%), whereas the sequence identity in the N- and C-terminal domains and extracellular loops appears to be rather modest (about 37%). The sites for opioid ligand binding are not unequivocally determined, but the role of Asp in the third transmembrane domain (TM3:08) and His in the sixth transmembrane domain (TM6:17) have been repeatedly shown to be relevant for opioid ligand binding. The large intracellular loop between TM5 and TM6 is presumed to be the contact site with the G-protein α-subunit.
Opioid Receptor, Fig. 3

Opioid receptor structure. Schematic representation of human MOP structure. Amino acids conserved between human MOP, DOP, and KOP are indicated in red. Putative asparagine-linked glycosylation sites in the extracellular N-terminus and alleged palmitoylation sites at cysteine residues in the C-terminus are indicated. A potential intramolecular disulfide bond between cysteine residues in extracellular loops 1 and 2 is also shown. The sites for opioid ligand binding are not unequivocally determined, but the role of Asp in the third transmembrane domain (TM3:08) and His in the sixth transmembrane domain (TM6:17) have been repeatedly shown to be relevant. The large intracellular loop between TM5 and TM6 is presumed to be the contact site with the G-protein α-subunit (Image reprinted with permission from Levac et al. (2002)). A schematic representation of the secondary structure all for types of opioid receptors is presented below

Opioid Receptor Isoforms

Naturally occurring differences in opioid receptor primary structure can alter opioid receptor binding properties and signaling, thereby predisposing a susceptibility to disease and responsiveness to therapy. Missense mutations and alternative splicing are two principle mechanisms through which opioid receptor variants are generated.

In missense mutations, a single nucleotide change yields a protein molecule with one different amino acid. Currently, 18 missense mutations have been identified in the human MOP gene OPRM1, with 12 missense mutations occurring naturally at a frequency >1%. Consequences of the most commonly occurring missense mutations in the OPRM1 gene on the MOP primary structure are schematically depicted in Fig. 4. For example, the N40D polymorphism (Fig. 4, highlighted in red) is suggested to be related with improved response to naltrexone, an opiate antagonist used clinically for treating addiction to opiate drugs and alcohol (Anton et al. 2008).
Opioid Receptor, Fig. 4

MOP variants generated by naturally occurring missense mutations. Schematic drawing of MOP structure with alterations in amino acid sequence due to the 12 most frequently encountered missense mutations (Image reprinted with permission from Fortin et al. (2010)). The N40D polymorphism (highlighted in red) is suggested to offer an improved response to naltrexone, an opiate antagonist used clinically for treating addiction to opiate drugs and alcohol (Kane et al. 2006)

Splicing is a regulated modification of the pre-mRNA generated by gene transcription in which introns are removed and exons are joined. Alternative splicing of pre-mRNA may result in the creation of different mRNAs, which may be translated into opioid receptor isoforms differing in several amino acids. So far, at least six alternative splicing variants of hMOP have been described (Anton et al. 2008).

Opioid Receptor Oligomerization

Surface receptor oligomerization is a common way to increase the functional repertoire of the receptor and represents a key regulatory step in the function of several GPCRs (Pan et al. 2003). In addition, receptor oligomerization may be a critical step for rapid “fine-tuning” of receptor density at the plasma membrane. The dynamic equilibrium between monomers and oligomers can be changed quickly in one direction or the other, rendering the receptor available/not available for ligand (Milligan 2010). Opioid receptor homo- and hetero-oligomerization has been inferred from a variety of studies. However, quantitative information on the cellular dynamics of opioid receptor dimers is still limited and many molecular details of the oligomerization process have yet to be resolved.

Opioid Receptor Association with Lipid Rafts

The cellular dynamics and function of opioid receptors can be significantly affected by the cell membrane microenvironment. The plasma membrane is highly organized into structurally and functionally distinct microdomains. Opioid receptors, G-proteins, and signaling effectors such as second-messenger-generating enzymes appear to be primarily localized to membrane microdomains known as lipid rafts (Fig. 5) (Vukojević et al. 2008; Baker et al. 2007). Lipid rafts may differentially affect opioid receptor function (Fig. 5ac), and their disruption may alter the binding properties and signal transduction of opioid receptors localized in lipid rafts. For example, it has been shown that the disruption of lipid rafts in rat caudate putamen membranes decreased the Emax values of both DAMGO and morphine at MOP without affecting their EC50 (Huang et al. 2008). Super-resolution fluorescence microscopy techniques have significantly evolved in the past few years, enabling molecular localization of proteins with high precision (∼10–25 nm). This approach can provide glimpses on how opioid receptors are arranged at the nanoscale level with respect to other molecules found within lipid rafts (Fig. 5d) (Tobin et al. 2014; Hall et al. 2016).
Opioid Receptor, Fig. 5

Schematic representation of lipid rafts role in opioid receptor function. (a) Lipid rafts are cholesterol- and sphingolipid-enriched submicroscopic assemblies of about 25–200 nm in diameter, which are spontaneously generated in the plasma membrane. In mammalian cells, these dynamic assemblies can be planar or flask-shaped invaginations of the plasma membrane in which signaling and effectors molecules, such as opioid receptors, G proteins, and second-messenger generating enzymes, may be located and poised to form functional signaling units. (b) The lipid raft signaling hypothesis proposes that signaling molecules are spatially organized to promote kinetically favorable interactions that are necessary for signal transduction. (c) Alternatively, lipid raft microdomains might inhibit interactions by separating the signaling molecules, thereby dampening signaling responses (Image reprinted with permission from Allen et al. (2007)). (d) Distribution of MOP and GPI at the nanoscale level by dual-color PhotoActivated Localization Microscopy (PALM). Top: Section of MDA-MB-468 cell (scale bar 2 μm) showing the distribution of antibody detected MOP (in red) and paGFP-GPI (in green). Peak centers are shown. Bottom: The cross-correlation curve indicates that MOP and GPI show partial colocalization in the steady state (gray squares, s.e.m., n = 23), suggesting that a fraction of MOP likely resides in GPI-enriched lipid rafts (Tobin et al. 2014) (Image used with permission)

Summary

The opioid neuromodulatory system is a dynamic, spatio-temporally orchestrated structure comprising signaling circuitries at all levels of organization – the cellular, organ, and organism levels. The opioid system is implicated in the regulation of physiological, sensory, cognitive, and emotional functions. The importance of the opioid system for normal physiology is long known and drugs targeting this innately complex system have been used for centuries recreationally and for medical purposes. Despite extensive utilization of opioid receptors as drug targets, advances in opiate pharmacotherapy, and intensive research, we still do not fully understand the function of the opioid system at the cellular and molecular level. Moreover, we have yet to learn how best to control the potentially deleterious effects of opioids. Given the manifold functions of the opioid system, it is not surprising that drugs targeting show numerous unwanted side effects, such as inhibition of gastrointestinal motility, respiratory depression, muscle rigidity, altered thermoregulation, sedation, mood disorders, dependence, and abuse.

This review succinctly summarizes our current understanding of the cellular and molecular mechanisms underlying opioid system function, with a focus on the opioid receptor role. Since the previous edition of the Encyclopedia of Signaling Molecules, significant progress has been made and the most pertinent information missing at that time is now available. In particular, the 3D structures of opioid receptors have been resolved (Manglik et al. 2012; Wu et al. 2012; Thompson et al. 2012; Granier et al. 2012), providing a basis for understanding mechanistic details of opioid receptor function at the atomic level (Huang et al. 2015; Sounier et al. 2015) and advancing drug discovery (Manglik et al. 2016). Despite these outstanding progresses, as the available opioid receptor crystal structures include only those forms of the receptors stabilized by high-affinity ligands, it is still unclear how opioid receptors can successfully accommodate and elicit a specific response to over dozens of compounds, differing widely in chemical composition and reactivity.

During the past few years, significant progress was also made in understanding the nanoscale distribution of MOP using super-resolution fluorescence microscopy techniques (Tobin et al. 2014; Jorand et al. 2016; Halls et al. 2016). These studies show that MOP largely organizes into nano-domains and that a fraction of this receptor associates with GPI-enriched domains (Tobin et al. 2014; Jorand et al. 2016). While a complete picture of the physiological importance of cell surface MOP lateral organization is lacking, a number of details are emerging (Halls et al. 2016), such as the chemical composition, size, and lifetime of opioid receptor receptor-harboring domains.

A better understanding of opioid receptor function will offer new insight into how drug-induced signals can be converted into long-term alterations in cellular function. Changes in opioid receptor trafficking and organization at the plasma membrane may represent the first steps in a cascade of events leading to the remodeling of signaling circuits and eventually to altered behavior, including drug-seeking and compulsive opiate use. Such changes at the neuronal level may even underlie the long persistence of addiction and the risk for relapse! Thus, studies on opioid receptor function at the molecular and cellular levels are of great importance for characterizing opioid system function. These studies may therefore deepen our understanding of the role of the opioid system in the development of tolerance, addiction, and adaptive transformations specific for opioid receptor-mediated signaling pathways that have largely restricted the effective use of opiates in clinical applications.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Vladana Vukojević
    • 1
  • Yu Ming
    • 1
  • Tijana Jovanović-Talisman
    • 2
  • Lars Terenius
    • 1
  1. 1.Center for Molecular Medicine, Department of Clinical NeuroscienceKarolinska InstituteStockholmSweden
  2. 2.Department of Molecular MedicineBeckman Research Institute of the City of Hope Comprehensive Cancer CenterDuarteUSA