{"gene":"OPRM1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1995,"finding":"MOR1 (OPRM1) protein is preferentially targeted to the somatodendritic domain in most neurons, but discrete neuronal populations (including some primary afferent neurons co-expressing DOR1) target MOR1 to axons, as determined by double-labeling with MAP2 and immunohistochemistry in brain and spinal cord.","method":"Immunohistochemistry with anti-C-terminal peptide antisera, Western blot, immunoisolation, double-labeling with MAP2","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunohistochemistry with validated antisera and double-labeling controls; single lab but multiple orthogonal methods","pmids":["7751913"],"is_preprint":false},{"year":1998,"finding":"Alternative splicing of the rat OPRM1 gene generates two isoforms, rMOR1 and rMOR1B, which exhibit similar pharmacological profiles but differ in agonist-induced desensitization of coupling to adenylate cyclase. MOR1B is predominantly localized to the olfactory bulb (external plexiform layer/mitral cell dendrites), while MOR1 is broadly distributed in pain-controlling brain areas including spinal cord dorsal horn, raphe nuclei, and periaqueductal gray.","method":"Isoform-specific polyclonal antibodies, immunocytochemistry, adenylate cyclase desensitization assays","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific antibodies with functional desensitization assay and differential localization; single lab","pmids":["9466465"],"is_preprint":false},{"year":1996,"finding":"In the superficial dorsal horn of the rat spinal cord, MOR1 immunoreactivity is present on cell bodies and dendrites of neurons in lamina II-III, and 94% of MOR1-immunoreactive neurons are neither GABA- nor glycine-immunoreactive, indicating they are predominantly excitatory interneurons rather than inhibitory neurons.","method":"Pre-embedding immunocytochemistry for MOR1 combined with post-embedding immunolabeling for GABA and glycine","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct double-labeling experiment with cellular phenotyping; single lab, two orthogonal immunolabeling methods","pmids":["8938756"],"is_preprint":false},{"year":2005,"finding":"The OPRM1 A118G SNP (N40D substitution) reduces OPRM1 mRNA levels approximately 1.5-fold and reduces protein levels more than 10-fold compared to the A118 allele when expressed in CHO cells; this effect is due to a defect in transcription or mRNA maturation rather than altered mRNA stability, as mRNA turnover after actinomycin D treatment is not different between alleles.","method":"Allele-specific mRNA expression in human autopsy brain tissue, CHO cell transfection with allelic cDNA constructs, Western blot, receptor binding assay, actinomycin D mRNA stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with allelic constructs, multiple orthogonal methods (Western blot, receptor binding, mRNA quantification, stability assay), validated in human tissue","pmids":["16046395"],"is_preprint":false},{"year":2008,"finding":"miRNA23b suppresses MOR1 (OPRM1) protein expression by interacting with a K box motif in the 3'-UTR of MOR1 mRNA and blocking its association with polysomes, thereby inhibiting translation; knockdown of endogenous miRNA23b in NS20Y cells increases MOR1 protein expression.","method":"Reporter assays with MOR1 3'-UTR, polysome fractionation, miRNA23b knockdown in NS20Y neuroblastoma cells","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic dissection with reporter assay, polysome fractionation, and loss-of-function knockdown; multiple orthogonal methods in one study","pmids":["18716031"],"is_preprint":false},{"year":2009,"finding":"Long-term morphine treatment increases miRNA23b expression in a dose- and time-dependent manner, which in turn represses MOR1 mRNA association with polysomes through the MOR1 3'-UTR, linking chronic morphine exposure to post-transcriptional downregulation of MOR1 protein.","method":"Dose-response morphine treatment, polysome-mRNA association assay, translational luciferase reporter assay with MOR1 3'-UTR","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic follow-up with reporter assay and polysome fractionation; single lab, multiple methods, builds on prior miRNA23b finding","pmids":["19144786"],"is_preprint":false},{"year":2009,"finding":"A mouse model carrying the equivalent of the human OPRM1 A118G SNP (A112G in mice) shows reduced Oprm1 mRNA expression and reduced receptor protein levels, along with reduced morphine-mediated antinociception, reduced morphine-mediated hyperactivity, and reduced locomotor sensitization; sex-specific reductions in morphine reward and naloxone-precipitated withdrawal aversion were also observed.","method":"Knock-in mouse model with A112G nucleotide substitution, receptor binding assay, Western blot, behavioral pharmacology (antinociception, locomotor activity, conditioned place preference, naloxone-precipitated withdrawal)","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-validated knock-in mouse model with molecular verification (mRNA, protein) and multiple behavioral readouts; multiple orthogonal methods","pmids":["19528658"],"is_preprint":false},{"year":2011,"finding":"In vivo PET imaging with [11C]carfentanil shows that smokers homozygous for the wild-type OPRM1 A allele have significantly higher mu-opioid receptor binding potential (receptor availability) in bilateral amygdala, left thalamus, and left anterior cingulate cortex compared to G allele carriers, demonstrating that the A118G SNP affects in vivo receptor levels in human brain.","method":"[11C]carfentanil PET imaging in genotyped human smokers","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo receptor quantification by PET in genotyped humans; single lab, single method but objective quantitative imaging","pmids":["21576462"],"is_preprint":false},{"year":2011,"finding":"Seven new exon 11-associated splice variants of rat OPRM1 were identified; one novel variant, rMOR-1H2, contains an additional 50 amino acids at the N-terminus and when expressed in CHO cells significantly alters agonist-induced G protein activation with little effect on opioid binding, indicating the N-terminal sequence influences G protein coupling efficiency.","method":"RT-PCR splice variant identification, CHO cell expression, G protein activation assay, opioid binding assay","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional characterization of novel splice variant in CHO cells with G protein coupling and binding assays; single lab","pmids":["21255438"],"is_preprint":false},{"year":2018,"finding":"MBD1 (methyl-CpG-binding domain protein 1) in DRG primary sensory neurons represses Oprm1 gene expression by recruiting DNA methyltransferase DNMT3a to the Oprm1 promoter; MBD1-deficient mice show reduced acute pain responses and blunted neuropathic pain, while DRG overexpression of MBD1 produces pain hypersensitivity and rescues acute pain sensitivity in MBD1-deficient mice.","method":"MBD1 knockout mice, DRG-specific overexpression via viral vector, ChIP-style recruitment assay of DNMT3a to Oprm1 promoter, behavioral pain testing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function in vivo experiments with molecular mechanistic evidence (DNMT3a recruitment to Oprm1 promoter), multiple orthogonal methods","pmids":["30266739"],"is_preprint":false},{"year":2020,"finding":"mu-Opioid agonists produce markedly different levels of G protein activation and β-arrestin2 recruitment among the full-length 7TM C-terminal splice variants of Oprm1 (e.g., MOR-1 vs. MOR-1O), leading to biased signaling that varies by both agonist and splice variant; MOR-1O (exon 7-associated) shows greater β-arrestin2 bias than MOR-1 (exon 4-associated) for most mu agonists.","method":"Cell-based G protein activation assay and β-arrestin2 recruitment assay for multiple C-terminal splice variants expressed in vitro","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional signaling assays with multiple splice variants and multiple agonists; single lab, two orthogonal signaling readouts","pmids":["33033993"],"is_preprint":false},{"year":2021,"finding":"MeCP2 in injured DRG neurons is upregulated after nerve injury, recruits HDAC1 to hypermethylated regions of the Oprm1 promoter, reduces histone H3 acetylation at the Oprm1 promoter, and thereby suppresses Oprm1 transcription and reduces MOR expression; MeCP2 knockdown restores MOR expression in injured DRG and enhances morphine analgesia, while HDAC1 inhibition prevents MOR reduction.","method":"MeCP2 knockdown (intrathecal viral vector), MeCP2 overexpression (viral vector), HDAC inhibitor (suberoylanilide hydroxamic acid) treatment, ChIP-like assay for HDAC1 binding and histone acetylation at Oprm1 promoter, qPCR, Western blot, behavioral morphine analgesia testing","journal":"Frontiers in neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function with mechanistic chromatin analysis, pharmacological inhibition, multiple orthogonal methods in vivo","pmids":["34803588"],"is_preprint":false},{"year":2019,"finding":"OPRM1 activation by D,L-methadone in leukemic cells triggers IP3R-mediated ER Ca2+ release and reduces the rate of Ca2+ efflux, causing a lethal rise in intracellular [Ca2+] that activates the calpain-1–Bid–cytochrome C–caspase-3/12 apoptotic pathway; OPRM1 loss blocks all these effects and prevents D,L-methadone-induced apoptosis, while BAPTA-AM chelation of intracellular Ca2+ also reverses apoptosis.","method":"OPRM1 knockdown/loss experiments, Ca2+ imaging (ER release and efflux), BAPTA-AM chelation, caspase-3/12 activation assay, cytochrome C release, Western blot for Bid truncation and calpain-1 activation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — mechanistic pathway dissection with loss-of-function, pharmacological rescue, Ca2+ measurements, and downstream apoptotic markers; multiple orthogonal methods","pmids":["33441856"],"is_preprint":false},{"year":2021,"finding":"Heterozygous genetic knockout of Oprm1 in mice increases inhibitory synaptic transmission specifically in D2-MSNs of the nucleus accumbens (males only) and increases gephyrin mRNA and inhibitory synaptic puncta density at D2-MSN cell bodies (both sexes); these synaptic changes are associated with deficits in social conditioned place preference and reciprocal social interaction, placing OPRM1 signaling in NAc microcircuitry as a regulator of social reward behavior.","method":"Heterozygous and homozygous Oprm1 knockout mice, electrophysiology (inhibitory synaptic transmission in D2-MSNs vs D1-MSNs), RNAscope for gephyrin mRNA, immunofluorescence for synaptic puncta, social conditioned place preference and reciprocal social interaction behavioral assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular electrophysiology phenotype, molecular synaptic analysis, and behavioral readouts; multiple orthogonal methods","pmids":["34301826"],"is_preprint":false},{"year":2019,"finding":"In a mouse model of OPRM1 A112G, MOR agonists (DAMGO and morphine) suppress both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to NAc medial shell, causing a shift in E/I balance and increased action potential firing; G/G allele mice show lower sensitivity to these effects, and DAMGO produces facilitatory effects on mEPSCs via presynaptic GABAB receptors predominantly in A/A mice, contributing to stronger dopamine neuron firing shifts in A/A mice.","method":"Electrophysiology (mIPSC, mEPSC, action potential firing) in VTA dopaminergic neurons from A112G knock-in mice, pharmacological dissection with DAMGO, morphine, GABAB receptor manipulation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous electrophysiology with genetic model, pharmacological dissection, and mechanistic circuit characterization; multiple orthogonal methods","pmids":["31109961"],"is_preprint":false},{"year":2012,"finding":"In MECP2 duplication mice with heightened anxiety and autism-like features, reducing Oprm1 expression (but not CRH/CRHR1 reduction) specifically improved abnormal social behavior, establishing Oprm1 as a downstream effector of MeCP2 overexpression that mediates social behavior deficits.","method":"Genetic epistasis in MECP2 duplication mice with reduced Oprm1 expression, behavioral assays for anxiety and social behavior","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis experiment with specific behavioral dissection of anxiety vs. social phenotypes; single lab","pmids":["22231481"],"is_preprint":false},{"year":2021,"finding":"Lung cancer cell-derived exosomal let-7d-5p is taken up by DRG neurons and directly inhibits OPRM1 protein levels via targeting of the OPRM1 mRNA; this suppression of OPRM1 in DRG neurons contributes to cancer-induced bone pain generation and maintenance in vivo.","method":"Exosome isolation, uptake assay in DRG neurons, let-7d-5p overexpression/inhibition, OPRM1 protein measurement (Western blot), mouse cancer-induced bone pain model with exosome injection","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-to-cell miRNA transfer with target validation and in vivo pain model; single lab, multiple methods","pmids":["34124049"],"is_preprint":false},{"year":2015,"finding":"Selective lesioning of nucleus accumbens MOR-expressing cells (using Cre-dependent caspase in Oprm1-Cre knock-in rats) decreased acquisition of heroin self-administration in males and had a stronger inhibitory effect on effort to self-administer heroin in females, establishing a cell-type-specific and sex-differentiated role for NAc OPRM1-expressing neurons in opioid reinforcement.","method":"CRISPR-based Oprm1-Cre knock-in rat, Cre-dependent AAV-caspase lesion of NAc MOR+ cells, heroin self-administration behavioral testing in male and female rats, HCR-FISH for Oprm1/iCre co-expression validation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic loss-of-function with validated Cre knock-in and defined behavioral phenotype; multiple orthogonal validation methods","pmids":["36717230"],"is_preprint":false},{"year":2015,"finding":"In the OPRM1 A112G mouse model, G allele carriers show increased home-cage dominance, increased motivation for social interaction, and resilience to social defeat with lack of subsequent social avoidance and reduced anhedonia; resilience is associated with greater c-fos induction in NAc and PAG, and the increase in social affiliation in G carriers is blocked by naloxone, indicating altered endogenous opioid tone mediates the social phenotype.","method":"A112G knock-in mice, social preference and dominance assays, social defeat paradigm, intracranial self-stimulation for anhedonia, c-fos immunohistochemistry, naloxone pharmacological blockade","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with pharmacological rescue (naloxone), circuit-level c-fos mapping, and multiple behavioral readouts; multiple orthogonal methods","pmids":["25716856"],"is_preprint":false},{"year":2019,"finding":"Taar1 and Oprm1 genotypes interact epistatically to regulate methamphetamine intake and thermal response to methamphetamine in mice; the independent effect of Taar1 on methamphetamine intake was dependent on genotype at Oprm1, as shown by interval mapping in recombinant inbred strains.","method":"Selective breeding, CRISPR-Cas9 Taar1 editing, recombinant inbred strain interval mapping, methamphetamine self-administration and thermal response assays, genetic epistasis analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in recombinant inbred panel with CRISPR-validated causal role of Taar1; Oprm1 epistasis established by mapping; single study","pmids":["31274109"],"is_preprint":false},{"year":2014,"finding":"Differential expression of the N-terminal OPRM1 splice variant MOR-1K (a single-TM variant mediating excitatory signaling) is observed in HIV-infected individuals with neurocognitive impairment and HIV encephalitis; overexpression of filamin A (FLNA), a network-identified interaction partner of MOR-1K, redistributes MOR-1K from intracellular compartments to the cell surface in HEK293 cells.","method":"RT-PCR for MOR-1K splice variant, network analysis of microarray data, FLNA overexpression in HEK293 cells with MOR-1K localization assessment","journal":"AIDS","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization experiment with overexpression in HEK293 cells, single lab, limited functional validation of the interaction","pmids":["24413261"],"is_preprint":false},{"year":2023,"finding":"MOR promoter (MORp)-based AAV constructs (derived from mouse Oprm1 upstream promoter regions) drive transgene expression selectively in endogenous MOR+ neurons in mouse brain, spinal cord, and periphery, and are functional in rats, shrews, and human iPSC-derived nociceptors; a human MORp efficiently transduced macaque cortical OPRM1+ cells, validating these constructs for cell-type-specific genetic access to mu-opioidergic neurons.","method":"AAV-delivered MOR promoter constructs, fiber photometry, chemogenetics (DREADDs), intersectional genetics, validation in multiple species including iPSC-derived nociceptors and macaque","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter-driven cell-type access validated across multiple species and methods; single lab but broad validation","pmids":["37704594"],"is_preprint":false}],"current_model":"OPRM1 encodes the mu-opioid receptor (MOR1), a GPCR that is predominantly targeted to the somatodendritic domain of neurons (with discrete axonal targeting in some populations), undergoes extensive alternative pre-mRNA splicing producing pharmacologically distinct isoforms with different G protein and β-arrestin2 signaling biases, is post-transcriptionally regulated by miRNA23b acting on a K box motif in the 3'-UTR to suppress polysome association and translation (a process upregulated by chronic morphine), and is epigenetically silenced by MBD1/DNMT3a and MeCP2/HDAC1 recruitment to the Oprm1 promoter under pain conditions; the common A118G (N40D) SNP reduces both mRNA and protein levels via a transcription/mRNA maturation defect and decreases receptor availability in vivo, alters synaptic regulation of VTA dopaminergic neurons and mesolimbic opioid signaling, and influences social behavior through endogenous opioid tone in the nucleus accumbens, where MOR-expressing neurons play a cell-type-specific, sex-differentiated role in opioid self-administration."},"narrative":{"mechanistic_narrative":"OPRM1 encodes the mu-opioid receptor (MOR1), a G protein-coupled receptor that is preferentially targeted to the somatodendritic domain of most neurons, with discrete axonal targeting in some primary afferent populations [PMID:7751913], and which couples agonist binding to G protein activation and adenylate cyclase regulation [PMID:9466465]. The gene undergoes extensive alternative splicing of both N-terminal and C-terminal exons, generating pharmacologically distinct isoforms: N-terminal variants alter G protein coupling efficiency [PMID:21255438] while full-length 7TM C-terminal variants display agonist- and isoform-dependent biases in G protein versus β-arrestin2 signaling, with exon 7-associated MOR-1O showing greater β-arrestin2 bias than exon 4-associated MOR-1 [PMID:33033993]. OPRM1 expression is tightly controlled at multiple post-transcriptional and epigenetic levels: miRNA23b binds a K box motif in the 3'-UTR to block polysome association and translation, a repression that is amplified by chronic morphine [PMID:18716031, PMID:19144786], while in sensory neurons MBD1/DNMT3a and MeCP2/HDAC1 are recruited to the Oprm1 promoter to silence transcription under pain conditions [PMID:30266739, PMID:34803588]. Functionally, MOR signaling governs antinociception, opioid reward, and social behavior through defined circuits — it shapes excitatory/inhibitory balance and firing of VTA dopaminergic neurons [PMID:31109961] and regulates inhibitory synaptic input onto nucleus accumbens MSNs, with NAc MOR-expressing neurons playing a cell-type-specific, sex-differentiated role in opioid self-administration [PMID:34301826, PMID:36717230]. The common A118G (N40D) variant reduces OPRM1 mRNA and protein via a transcription/mRNA maturation defect [PMID:16046395] and lowers receptor availability in human brain [PMID:21576462]. Activation of OPRM1 can also drive IP3R-mediated ER Ca2+ release and a calpain-1–Bid–cytochrome C–caspase apoptotic cascade in leukemic cells [PMID:33441856].","teleology":[{"year":1996,"claim":"Establishing where MOR1 protein resides and which neurons express it was needed to map opioid action; immunolocalization showed somatodendritic targeting with discrete axonal targeting, and that spinal MOR1+ neurons are predominantly excitatory interneurons.","evidence":"Immunohistochemistry with C-terminal antisera, MAP2 double-labeling, and GABA/glycine co-labeling in rat brain and spinal cord","pmids":["7751913","8938756"],"confidence":"Medium","gaps":["Single-lab antisera-based localization","Functional consequence of differential targeting not tested","Human distribution not directly addressed"]},{"year":1998,"claim":"Whether splice isoforms differ functionally was unknown; rMOR1 versus rMOR1B showed similar binding but distinct agonist-induced desensitization and differential anatomical distribution, establishing isoform-specific pharmacology.","evidence":"Isoform-specific antibodies, immunocytochemistry, and adenylate cyclase desensitization assays in rat","pmids":["9466465"],"confidence":"Medium","gaps":["Mechanism of differential desensitization not resolved","Single lab","Human isoform relevance untested"]},{"year":2005,"claim":"The molecular basis of the A118G (N40D) functional effect was unclear; allelic expression showed the G allele reduces mRNA ~1.5-fold and protein >10-fold via a transcription/mRNA maturation defect rather than altered stability.","evidence":"Allele-specific expression in human autopsy brain and CHO cells, Western blot, binding, and actinomycin D stability assay","pmids":["16046395"],"confidence":"High","gaps":["Exact transcription/maturation step affected not pinpointed","Heterologous cell context","Disconnect between mRNA and protein magnitude unexplained"]},{"year":2009,"claim":"How MOR1 protein is post-transcriptionally tuned was unknown; miRNA23b was shown to bind a 3'-UTR K box and block polysome association, and chronic morphine was shown to upregulate miRNA23b, linking opioid exposure to translational downregulation.","evidence":"3'-UTR reporter assays, polysome fractionation, miRNA23b knockdown in NS20Y cells, and dose/time morphine treatment","pmids":["18716031","19144786"],"confidence":"High","gaps":["In vivo physiological role of miRNA23b not established","Cell line context","Link to behavioral tolerance not tested"]},{"year":2009,"claim":"Whether the A118G effect translates to organismal opioid responses was untested; an A112G knock-in mouse recapitulated reduced mRNA/protein and showed reduced morphine antinociception, sensitization, and sex-specific reward/withdrawal changes.","evidence":"A112G knock-in mouse, binding, Western blot, and behavioral pharmacology","pmids":["19528658"],"confidence":"High","gaps":["Circuit basis of behavioral changes not resolved here","Sex-difference mechanism unknown"]},{"year":2011,"claim":"Whether the A118G effect alters receptor availability in living human brain was unknown; PET imaging showed AA homozygotes have higher mu-receptor binding potential in amygdala, thalamus, and anterior cingulate than G carriers.","evidence":"[11C]carfentanil PET in genotyped human smokers","pmids":["21576462"],"confidence":"Medium","gaps":["Smoker-only cohort","Single radioligand method","Causal link to behavior not established"]},{"year":2011,"claim":"Whether N-terminal sequence influences signaling was open; the exon 11-associated variant rMOR-1H2 with an extended N-terminus altered agonist-induced G protein activation without changing binding, showing the N-terminus tunes coupling efficiency.","evidence":"RT-PCR variant identification and CHO-cell G protein activation and binding assays","pmids":["21255438"],"confidence":"Medium","gaps":["In vivo expression and role of rMOR-1H2 unknown","Single heterologous system"]},{"year":2018,"claim":"How Oprm1 is transcriptionally silenced in pain states was unknown; MBD1 was shown to recruit DNMT3a to the Oprm1 promoter in DRG neurons, with MBD1 loss/gain bidirectionally controlling pain sensitivity.","evidence":"MBD1 knockout and DRG overexpression mice, DNMT3a recruitment assay, and pain behavior","pmids":["30266739"],"confidence":"High","gaps":["Trigger for MBD1 promoter recruitment unclear","Whether MOR is the sole MBD1 target mediating pain not resolved"]},{"year":2021,"claim":"A second epigenetic silencing route in injured sensory neurons was defined; MeCP2 recruits HDAC1 to hypermethylated Oprm1 promoter regions, reducing H3 acetylation and MOR expression, with knockdown restoring MOR and morphine analgesia.","evidence":"MeCP2 knockdown/overexpression, HDAC inhibition, chromatin assays, qPCR, Western blot, and morphine analgesia testing","pmids":["34803588"],"confidence":"High","gaps":["Interplay between MBD1/DNMT3a and MeCP2/HDAC1 routes not integrated","Human relevance untested"]},{"year":2020,"claim":"Whether C-terminal splice variants differ in signaling bias was open; full-length 7TM variants showed agonist- and isoform-dependent G protein versus β-arrestin2 recruitment, with MOR-1O more β-arrestin2-biased than MOR-1.","evidence":"Cell-based G protein activation and β-arrestin2 recruitment assays across multiple variants and agonists","pmids":["33033993"],"confidence":"Medium","gaps":["In vivo consequences of variant-specific bias not shown","Single lab heterologous assays"]},{"year":2019,"claim":"The circuit mechanism by which A118G alters reward was unknown; in A112G mice MOR agonists shifted E/I balance and firing of NAc-projecting VTA dopamine neurons, with G/G mice showing blunted sensitivity and presynaptic GABAB-mediated mEPSC facilitation predominant in A/A mice.","evidence":"Electrophysiology (mIPSC, mEPSC, firing) in VTA dopamine neurons from A112G knock-in mice with pharmacological dissection","pmids":["31109961"],"confidence":"High","gaps":["Behavioral linkage of the firing shift not directly demonstrated here","Mechanism of GABAB recruitment differences unclear"]},{"year":2021,"claim":"How OPRM1 shapes social reward circuitry was unresolved; heterozygous Oprm1 knockout selectively increased inhibitory transmission and gephyrin/synaptic puncta at NAc D2-MSNs, accompanied by social reward and interaction deficits.","evidence":"Oprm1 knockout mice, D1/D2-MSN electrophysiology, gephyrin RNAscope, synaptic immunofluorescence, and social behavior assays","pmids":["34301826"],"confidence":"High","gaps":["Cell-autonomous versus circuit origin of synaptic change not separated","Sex difference in electrophysiology mechanism unknown"]},{"year":2015,"claim":"Whether NAc MOR+ neurons are causally required for opioid reinforcement was untested; Cre-dependent caspase ablation of NAc MOR+ cells in Oprm1-Cre rats reduced heroin self-administration acquisition in males and effort in females, establishing a sex-differentiated cell-type-specific role.","evidence":"Oprm1-Cre knock-in rat, AAV-caspase lesion, heroin self-administration, and HCR-FISH validation","pmids":["36717230"],"confidence":"High","gaps":["Identity of the relevant NAc MOR+ neuron subtypes not fully defined","Mechanism of sex difference unresolved"]},{"year":2018,"claim":"OPRM1 was placed in social-behavior and addiction genetic networks; it acts as a downstream effector of MeCP2 overexpression mediating social deficits, its A112G G allele confers social resilience via naloxone-sensitive endogenous opioid tone, and it interacts epistatically with Taar1 to set methamphetamine intake.","evidence":"MECP2 duplication mouse epistasis, A112G knock-in social/defeat assays with naloxone and c-fos mapping, and recombinant inbred Taar1×Oprm1 interval mapping","pmids":["22231481","25716856","31274109"],"confidence":"Medium","gaps":["Molecular basis of Oprm1-Taar1 epistasis unknown","Human translation of social-resilience phenotype untested"]},{"year":2019,"claim":"A non-neuronal pro-apoptotic role and an additional regulatory miRNA were identified; OPRM1 activation by D,L-methadone triggers an IP3R/Ca2+–calpain-1–Bid–cytochrome C–caspase cascade in leukemic cells, and tumor-derived exosomal let-7d-5p directly suppresses OPRM1 in DRG neurons to drive cancer pain.","evidence":"OPRM1 loss-of-function, Ca2+ imaging, BAPTA-AM rescue and apoptotic-marker assays in leukemic cells; exosomal let-7d-5p uptake, target validation, and bone-pain model","pmids":["33441856","34124049"],"confidence":"High","gaps":["Generality of the apoptotic pathway beyond leukemic cells unknown","Endogenous physiological relevance of methadone-driven Ca2+ pathway unclear"]},{"year":2023,"claim":"Tools for cell-type-specific access to MOR+ neurons were lacking; MOR promoter-based AAV constructs drove selective expression in endogenous MOR+ neurons across mouse, rat, shrew, iPSC-derived nociceptors, and macaque, enabling targeted manipulation of mu-opioidergic cells.","evidence":"AAV MOR-promoter constructs with fiber photometry, DREADD chemogenetics, and cross-species validation","pmids":["37704594"],"confidence":"Medium","gaps":["Promoter fidelity relative to full endogenous OPRM1 expression incomplete","Long-term and clinical applicability not established"]},{"year":null,"claim":"How the multiple regulatory layers — alternative splicing, miRNA repression, and competing MBD1/DNMT3a versus MeCP2/HDAC1 epigenetic silencing — are integrated to set MOR levels in specific neuron types and circuits, and how A118G acts mechanistically at the transcription/maturation step, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking splice-variant bias to circuit-specific behavior","Exact molecular lesion of A118G undefined","Cross-talk among regulatory layers unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,8,10,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,10,14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13,14,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,5,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12]}],"complexes":[],"partners":["ARRB2","DNMT3A","MBD1","MECP2","HDAC1","FLNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35372","full_name":"Mu-type opioid receptor","aliases":["Mu opiate receptor","Mu opioid receptor","MOP","hMOP"],"length_aa":400,"mass_kda":44.8,"function":"Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:10529478, PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:10529478, PubMed:10836142, PubMed:12589820, PubMed:19300905, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity) Couples to GNAS and is proposed to be involved in excitatory effects Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity Does not bind agonists but may act through oligomerization with binding-competent OPRM1 isoforms and reduce their ligand binding activity","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P35372/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OPRM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OPRM1","total_profiled":1310},"omim":[{"mim_id":"618925","title":"G PROTEIN-COUPLED RECEPTOR 171; GPR171","url":"https://www.omim.org/entry/618925"},{"mim_id":"613242","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 14C; PPP1R14C","url":"https://www.omim.org/entry/613242"},{"mim_id":"610064","title":"OPIOID DEPENDENCE, SUSCEPTIBILITY TO, 1","url":"https://www.omim.org/entry/610064"},{"mim_id":"605051","title":"CANNABINOID RECEPTOR 2; CNR2","url":"https://www.omim.org/entry/605051"},{"mim_id":"600731","title":"G PROTEIN-COUPLED RECEPTOR 8; GPR8","url":"https://www.omim.org/entry/600731"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.4},{"tissue":"testis","ntpm":2.6}],"url":"https://www.proteinatlas.org/search/OPRM1"},"hgnc":{"alias_symbol":["MOR1","MOP"],"prev_symbol":[]},"alphafold":{"accession":"P35372","domains":[{"cath_id":"1.20.1070.10","chopping":"68-354","consensus_level":"high","plddt":89.183,"start":68,"end":354}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35372","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35372-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35372-F1-predicted_aligned_error_v6.png","plddt_mean":76.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OPRM1","jax_strain_url":"https://www.jax.org/strain/search?query=OPRM1"},"sequence":{"accession":"P35372","fasta_url":"https://rest.uniprot.org/uniprotkb/P35372.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35372/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35372"}},"corpus_meta":[{"pmid":"7751913","id":"PMC_7751913","title":"Distribution 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A Study with Novel Oprm1-Cre Knock-in Rats.","date":"2023","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36717230","citation_count":17,"is_preprint":false},{"pmid":"31109961","id":"PMC_31109961","title":"Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31109961","citation_count":17,"is_preprint":false},{"pmid":"23909491","id":"PMC_23909491","title":"Effects of OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor: a meta-analysis.","date":"2013","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/23909491","citation_count":17,"is_preprint":false},{"pmid":"25300626","id":"PMC_25300626","title":"OPRM1 receptor as new biomarker to help the prediction of post mastectomy pain and 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MOR1B is predominantly localized to the olfactory bulb (external plexiform layer/mitral cell dendrites), while MOR1 is broadly distributed in pain-controlling brain areas including spinal cord dorsal horn, raphe nuclei, and periaqueductal gray.\",\n      \"method\": \"Isoform-specific polyclonal antibodies, immunocytochemistry, adenylate cyclase desensitization assays\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific antibodies with functional desensitization assay and differential localization; single lab\",\n      \"pmids\": [\"9466465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"In the superficial dorsal horn of the rat spinal cord, MOR1 immunoreactivity is present on cell bodies and dendrites of neurons in lamina II-III, and 94% of MOR1-immunoreactive neurons are neither GABA- nor glycine-immunoreactive, indicating they are predominantly excitatory interneurons rather than inhibitory neurons.\",\n      \"method\": \"Pre-embedding immunocytochemistry for MOR1 combined with post-embedding immunolabeling for GABA and glycine\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct double-labeling experiment with cellular phenotyping; single lab, two orthogonal immunolabeling methods\",\n      \"pmids\": [\"8938756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The OPRM1 A118G SNP (N40D substitution) reduces OPRM1 mRNA levels approximately 1.5-fold and reduces protein levels more than 10-fold compared to the A118 allele when expressed in CHO cells; this effect is due to a defect in transcription or mRNA maturation rather than altered mRNA stability, as mRNA turnover after actinomycin D treatment is not different between alleles.\",\n      \"method\": \"Allele-specific mRNA expression in human autopsy brain tissue, CHO cell transfection with allelic cDNA constructs, Western blot, receptor binding assay, actinomycin D mRNA stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with allelic constructs, multiple orthogonal methods (Western blot, receptor binding, mRNA quantification, stability assay), validated in human tissue\",\n      \"pmids\": [\"16046395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"miRNA23b suppresses MOR1 (OPRM1) protein expression by interacting with a K box motif in the 3'-UTR of MOR1 mRNA and blocking its association with polysomes, thereby inhibiting translation; knockdown of endogenous miRNA23b in NS20Y cells increases MOR1 protein expression.\",\n      \"method\": \"Reporter assays with MOR1 3'-UTR, polysome fractionation, miRNA23b knockdown in NS20Y neuroblastoma cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic dissection with reporter assay, polysome fractionation, and loss-of-function knockdown; multiple orthogonal methods in one study\",\n      \"pmids\": [\"18716031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Long-term morphine treatment increases miRNA23b expression in a dose- and time-dependent manner, which in turn represses MOR1 mRNA association with polysomes through the MOR1 3'-UTR, linking chronic morphine exposure to post-transcriptional downregulation of MOR1 protein.\",\n      \"method\": \"Dose-response morphine treatment, polysome-mRNA association assay, translational luciferase reporter assay with MOR1 3'-UTR\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic follow-up with reporter assay and polysome fractionation; single lab, multiple methods, builds on prior miRNA23b finding\",\n      \"pmids\": [\"19144786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A mouse model carrying the equivalent of the human OPRM1 A118G SNP (A112G in mice) shows reduced Oprm1 mRNA expression and reduced receptor protein levels, along with reduced morphine-mediated antinociception, reduced morphine-mediated hyperactivity, and reduced locomotor sensitization; sex-specific reductions in morphine reward and naloxone-precipitated withdrawal aversion were also observed.\",\n      \"method\": \"Knock-in mouse model with A112G nucleotide substitution, receptor binding assay, Western blot, behavioral pharmacology (antinociception, locomotor activity, conditioned place preference, naloxone-precipitated withdrawal)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-validated knock-in mouse model with molecular verification (mRNA, protein) and multiple behavioral readouts; multiple orthogonal methods\",\n      \"pmids\": [\"19528658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In vivo PET imaging with [11C]carfentanil shows that smokers homozygous for the wild-type OPRM1 A allele have significantly higher mu-opioid receptor binding potential (receptor availability) in bilateral amygdala, left thalamus, and left anterior cingulate cortex compared to G allele carriers, demonstrating that the A118G SNP affects in vivo receptor levels in human brain.\",\n      \"method\": \"[11C]carfentanil PET imaging in genotyped human smokers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo receptor quantification by PET in genotyped humans; single lab, single method but objective quantitative imaging\",\n      \"pmids\": [\"21576462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Seven new exon 11-associated splice variants of rat OPRM1 were identified; one novel variant, rMOR-1H2, contains an additional 50 amino acids at the N-terminus and when expressed in CHO cells significantly alters agonist-induced G protein activation with little effect on opioid binding, indicating the N-terminal sequence influences G protein coupling efficiency.\",\n      \"method\": \"RT-PCR splice variant identification, CHO cell expression, G protein activation assay, opioid binding assay\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional characterization of novel splice variant in CHO cells with G protein coupling and binding assays; single lab\",\n      \"pmids\": [\"21255438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MBD1 (methyl-CpG-binding domain protein 1) in DRG primary sensory neurons represses Oprm1 gene expression by recruiting DNA methyltransferase DNMT3a to the Oprm1 promoter; MBD1-deficient mice show reduced acute pain responses and blunted neuropathic pain, while DRG overexpression of MBD1 produces pain hypersensitivity and rescues acute pain sensitivity in MBD1-deficient mice.\",\n      \"method\": \"MBD1 knockout mice, DRG-specific overexpression via viral vector, ChIP-style recruitment assay of DNMT3a to Oprm1 promoter, behavioral pain testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function in vivo experiments with molecular mechanistic evidence (DNMT3a recruitment to Oprm1 promoter), multiple orthogonal methods\",\n      \"pmids\": [\"30266739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"mu-Opioid agonists produce markedly different levels of G protein activation and β-arrestin2 recruitment among the full-length 7TM C-terminal splice variants of Oprm1 (e.g., MOR-1 vs. MOR-1O), leading to biased signaling that varies by both agonist and splice variant; MOR-1O (exon 7-associated) shows greater β-arrestin2 bias than MOR-1 (exon 4-associated) for most mu agonists.\",\n      \"method\": \"Cell-based G protein activation assay and β-arrestin2 recruitment assay for multiple C-terminal splice variants expressed in vitro\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional signaling assays with multiple splice variants and multiple agonists; single lab, two orthogonal signaling readouts\",\n      \"pmids\": [\"33033993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MeCP2 in injured DRG neurons is upregulated after nerve injury, recruits HDAC1 to hypermethylated regions of the Oprm1 promoter, reduces histone H3 acetylation at the Oprm1 promoter, and thereby suppresses Oprm1 transcription and reduces MOR expression; MeCP2 knockdown restores MOR expression in injured DRG and enhances morphine analgesia, while HDAC1 inhibition prevents MOR reduction.\",\n      \"method\": \"MeCP2 knockdown (intrathecal viral vector), MeCP2 overexpression (viral vector), HDAC inhibitor (suberoylanilide hydroxamic acid) treatment, ChIP-like assay for HDAC1 binding and histone acetylation at Oprm1 promoter, qPCR, Western blot, behavioral morphine analgesia testing\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function with mechanistic chromatin analysis, pharmacological inhibition, multiple orthogonal methods in vivo\",\n      \"pmids\": [\"34803588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OPRM1 activation by D,L-methadone in leukemic cells triggers IP3R-mediated ER Ca2+ release and reduces the rate of Ca2+ efflux, causing a lethal rise in intracellular [Ca2+] that activates the calpain-1–Bid–cytochrome C–caspase-3/12 apoptotic pathway; OPRM1 loss blocks all these effects and prevents D,L-methadone-induced apoptosis, while BAPTA-AM chelation of intracellular Ca2+ also reverses apoptosis.\",\n      \"method\": \"OPRM1 knockdown/loss experiments, Ca2+ imaging (ER release and efflux), BAPTA-AM chelation, caspase-3/12 activation assay, cytochrome C release, Western blot for Bid truncation and calpain-1 activation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mechanistic pathway dissection with loss-of-function, pharmacological rescue, Ca2+ measurements, and downstream apoptotic markers; multiple orthogonal methods\",\n      \"pmids\": [\"33441856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Heterozygous genetic knockout of Oprm1 in mice increases inhibitory synaptic transmission specifically in D2-MSNs of the nucleus accumbens (males only) and increases gephyrin mRNA and inhibitory synaptic puncta density at D2-MSN cell bodies (both sexes); these synaptic changes are associated with deficits in social conditioned place preference and reciprocal social interaction, placing OPRM1 signaling in NAc microcircuitry as a regulator of social reward behavior.\",\n      \"method\": \"Heterozygous and homozygous Oprm1 knockout mice, electrophysiology (inhibitory synaptic transmission in D2-MSNs vs D1-MSNs), RNAscope for gephyrin mRNA, immunofluorescence for synaptic puncta, social conditioned place preference and reciprocal social interaction behavioral assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular electrophysiology phenotype, molecular synaptic analysis, and behavioral readouts; multiple orthogonal methods\",\n      \"pmids\": [\"34301826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In a mouse model of OPRM1 A112G, MOR agonists (DAMGO and morphine) suppress both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to NAc medial shell, causing a shift in E/I balance and increased action potential firing; G/G allele mice show lower sensitivity to these effects, and DAMGO produces facilitatory effects on mEPSCs via presynaptic GABAB receptors predominantly in A/A mice, contributing to stronger dopamine neuron firing shifts in A/A mice.\",\n      \"method\": \"Electrophysiology (mIPSC, mEPSC, action potential firing) in VTA dopaminergic neurons from A112G knock-in mice, pharmacological dissection with DAMGO, morphine, GABAB receptor manipulation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous electrophysiology with genetic model, pharmacological dissection, and mechanistic circuit characterization; multiple orthogonal methods\",\n      \"pmids\": [\"31109961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In MECP2 duplication mice with heightened anxiety and autism-like features, reducing Oprm1 expression (but not CRH/CRHR1 reduction) specifically improved abnormal social behavior, establishing Oprm1 as a downstream effector of MeCP2 overexpression that mediates social behavior deficits.\",\n      \"method\": \"Genetic epistasis in MECP2 duplication mice with reduced Oprm1 expression, behavioral assays for anxiety and social behavior\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis experiment with specific behavioral dissection of anxiety vs. social phenotypes; single lab\",\n      \"pmids\": [\"22231481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lung cancer cell-derived exosomal let-7d-5p is taken up by DRG neurons and directly inhibits OPRM1 protein levels via targeting of the OPRM1 mRNA; this suppression of OPRM1 in DRG neurons contributes to cancer-induced bone pain generation and maintenance in vivo.\",\n      \"method\": \"Exosome isolation, uptake assay in DRG neurons, let-7d-5p overexpression/inhibition, OPRM1 protein measurement (Western blot), mouse cancer-induced bone pain model with exosome injection\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-to-cell miRNA transfer with target validation and in vivo pain model; single lab, multiple methods\",\n      \"pmids\": [\"34124049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Selective lesioning of nucleus accumbens MOR-expressing cells (using Cre-dependent caspase in Oprm1-Cre knock-in rats) decreased acquisition of heroin self-administration in males and had a stronger inhibitory effect on effort to self-administer heroin in females, establishing a cell-type-specific and sex-differentiated role for NAc OPRM1-expressing neurons in opioid reinforcement.\",\n      \"method\": \"CRISPR-based Oprm1-Cre knock-in rat, Cre-dependent AAV-caspase lesion of NAc MOR+ cells, heroin self-administration behavioral testing in male and female rats, HCR-FISH for Oprm1/iCre co-expression validation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic loss-of-function with validated Cre knock-in and defined behavioral phenotype; multiple orthogonal validation methods\",\n      \"pmids\": [\"36717230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the OPRM1 A112G mouse model, G allele carriers show increased home-cage dominance, increased motivation for social interaction, and resilience to social defeat with lack of subsequent social avoidance and reduced anhedonia; resilience is associated with greater c-fos induction in NAc and PAG, and the increase in social affiliation in G carriers is blocked by naloxone, indicating altered endogenous opioid tone mediates the social phenotype.\",\n      \"method\": \"A112G knock-in mice, social preference and dominance assays, social defeat paradigm, intracranial self-stimulation for anhedonia, c-fos immunohistochemistry, naloxone pharmacological blockade\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with pharmacological rescue (naloxone), circuit-level c-fos mapping, and multiple behavioral readouts; multiple orthogonal methods\",\n      \"pmids\": [\"25716856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Taar1 and Oprm1 genotypes interact epistatically to regulate methamphetamine intake and thermal response to methamphetamine in mice; the independent effect of Taar1 on methamphetamine intake was dependent on genotype at Oprm1, as shown by interval mapping in recombinant inbred strains.\",\n      \"method\": \"Selective breeding, CRISPR-Cas9 Taar1 editing, recombinant inbred strain interval mapping, methamphetamine self-administration and thermal response assays, genetic epistasis analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in recombinant inbred panel with CRISPR-validated causal role of Taar1; Oprm1 epistasis established by mapping; single study\",\n      \"pmids\": [\"31274109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Differential expression of the N-terminal OPRM1 splice variant MOR-1K (a single-TM variant mediating excitatory signaling) is observed in HIV-infected individuals with neurocognitive impairment and HIV encephalitis; overexpression of filamin A (FLNA), a network-identified interaction partner of MOR-1K, redistributes MOR-1K from intracellular compartments to the cell surface in HEK293 cells.\",\n      \"method\": \"RT-PCR for MOR-1K splice variant, network analysis of microarray data, FLNA overexpression in HEK293 cells with MOR-1K localization assessment\",\n      \"journal\": \"AIDS\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization experiment with overexpression in HEK293 cells, single lab, limited functional validation of the interaction\",\n      \"pmids\": [\"24413261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MOR promoter (MORp)-based AAV constructs (derived from mouse Oprm1 upstream promoter regions) drive transgene expression selectively in endogenous MOR+ neurons in mouse brain, spinal cord, and periphery, and are functional in rats, shrews, and human iPSC-derived nociceptors; a human MORp efficiently transduced macaque cortical OPRM1+ cells, validating these constructs for cell-type-specific genetic access to mu-opioidergic neurons.\",\n      \"method\": \"AAV-delivered MOR promoter constructs, fiber photometry, chemogenetics (DREADDs), intersectional genetics, validation in multiple species including iPSC-derived nociceptors and macaque\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter-driven cell-type access validated across multiple species and methods; single lab but broad validation\",\n      \"pmids\": [\"37704594\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OPRM1 encodes the mu-opioid receptor (MOR1), a GPCR that is predominantly targeted to the somatodendritic domain of neurons (with discrete axonal targeting in some populations), undergoes extensive alternative pre-mRNA splicing producing pharmacologically distinct isoforms with different G protein and β-arrestin2 signaling biases, is post-transcriptionally regulated by miRNA23b acting on a K box motif in the 3'-UTR to suppress polysome association and translation (a process upregulated by chronic morphine), and is epigenetically silenced by MBD1/DNMT3a and MeCP2/HDAC1 recruitment to the Oprm1 promoter under pain conditions; the common A118G (N40D) SNP reduces both mRNA and protein levels via a transcription/mRNA maturation defect and decreases receptor availability in vivo, alters synaptic regulation of VTA dopaminergic neurons and mesolimbic opioid signaling, and influences social behavior through endogenous opioid tone in the nucleus accumbens, where MOR-expressing neurons play a cell-type-specific, sex-differentiated role in opioid self-administration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OPRM1 encodes the mu-opioid receptor (MOR1), a G protein-coupled receptor that is preferentially targeted to the somatodendritic domain of most neurons, with discrete axonal targeting in some primary afferent populations [#0], and which couples agonist binding to G protein activation and adenylate cyclase regulation [#1]. The gene undergoes extensive alternative splicing of both N-terminal and C-terminal exons, generating pharmacologically distinct isoforms: N-terminal variants alter G protein coupling efficiency [#8] while full-length 7TM C-terminal variants display agonist- and isoform-dependent biases in G protein versus β-arrestin2 signaling, with exon 7-associated MOR-1O showing greater β-arrestin2 bias than exon 4-associated MOR-1 [#10]. OPRM1 expression is tightly controlled at multiple post-transcriptional and epigenetic levels: miRNA23b binds a K box motif in the 3'-UTR to block polysome association and translation, a repression that is amplified by chronic morphine [#4, #5], while in sensory neurons MBD1/DNMT3a and MeCP2/HDAC1 are recruited to the Oprm1 promoter to silence transcription under pain conditions [#9, #11]. Functionally, MOR signaling governs antinociception, opioid reward, and social behavior through defined circuits — it shapes excitatory/inhibitory balance and firing of VTA dopaminergic neurons [#14] and regulates inhibitory synaptic input onto nucleus accumbens MSNs, with NAc MOR-expressing neurons playing a cell-type-specific, sex-differentiated role in opioid self-administration [#13, #17]. The common A118G (N40D) variant reduces OPRM1 mRNA and protein via a transcription/mRNA maturation defect [#3] and lowers receptor availability in human brain [#7]. Activation of OPRM1 can also drive IP3R-mediated ER Ca2+ release and a calpain-1–Bid–cytochrome C–caspase apoptotic cascade in leukemic cells [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing where MOR1 protein resides and which neurons express it was needed to map opioid action; immunolocalization showed somatodendritic targeting with discrete axonal targeting, and that spinal MOR1+ neurons are predominantly excitatory interneurons.\",\n      \"evidence\": \"Immunohistochemistry with C-terminal antisera, MAP2 double-labeling, and GABA/glycine co-labeling in rat brain and spinal cord\",\n      \"pmids\": [\"7751913\", \"8938756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab antisera-based localization\", \"Functional consequence of differential targeting not tested\", \"Human distribution not directly addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Whether splice isoforms differ functionally was unknown; rMOR1 versus rMOR1B showed similar binding but distinct agonist-induced desensitization and differential anatomical distribution, establishing isoform-specific pharmacology.\",\n      \"evidence\": \"Isoform-specific antibodies, immunocytochemistry, and adenylate cyclase desensitization assays in rat\",\n      \"pmids\": [\"9466465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of differential desensitization not resolved\", \"Single lab\", \"Human isoform relevance untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The molecular basis of the A118G (N40D) functional effect was unclear; allelic expression showed the G allele reduces mRNA ~1.5-fold and protein >10-fold via a transcription/mRNA maturation defect rather than altered stability.\",\n      \"evidence\": \"Allele-specific expression in human autopsy brain and CHO cells, Western blot, binding, and actinomycin D stability assay\",\n      \"pmids\": [\"16046395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact transcription/maturation step affected not pinpointed\", \"Heterologous cell context\", \"Disconnect between mRNA and protein magnitude unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"How MOR1 protein is post-transcriptionally tuned was unknown; miRNA23b was shown to bind a 3'-UTR K box and block polysome association, and chronic morphine was shown to upregulate miRNA23b, linking opioid exposure to translational downregulation.\",\n      \"evidence\": \"3'-UTR reporter assays, polysome fractionation, miRNA23b knockdown in NS20Y cells, and dose/time morphine treatment\",\n      \"pmids\": [\"18716031\", \"19144786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological role of miRNA23b not established\", \"Cell line context\", \"Link to behavioral tolerance not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether the A118G effect translates to organismal opioid responses was untested; an A112G knock-in mouse recapitulated reduced mRNA/protein and showed reduced morphine antinociception, sensitization, and sex-specific reward/withdrawal changes.\",\n      \"evidence\": \"A112G knock-in mouse, binding, Western blot, and behavioral pharmacology\",\n      \"pmids\": [\"19528658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit basis of behavioral changes not resolved here\", \"Sex-difference mechanism unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether the A118G effect alters receptor availability in living human brain was unknown; PET imaging showed AA homozygotes have higher mu-receptor binding potential in amygdala, thalamus, and anterior cingulate than G carriers.\",\n      \"evidence\": \"[11C]carfentanil PET in genotyped human smokers\",\n      \"pmids\": [\"21576462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Smoker-only cohort\", \"Single radioligand method\", \"Causal link to behavior not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether N-terminal sequence influences signaling was open; the exon 11-associated variant rMOR-1H2 with an extended N-terminus altered agonist-induced G protein activation without changing binding, showing the N-terminus tunes coupling efficiency.\",\n      \"evidence\": \"RT-PCR variant identification and CHO-cell G protein activation and binding assays\",\n      \"pmids\": [\"21255438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo expression and role of rMOR-1H2 unknown\", \"Single heterologous system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How Oprm1 is transcriptionally silenced in pain states was unknown; MBD1 was shown to recruit DNMT3a to the Oprm1 promoter in DRG neurons, with MBD1 loss/gain bidirectionally controlling pain sensitivity.\",\n      \"evidence\": \"MBD1 knockout and DRG overexpression mice, DNMT3a recruitment assay, and pain behavior\",\n      \"pmids\": [\"30266739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for MBD1 promoter recruitment unclear\", \"Whether MOR is the sole MBD1 target mediating pain not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A second epigenetic silencing route in injured sensory neurons was defined; MeCP2 recruits HDAC1 to hypermethylated Oprm1 promoter regions, reducing H3 acetylation and MOR expression, with knockdown restoring MOR and morphine analgesia.\",\n      \"evidence\": \"MeCP2 knockdown/overexpression, HDAC inhibition, chromatin assays, qPCR, Western blot, and morphine analgesia testing\",\n      \"pmids\": [\"34803588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between MBD1/DNMT3a and MeCP2/HDAC1 routes not integrated\", \"Human relevance untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether C-terminal splice variants differ in signaling bias was open; full-length 7TM variants showed agonist- and isoform-dependent G protein versus β-arrestin2 recruitment, with MOR-1O more β-arrestin2-biased than MOR-1.\",\n      \"evidence\": \"Cell-based G protein activation and β-arrestin2 recruitment assays across multiple variants and agonists\",\n      \"pmids\": [\"33033993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo consequences of variant-specific bias not shown\", \"Single lab heterologous assays\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The circuit mechanism by which A118G alters reward was unknown; in A112G mice MOR agonists shifted E/I balance and firing of NAc-projecting VTA dopamine neurons, with G/G mice showing blunted sensitivity and presynaptic GABAB-mediated mEPSC facilitation predominant in A/A mice.\",\n      \"evidence\": \"Electrophysiology (mIPSC, mEPSC, firing) in VTA dopamine neurons from A112G knock-in mice with pharmacological dissection\",\n      \"pmids\": [\"31109961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Behavioral linkage of the firing shift not directly demonstrated here\", \"Mechanism of GABAB recruitment differences unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How OPRM1 shapes social reward circuitry was unresolved; heterozygous Oprm1 knockout selectively increased inhibitory transmission and gephyrin/synaptic puncta at NAc D2-MSNs, accompanied by social reward and interaction deficits.\",\n      \"evidence\": \"Oprm1 knockout mice, D1/D2-MSN electrophysiology, gephyrin RNAscope, synaptic immunofluorescence, and social behavior assays\",\n      \"pmids\": [\"34301826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous versus circuit origin of synaptic change not separated\", \"Sex difference in electrophysiology mechanism unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether NAc MOR+ neurons are causally required for opioid reinforcement was untested; Cre-dependent caspase ablation of NAc MOR+ cells in Oprm1-Cre rats reduced heroin self-administration acquisition in males and effort in females, establishing a sex-differentiated cell-type-specific role.\",\n      \"evidence\": \"Oprm1-Cre knock-in rat, AAV-caspase lesion, heroin self-administration, and HCR-FISH validation\",\n      \"pmids\": [\"36717230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the relevant NAc MOR+ neuron subtypes not fully defined\", \"Mechanism of sex difference unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"OPRM1 was placed in social-behavior and addiction genetic networks; it acts as a downstream effector of MeCP2 overexpression mediating social deficits, its A112G G allele confers social resilience via naloxone-sensitive endogenous opioid tone, and it interacts epistatically with Taar1 to set methamphetamine intake.\",\n      \"evidence\": \"MECP2 duplication mouse epistasis, A112G knock-in social/defeat assays with naloxone and c-fos mapping, and recombinant inbred Taar1×Oprm1 interval mapping\",\n      \"pmids\": [\"22231481\", \"25716856\", \"31274109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of Oprm1-Taar1 epistasis unknown\", \"Human translation of social-resilience phenotype untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A non-neuronal pro-apoptotic role and an additional regulatory miRNA were identified; OPRM1 activation by D,L-methadone triggers an IP3R/Ca2+–calpain-1–Bid–cytochrome C–caspase cascade in leukemic cells, and tumor-derived exosomal let-7d-5p directly suppresses OPRM1 in DRG neurons to drive cancer pain.\",\n      \"evidence\": \"OPRM1 loss-of-function, Ca2+ imaging, BAPTA-AM rescue and apoptotic-marker assays in leukemic cells; exosomal let-7d-5p uptake, target validation, and bone-pain model\",\n      \"pmids\": [\"33441856\", \"34124049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the apoptotic pathway beyond leukemic cells unknown\", \"Endogenous physiological relevance of methadone-driven Ca2+ pathway unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tools for cell-type-specific access to MOR+ neurons were lacking; MOR promoter-based AAV constructs drove selective expression in endogenous MOR+ neurons across mouse, rat, shrew, iPSC-derived nociceptors, and macaque, enabling targeted manipulation of mu-opioidergic cells.\",\n      \"evidence\": \"AAV MOR-promoter constructs with fiber photometry, DREADD chemogenetics, and cross-species validation\",\n      \"pmids\": [\"37704594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter fidelity relative to full endogenous OPRM1 expression incomplete\", \"Long-term and clinical applicability not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers — alternative splicing, miRNA repression, and competing MBD1/DNMT3a versus MeCP2/HDAC1 epigenetic silencing — are integrated to set MOR levels in specific neuron types and circuits, and how A118G acts mechanistically at the transcription/maturation step, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking splice-variant bias to circuit-specific behavior\", \"Exact molecular lesion of A118G undefined\", \"Cross-talk among regulatory layers unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 8, 10, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 10, 14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13, 14, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 5, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARRB2\", \"DNMT3a\", \"MBD1\", \"MeCP2\", \"HDAC1\", \"FLNA\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}