Alternative titles; symbols
HGNC Approved Gene Symbol: OPRM1
Cytogenetic location: 6q25.2 Genomic coordinates (GRCh38) : 6:154,010,496-154,246,867 (from NCBI)
The OPRM1 gene encodes the mu opioid receptor, which is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. It is also the primary receptor for endogenous opioid peptides beta-endorphin (see POMC, 176830) and the enkephalins (see PENK, 131330). The OPRM1 receptor is a member of the G protein-coupled receptor family (Bond et al., 1998). There are at least 3 types of opioid receptors, mu, kappa (OPRK1; 165196), and delta (OPRD1; 165195), each with a distinct pharmacologic profile (Chen et al., 1993).
Chen et al. (1993) cloned cDNAs for the mu receptor from rat brain. They demonstrated that this receptor, like the kappa-opioid receptor, possesses a putative secondary structure of 7 transmembrane domains common to G protein-coupled receptors and displays functional coupling to adenylyl cyclase.
Using rat mu opiate receptor cDNA to screen a human cerebral cortex cDNA library, Wang et al. (1994) cloned OPRM1, which they called MOR1. The deduced 400-amino acid protein contains 5 N-glycosylation sites near the N terminus, followed 7 transmembrane domains spread throughout the molecule.
Cadet et al. (2003) identified an OPRM1 splice variant that they termed mu-3. The deduced protein contains 434 amino acids. Northern blot analysis detected a 1.3-kb mu-3 transcript in heart endothelium and leukocytes.
Pan et al. (2003) cloned 2 OPRM splice variants that they termed MOR1O and MOR1X. Both have alternative exons (exons O and X, respectively).
Pan (2005) reviewed the complex splicing of the mouse, rat, and human OPRM1 genes. Of the 12 splice variants of human OPRM1 he reported, 10 differ at their 3-prime ends and encode proteins with different C termini, which alters the kinase that can phosphorylate them. The other 2 human variants are mu-3 and MOR1S, which lacks the internal exons 2 and 3.
Shabalina et al. (2009) cloned 2 OPRM1 splice variants that they termed MOR1K1 and MOR1K2. The longer MOR1K1 variant is preferentially expressed in the medulla oblongata, while the shorter MOR1K2 variant is preferentially expressed in the spinal cord. Both variants are present in the frontal lobe and nucleus accumbens. The MOR1K isoforms encode a truncated OPRM1 protein that lacks the extracellular N-terminal domain and transmembrane domain I. The transcriptional start site was mapped to an OPRM1 promoter region upstream of exon 13.
Shabalina et al. (2009) characterized an expanded human OPRM1 gene with additional promoters, alternative exons, and regulatory elements. They determined that the OPRM1 gene contains 18 exons, which they designated from 5-prime to 3-prime as exons 11, 1, T, 14, 13, 2, 3, R, Y, 16, X, 17, 5, 4, 18, 6, O/7, and 9.
Using multilocus cross analysis in the mouse, Kozak et al. (1994) located the mu receptor gene, Oprm, to chromosome 10. Since the kappa receptor gene, Oprk1, maps to chromosome 1, the 2 opioid receptors must represent different gene products and not the product of differential splicing from the same gene. Oprm is located in a region of chromosome 10 that is homologous to 6q. Wang et al. (1994) isolated an 18-kb genomic clone and showed by in situ hybridization that the OPRM1 gene maps to chromosome 6q24-q25. They identified an MspI polymorphism and suggested that it might be useful in assessing the involvement of the gene in neuropsychiatric disorders.
Wang et al. (1994) found that human MOR1 expressed in COS cells bound with high affinity to a mu opiate-specific ligand. Binding between MOR1 and the ligand was disrupted by related opiate drugs and peptides and was sensitive to sodium and GTP.
Mansour et al. (1995) demonstrated that immunoreactive fibers and/or perikarya to polyclonal antibodies generated to the C terminal 63 amino acids of the cloned mu receptor are distributed widely in the central nervous system of the rat.
Using positron emission tomography and radioactive carfentanil, a selective OPRM1 radiotracer, and by following up with magnetic resonance imaging and the McGill Pain Questionnaire, Zubieta et al. (2001) examined the function of the opioid system and mu opioid receptors in individuals exposed to placebo and sustained pain applied to the jaw muscles. They observed an increased release of endogenous opioids blocking the OPRM1 sites in the ipsilateral amygdala and in the contralateral ventrolateral portion of the thalamus. The interaction with OPRM1 was associated with attenuation of the sensory and pain-specific affective responses to a sustained painful stimulus.
He et al. (2002) demonstrated that DAMGO, a hydrolysis-resistant derivative of enkephalin (see 131330), can facilitate the ability of morphine to stimulate OPRM1 endocytosis. As a consequence, rats treated chronically with both drugs showed reduced analgesic tolerance compared to rats treated with morphine alone. These results demonstrated that endocytosis of OPRM1 can reduce the development of tolerance and suggested an approach for the development of opiate analogs with enhanced efficacy for the treatment of chronic pain.
Cadet et al. (2003) found that the mu-3 OPRM variant selectively responded to opiate alkaloids, releasing nitric oxide in response to morphine. The mu-3 variant was insensitive to opioid peptides.
Pan et al. (2003) found that the MOR1O and MOR1X OPRM splice variants showed high selectivity for mu opioids in binding assays.
Zubieta et al. (2003) examined the influence of a common functional genetic polymorphism, the val158-to-met allele of COMT (116790.0001), which affects the metabolism of catecholamines, on the modulation of responses to sustained pain in humans. Individuals homozygous for the met158 allele showed diminished regional mu opioid system responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in the val158 homozygotes. Zubieta et al. (2003) concluded that the COMT val158-to-met polymorphism influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli.
Paradoxically, morphine fails to promote desensitization and endocytosis of MOR, processes that typically contribute to tolerance with other receptors. Finn and Whistler (2001) showed that replacing the cytoplasmic tail of mouse Mor with that of the delta opioid receptor facilitated endocytosis and led to reduced development of cellular tolerance and cAMP superactivation, a cellular hallmark of withdrawal. Furthermore, mutant receptors with reduced endocytosis produced exacerbated superactivation. Finn and Whistler (2001) concluded that receptor endocytosis plays a critical role in the development of adverse side effects associated with prolonged opiate use.
Agirregoitia et al. (2006) studied the expression and localization of delta (OPRD1; 165195), kappa (OPRK1; 165196), and mu (OPRM1) opioid receptors on human spermatozoa and the implication in sperm motility. These receptors are located in different parts of the head, in the middle region, and in the tail of the sperm. Progressive motility of spermatozoa, an important parameter to evaluate male fertility, was significantly reduced after incubation with the mu receptor agonist morphine, whereas this effect was antagonized in the presence of the corresponding antagonist naloxone. The delta receptor antagonist naltrindole significantly reduced progressive motility immediately after its addition. However, the delta receptor agonist DPDPE had no significant effect. Finally, neither the kappa receptor agonist U50488 nor its antagonist norbinaltorphimine significantly affected the progressive motility of human spermatozoa.
Duraffourd et al. (2012) found that Mor present in rodent nerves and portal vein walls responded to infused or dietary peptides and regulated intestinal gluconeogenesis and satiety.
Corder et al. (2013) found that tissue injury produced OPRM1 constitutive activity that repressed spinal nociceptive signaling for months. Pharmacologic blockade during the post-hyperalgesia state with OPRM1 inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including AMP overshoot and hyperalgesia) that required NMDA receptor activation of adenylyl cyclase type 1 (ADCY1; 103072). Thus, OPRM1 initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Corder et al. (2013) suggested that tonic OPRM1 suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.
Mogil (1999) and Uhl et al. (1999) reviewed the genetic basis of individual differences in sensitivity to pain and its inhibition, and suggested that the mu opiate receptor may be a candidate gene for variation in pain perception and response to opioids. They noted that there are differences between human individuals and between mouse strains in levels of mu opiate receptor expression, responses to painful stimuli, and responses to opiate drugs.
Hoehe et al. (2000) used a multiplex sequence comparison method to test the potential role of OPRM1 in substance (heroin/cocaine) dependence (see susceptibility to opioid dependence, 610064) in 250 cases and controls. A total of 43 variants were identified within coding and noncoding regions of the OPRM1 gene, and 52 different haplotypes were predicted in the subgroup of 172 African Americans. These haplotypes were classified by similarity clustering into functionally related categories, one of which was significantly more frequent in substance-dependent individuals. Common to this category was a characteristic pattern of sequence variants [-1793T-A, -1699insT, -1320A-G, -111C-T, +17C-T(A6V)], which was associated with substance dependence.
Among 318 European American individuals with substance dependence (opioid and alcohol dependence; 103780) and 179 controls, Luo et al. (2003) found a significant difference in haplotype frequency of alleles at the OPRM1 locus (p = 0.0036). Allele -2044C-A, in the 5-prime putative regulatory region, and haplotypes that included -2044C-A were the susceptibility allele and haplotypes, respectively, associated with substance dependence. However, similar associations were not found among 124 African Americans with substance abuse and 55 African American controls. The findings suggested that OPRM1 may play a role in the pathophysiology of substance dependence and that the role is population-specific.
Befort et al. (2001) investigated whether the mutations asn40 to asp (N40D; rs1799971; 600018.0001) in the extracellular N-terminal region, asn152 to asp (N152D) in the third transmembrane domain, and arg265 to his (R265H) and ser268 to pro (S268P) in the third intracellular loop (Hoehe et al., 2000) altered functional properties when the receptor was expressed in COS cells. Binding analysis determined that affinities to structurally diverse opioids and opioid peptides were not markedly different in the mutant receptors. However, Scatchard analysis showed that expression of N152D was significantly lower than that of the wildtype receptor. Binding and reporter gene analysis indicated that both mutations in the third intracellular loop, particularly S268P, impair signaling along the cAMP signaling cascade. Given the ability of OPRM1 antagonists to alter drug and alcohol dependence, Befort et al. (2001) proposed that examination of patients expressing S268P from one or both alleles may illuminate the functional consequences of decreased OPRM1 receptor function in humans.
Wang et al. (2001) studied 3 SNPs causing amino acid substitutions in the third intracellular loop of MOR: S268P, R265H, and arg260 to his (R260H). The 3 variants and wildtype MOR responded comparably to morphine in terms of G protein coupling. However, spontaneous agonist-independent (basal) MOR signaling, which is thought to play a role in opioid tolerance and dependence, was significantly reduced in the R260H and R265H variants. Furthermore, the R265H and R268H variants showed deficient calmodulin (see CALM1; 114180) binding. Wang et al. (2001) suggested that carriers of these 3 variants, which all show substantial changes in basal G protein coupling, calmodulin binding, or both, may display altered response to narcotic analgesics.
Hao et al. (2004) conducted a large-scale case-control study exploring the associations of 426 single-nucleotide polymorphisms (SNPs) with preterm delivery (PTD) in 300 mothers with PTD and 458 mothers with term deliveries. Twenty-five candidate genes were included in the final haplotype analysis. Gene haplotypes at IL1R2 (147811) in blacks, NOS2A (163730) in whites, and OPRM1 in Hispanics were only associated with PTD in these specific ethnic groups.
By haplotype analysis, Shabalina et al. (2009) identified a novel C-T variant (rs563649) in the 5-prime untranslated region of the MOR1K isoforms that was the strongest individual contributor to measured pain sensitivity responses in 196 pain-free European American females. The C-T variant is located within a structurally conserved internal ribosome entry site (IRES) upstream of exon 13 and affects both mRNA levels and translation efficiency of MOR1K isoforms. Strong linkage disequilibrium was identified between rs563649 and rs1799971, and the minor T allele of rs563649 tagged a 6-SNP (AGTCTG) haplotype associated with high pain sensitivity. Shabalina et al. (2009) proposed an essential role for MOR1K isoforms in nociceptive signaling and suggested that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.
For a discussion of a possible association between variation in the OPRM1 gene and susceptibility to idiopathic generalized epilepsy, see 600669.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including OPRM1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Crystal Structure
Manglik et al. (2012) described the 2.8-angstrom crystal structure of the mouse mu-opioid receptor in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the mu-opioid receptor crystallizes as a 2-fold symmetrical dimer through a 4-helix bundle motif formed by transmembrane segments 5 and 6.
Huang et al. (2015) reported a 2.1-angstrom X-ray crystal structure of the murine mu-opioid receptor bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the mu-opioid receptor binding pocket are subtle and differ from those observed for agonist-bound structures of the beta(2)-adrenergic receptor (ADRB2; 109690) and the M2 muscarinic receptor (CHRM2; 118493). Comparison with active ADRB2 revealed a common rearrangement in the packing of 3 conserved amino acids in the core of the mu-opioid receptor, and molecular dynamics simulations illustrated how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all 3 G protein-coupled receptors.
Matthes et al. (1996) found that heterozygous or homozygous Oprm1-knockout mice had no obvious morphologic abnormalities and no overt behavioral abnormalities. Lack of the receptor abolished the analgesic effect of morphine, as well as physical dependence, in mutant mice. The findings indicated that Oprm1 is the molecular target of morphine in vivo.
Moles et al. (2004) reported that mu opioid receptor knockout mouse pups emit fewer ultrasonic vocalizations when removed from their mothers but not when exposed to cold or male mice odors. Moreover these knockout pups do not show a preference toward their mothers' cues and do not show ultrasonic calls potentiation after brief maternal exposure. Moles et al. (2004) concluded that their results from this study may indicate a molecular mechanism for diseases characterized by deficits in attachment behavior, such as autism or reactive attachment disorder. Gernsbacher et al. (2005) questioned the validity of Moles et al. (2004) assertion that autism is a deficit in attachment behavior.
Rousseaux et al. (2007) found that the probiotic bacterial strain Lactobacillus acidophilus NCFM induced a sustained increase of OPRM1 and cannabinoid receptor-2 (CNR2; 605051) mRNA expression in human intestinal epithelial cells. In vivo experiments in mice and rats revealed that oral administration of L. bacillus NCFM induced colonic expression of OPRM1 and CNR2 and, in studies in rats, decreased normal visceral perception with a 20% increase in the pain threshold as elicited by colorectal distention. In a rat model of chronic colonic hypersensitivity that mimics irritable bowel syndrome, oral administration of NCFM resulted in an antinociceptive effect of the same magnitude as that caused by the subcutaneous administration of 1 mg per kg of morphine. NCFM-induced analgesia was significantly inhibited by peritoneal administration of a CNR2-selective antagonist but not by an opioid receptor antagonist. Rousseaux et al. (2007) concluded that direct contact of NCFM with epithelial cells can induce OPRM1 and CNR2 expression and can contribute to modulation and restoration of the normal perception of visceral pain.
This variant, formerly titled RESPONSE TO MORPHINE-6-GLUCURONIDE and SUSCEPTIBILITY TO OPIOID DEPENDENCE (Lotsch et al., 2002 and Bart et al., 2004), has been reclassified based on the findings of Hollt (2002) and Arias et al. (2006).
The 118A-G SNP in the OPRM1 gene results in an asn40-to-asp (N40D) substitution in the-N terminal region of the protein, and is predicted to result in the loss of a putative N-glycosylation site (Bond et al., 1998).
The overall frequency of the 118G allele is about 10.5%, but varies significantly between different ethnic groups (African American, 0.016; Caucasian, 0.115; Hispanic, 0.142) (Bond et al., 1998). The 118G allele has a frequency varying from 0.078 to 0.341 in various populations (LaForge et al., 2000). It is present in 49 to 60% of those of Asian ancestry (Mague et al., 2009).
Bond et al. (1998) found that the asp40 variant receptor bound the endogenous agonist beta-endorphin (see POMC, 176830) 3 times more tightly than the wildtype receptor in Xenopus oocytes. No differences in binding affinity were observed for other opioid alkaloids or peptides. In contrast, Beyer et al. (2004) and Mague et al. (2009) found no differences in binding affinities between the 2 SNP alleles for several agonists, including morphine, beta-endorphin, naxolone, and morphine-6-glucuronide in human embryonic kidney 293 cells and mouse brain, respectively.
Zhang et al. (2005) observed that the OPRM1 118A mRNA allele was 1.5- to 2.5-fold more abundant than the 118G allele in heterozygous brain autopsy tissues. Transfection and inhibition studies showed that only 118G, and not substitutions at position 118 with A, T, or C, resulted in lower mRNA levels, in spite of equal stability. Moreover, 118G caused a 10-fold lower OPRM1 protein level as measured by Western blot and receptor binding analyses. Zhang et al. (2005) concluded that 118G is a functional variant that results in decreased levels of OPRM1 mRNA and protein. These results were confirmed by Mague et al. (2009) in mice.
STUDIES OF PHENOTYPIC ASSOCIATIONS
The 118A-G SNP in OPRM1 has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the results are conflicting and the mechanisms underlying these potential associations remain elusive (Mague et al., 2009).
Although Bart et al. (2004) and Drakenberg et al. (2006) independently reported an association between the 118G allele and opioid dependence (610064), a metaanalysis of 22 published papers on the subject (Arias et al., 2006) concluded that the N40D SNP does not affect the risk for substance dependence. Hollt (2002) also noted that association studies do not provide clear evidence that the 118A-G polymorphism is involved in opioid or alcohol addiction.
In a study of 20 healthy individuals, comprising 10 118A/A homozygotes, Lotsch et al. (2002) presented evidence that the 118G allele is associated with decreased pupil constrictory effect of morphine-6-glucuronide, the major metabolite of morphine. However, in reviewing the findings of Lotsch et al. (2002), Hollt (2002) concluded that differences in potencies most probably reflected a much lower blood-brain barrier permeability of M6G compared to morphine, since the receptor affinities of the 2 drugs are comparable (Wu et al., 1997).
In a study of 20 healthy individuals, comprising 10 118A/A homozygotes, 6 118G/G homozygotes, and 4 118A/G heterozygotes, Oertel et al. (2006) found that carriers of the 118G allele showed decreased tolerance to pain stimuli and decreased respiratory depression after alfentanil administration compared to those without the 118G allele. When compared to noncarriers, homozygous carriers needed 2 to 4 times higher alfentanil concentrations to produce the same amount of analgesia, and 10 to 12 times higher concentrations to produce the same degree of respiratory depression. Oertel et al. (2006) concluded that while both homozygous and heterozygous carriers of the 118G allele may show decreased opioid-induced analgesia, only homozygous carriers of 118G show decreased opioid-induced respiratory depressive effects.
Mague et al. (2009) found that mice homozygous for the 118G allele failed to exhibit morphine-induced hyperactivity, as seen in wildtype mice. Homozygous G/G mice also showed a decrease in morphine-induced antinociception compared to wildtype mice. Although G/G males were similar to wildtype in preference to morphine-paired environments, G/G females did not show a preference to morphine-paired environments.
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