1 4861 111 ORGANIC ANION TRANSPORTER 1 IS AN HDAC4-REGULATED MEDIATOR OF NOCICEPTIVE HYPERSENSITIVITY IN MICE. PERSISTENT PAIN IS SUSTAINED BY MALADAPTIVE CHANGES IN GENE TRANSCRIPTION RESULTING IN ALTERED FUNCTION OF THE RELEVANT CIRCUITS; THERAPIES ARE STILL UNSATISFACTORY. THE EPIGENETIC MECHANISMS AND AFFECTED GENES LINKING NOCICEPTIVE ACTIVITY TO TRANSCRIPTIONAL CHANGES AND PATHOLOGICAL SENSITIVITY ARE UNCLEAR. HERE, WE FOUND THAT, AMONG SEVERAL HISTONE DEACETYLASES (HDACS), SYNAPTIC ACTIVITY SPECIFICALLY AFFECTS HDAC4 IN MURINE SPINAL CORD DORSAL HORN NEURONS. NOXIOUS STIMULI THAT INDUCE LONG-LASTING INFLAMMATORY HYPERSENSITIVITY CAUSE NUCLEAR EXPORT AND INACTIVATION OF HDAC4. THE DEVELOPMENT OF INFLAMMATION-ASSOCIATED MECHANICAL HYPERSENSITIVITY, BUT NEITHER ACUTE NOR BASAL SENSITIVITY, IS IMPAIRED BY THE EXPRESSION OF A CONSTITUTIVELY NUCLEAR LOCALIZED HDAC4 MUTANT. NEXT GENERATION RNA-SEQUENCING REVEALED AN HDAC4-REGULATED GENE PROGRAM COMPRISING MEDIATORS OF SENSITIZATION INCLUDING THE ORGANIC ANION TRANSPORTER OAT1, KNOWN FOR ITS RENAL TRANSPORT FUNCTION. USING PHARMACOLOGICAL AND MOLECULAR TOOLS TO MODULATE OAT1 ACTIVITY OR EXPRESSION, WE CAUSALLY LINK OAT1 TO PERSISTENT INFLAMMATORY HYPERSENSITIVITY IN MICE. THUS, HDAC4 IS A KEY EPIGENETIC REGULATOR THAT TRANSLATES NOCICEPTIVE ACTIVITY INTO SENSITIZATION BY REGULATING OAT1, WHICH IS A POTENTIAL TARGET FOR PAIN-RELIEVING THERAPIES. 2022 2 2246 24 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS. 2018 3 5474 32 RESTORATION OF HISTONE ACETYLATION AMELIORATES DISEASE AND METABOLIC ABNORMALITIES IN A FUS MOUSE MODEL. DYSREGULATION OF EPIGENETIC MECHANISMS IS EMERGING AS A CENTRAL EVENT IN NEURODEGENERATIVE DISORDERS, INCLUDING AMYOTROPHIC LATERAL SCLEROSIS (ALS). IN MANY MODELS OF NEURODEGENERATION, GLOBAL HISTONE ACETYLATION IS DECREASED IN THE AFFECTED NEURONAL TISSUES. HISTONE ACETYLATION IS CONTROLLED BY THE ANTAGONISTIC ACTIONS OF TWO PROTEIN FAMILIES -THE HISTONE ACETYLTRANSFERASES (HATS) AND THE HISTONE DEACETYLASES (HDACS). DRUGS INHIBITING HDAC ACTIVITY ARE ALREADY USED IN THE CLINIC AS ANTI-CANCER AGENTS. THE AIM OF THIS STUDY WAS TO EXPLORE THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE CONTEXT OF ALS. WE DISCOVERED THAT TRANSGENIC MICE OVEREXPRESSING WILD-TYPE FUS ("TG FUS+/+"), WHICH RECAPITULATE MANY ASPECTS OF HUMAN ALS, SHOWED REDUCED GLOBAL HISTONE ACETYLATION AND ALTERATIONS IN METABOLIC GENE EXPRESSION, RESULTING IN A DYSREGULATED METABOLIC HOMEOSTASIS. CHRONIC TREATMENT OF TG FUS+/+ MICE WITH ACY-738, A POTENT HDAC INHIBITOR THAT CAN CROSS THE BLOOD-BRAIN BARRIER, AMELIORATED THE MOTOR PHENOTYPE AND SUBSTANTIALLY EXTENDED THE LIFE SPAN OF THE TG FUS+/+ MICE. AT THE MOLECULAR LEVEL, ACY-738 RESTORED GLOBAL HISTONE ACETYLATION AND METABOLIC GENE EXPRESSION, THEREBY RE-ESTABLISHING METABOLITE LEVELS IN THE SPINAL CORD. TAKEN TOGETHER, OUR FINDINGS LINK EPIGENETIC ALTERATIONS TO METABOLIC DYSREGULATION IN ALS PATHOLOGY, AND HIGHLIGHT ACY-738 AS A POTENTIAL THERAPEUTIC STRATEGY TO TREAT THIS DEVASTATING DISEASE. 2019 4 5347 25 RARBETA AGONIST DRUG (C286) DEMONSTRATES EFFICACY IN A PRE-CLINICAL NEUROPATHIC PAIN MODEL RESTORING MULTIPLE PATHWAYS VIA DNA REPAIR MECHANISMS. NEUROPATHIC PAIN (NP) IS ASSOCIATED WITH PROFOUND GENE EXPRESSION ALTERATIONS WITHIN THE NOCICEPTIVE SYSTEM. DNA MECHANISMS, SUCH AS EPIGENETIC REMODELING AND REPAIR PATHWAYS HAVE BEEN IMPLICATED IN NP. HERE WE HAVE USED A RAT MODEL OF PERIPHERAL NERVE INJURY TO STUDY THE EFFECT OF A RECENTLY DEVELOPED RARBETA AGONIST, C286, CURRENTLY UNDER CLINICAL RESEARCH, IN NP. A 4-WEEK TREATMENT INITIATED 2 DAYS AFTER THE INJURY NORMALIZED PAIN SENSATION. GENOME-WIDE AND PATHWAY ENRICHMENT ANALYSIS SHOWED THAT MULTIPLE MECHANISMS PERSISTENTLY ALTERED IN THE SPINAL CORD WERE RESTORED TO PREINJURY LEVELS BY THE AGONIST. CONCOMITANT UPREGULATION OF DNA REPAIR PROTEINS, ATM AND BRCA1, THE LATTER BEING REQUIRED FOR C286-MEDIATED PAIN MODULATION, SUGGESTS THAT EARLY DNA REPAIR MAY BE IMPORTANT TO PREVENT PHENOTYPIC EPIGENETIC IMPRINTS IN NP. THUS, C286 IS A PROMISING DRUG CANDIDATE FOR NEUROPATHIC PAIN AND DNA REPAIR MECHANISMS MAY BE USEFUL THERAPEUTIC TARGETS TO EXPLORE. 2019 5 2442 28 EPIGENETIC STABILITY IN THE ADULT MOUSE CORTEX UNDER CONDITIONS OF PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION. HISTONE ACETYLATION IS CONSIDERED A MAJOR EPIGENETIC PROCESS THAT AFFECTS BRAIN DEVELOPMENT AND SYNAPTIC PLASTICITY, AS WELL AS LEARNING AND MEMORY. THE TRANSCRIPTIONAL EFFECTORS AND MORPHOLOGICAL CHANGES RESPONSIBLE FOR PLASTICITY AS A RESULT OF LONG-TERM MODIFICATIONS TO HISTONE ACETYLATION ARE NOT FULLY UNDERSTOOD. TO THIS END, WE PHARMACOLOGICALLY INHIBITED HISTONE DEACETYLATION USING TRICHOSTATIN A IN ADULT (6-MONTH-OLD) MICE AND FOUND SIGNIFICANT INCREASES IN THE LEVELS OF THE ACETYLATED HISTONE MARKS H3LYS9, H3LYS14 AND H4LYS12. HIGH-RESOLUTION TRANSCRIPTOME ANALYSIS OF DIVERSE BRAIN REGIONS UNCOVERED FEW DIFFERENCES IN GENE EXPRESSION BETWEEN TREATED AND CONTROL ANIMALS, NONE OF WHICH WERE PLASTICITY RELATED. INSTEAD, AFTER INCREASED HISTONE ACETYLATION, WE DETECTED A LARGE NUMBER OF NOVEL TRANSCRIPTIONALLY ACTIVE REGIONS, WHICH CORRESPOND TO LONG NON-CODING RNAS (LNCRNAS). WE ALSO SURPRISINGLY FOUND NO SIGNIFICANT CHANGES IN DENDRITIC SPINE PLASTICITY IN LAYERS 1 AND 2/3 OF THE VISUAL CORTEX USING LONG-TERM IN VIVO TWO-PHOTON IMAGING. OUR RESULTS INDICATE THAT CHRONIC PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION CAN BE DECOUPLED FROM GENE EXPRESSION AND INSTEAD, MAY POTENTIALLY EXERT A POST-TRANSCRIPTIONAL EFFECT THROUGH THE DIFFERENTIAL PRODUCTION OF LNCRNAS. 2016 6 4499 24 MORPHINE WITHDRAWAL PRODUCES ERK-DEPENDENT AND ERK-INDEPENDENT EPIGENETIC MARKS IN NEURONS OF THE NUCLEUS ACCUMBENS AND LATERAL SEPTUM. EPIGENETIC CHANGES SUCH AS COVALENT MODIFICATIONS OF HISTONE PROTEINS REPRESENT COMPLEX MOLECULAR SIGNATURES THAT PROVIDE A CELLULAR MEMORY OF PREVIOUSLY EXPERIENCED STIMULI WITHOUT IRREVERSIBLE CHANGES OF THE GENETIC CODE. IN THIS STUDY WE SHOW THAT NEW GENE EXPRESSION INDUCED IN VIVO BY MORPHINE WITHDRAWAL OCCURS WITH CONCOMITANT EPIGENETIC MODIFICATIONS IN BRAIN REGIONS CRITICALLY INVOLVED IN DRUG-DEPENDENT BEHAVIORS. WE FOUND THAT NALOXONE-PRECIPITATED WITHDRAWAL, BUT NOT CHRONIC MORPHINE ADMINISTRATION, CAUSED A STRONG INDUCTION OF PHOSPHO-HISTONE H3 IMMUNOREACTIVITY IN THE NUCLEUS ACCUMBENS (NAC) SHELL/CORE AND IN THE LATERAL SEPTUM (LS), A CHANGE THAT WAS ACCOMPANIED BY AUGMENTED H3 ACETYLATION (LYS14) IN NEURONS OF THE NAC SHELL. MORPHINE WITHDRAWAL INDUCED THE PHOSPHORYLATION OF THE EPIGENETIC FACTOR METHYL-CPG-BINDING PROTEIN 2 (MECP2) IN SER421 BOTH IN THE LS AND THE NAC SHELL. THESE EPIGENETIC CHANGES WERE ACCOMPANIED BY THE ACTIVATION OF MEMBERS OF THE ERK PATHWAY AS WELL AS INCREASED EXPRESSION OF THE IMMEDIATE EARLY GENES (IEG) C-FOS AND ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN (ARC/ARG3.1). USING A PHARMACOLOGICAL APPROACH, WE FOUND THAT H3 PHOSPHORYLATION AND IEG EXPRESSION WERE PARTIALLY DEPENDENT ON ERK ACTIVATION, WHILE MECP2 PHOSPHORYLATION WAS FULLY ERK-INDEPENDENT. THESE FINDINGS PROVIDE NEW IMPORTANT INFORMATION ON THE ROLE OF THE ERK PATHWAY IN THE REGULATION OF EPIGENETIC MARKS AND GENE EXPRESSION THAT MAY CONCUR TO REGULATE IN VIVO THE CELLULAR CHANGES UNDERLYING THE ONSET OF THE OPIOID WITHDRAWAL SYNDROME. 2013 7 3370 33 HISTONE MODIFICATION OF NEDD4 UBIQUITIN LIGASE CONTROLS THE LOSS OF AMPA RECEPTORS AND COGNITIVE IMPAIRMENT INDUCED BY REPEATED STRESS. STRESS AND THE MAJOR STRESS HORMONE CORTICOSTERONE INDUCE PROFOUND INFLUENCES IN THE BRAIN. ALTERED HISTONE MODIFICATION AND TRANSCRIPTIONAL DYSFUNCTION HAVE BEEN IMPLICATED IN STRESS-RELATED MENTAL DISORDERS. WE PREVIOUSLY FOUND THAT REPEATED STRESS CAUSED AN IMPAIRMENT OF PREFRONTAL CORTEX (PFC)-MEDIATED COGNITIVE FUNCTIONS BY INCREASING THE UBIQUITINATION AND DEGRADATION OF AMPA-TYPE GLUTAMATE RECEPTORS VIA A MECHANISM DEPENDING ON THE E3 UBIQUITIN LIGASE NEDD4. HERE, WE DEMONSTRATED THAT IN PFC OF REPEATEDLY STRESSED RATS, ACTIVE GLUCOCORTICOID RECEPTOR HAD THE INCREASED BINDING TO THE GLUCOCORTICOID RESPONSE ELEMENT OF HISTONE DEACETYLASE 2 (HDAC2) PROMOTER, RESULTING IN THE UPREGULATION OF HDAC2. INHIBITION OR KNOCK-DOWN OF HDAC2 BLOCKED THE STRESS-INDUCED IMPAIRMENT OF SYNAPTIC TRANSMISSION, AMPAR EXPRESSION, AND RECOGNITION MEMORY. FURTHERMORE, WE FOUND THAT, IN STRESSED ANIMALS, THE HDAC2-DEPENDENT DOWNREGULATION OF HISTONE METHYLTRANSFERASE EHMT2 (G9A) LED TO THE LOSS OF REPRESSIVE HISTONE METHYLATION AT THE NEDD4-1 PROMOTER AND THE TRANSCRIPTIONAL ACTIVATION OF NEDD4. THESE RESULTS HAVE PROVIDED AN EPIGENETIC MECHANISM AND A POTENTIAL TREATMENT STRATEGY FOR THE DETRIMENTAL EFFECTS OF CHRONIC STRESS. SIGNIFICANCE STATEMENT: PROLONGED STRESS EXPOSURE CAN INDUCE ALTERED HISTONE MODIFICATION AND TRANSCRIPTIONAL DYSFUNCTION, WHICH MAY UNDERLIE THE PROFOUND INFLUENCE OF STRESS IN REGULATING BRAIN FUNCTIONS. WE REPORT AN IMPORTANT FINDING ABOUT THE EPIGENETIC MECHANISM CONTROLLING THE DETRIMENTAL EFFECTS OF REPEATED STRESS ON SYNAPTIC TRANSMISSION AND COGNITIVE FUNCTION. FIRST, IT HAS REVEALED THE STRESS-INDUCED ALTERATION OF KEY EPIGENETIC REGULATORS HDAC2 AND EHMT2, WHICH DETERMINES THE SYNAPTIC AND BEHAVIORAL EFFECTS OF REPEATED STRESS. SECOND, IT HAS UNCOVERED THE STRESS-INDUCED HISTONE MODIFICATION OF THE TARGET GENE NEDD4, AN E3 LIGASE THAT IS CRITICALLY INVOLVED IN THE UBIQUITINATION AND DEGRADATION OF AMPA RECEPTORS AND COGNITION. THIRD, IT HAS PROVIDED THE EPIGENETIC APPROACH, HDAC2 INHIBITION OR KNOCK-DOWN, TO RESCUE SYNAPTIC AND COGNITIVE FUNCTIONS IN STRESSED ANIMALS. 2016 8 195 25 ACF CHROMATIN-REMODELING COMPLEX MEDIATES STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIOR. IMPROVED TREATMENT FOR MAJOR DEPRESSIVE DISORDER (MDD) REMAINS ELUSIVE BECAUSE OF THE LIMITED UNDERSTANDING OF ITS UNDERLYING BIOLOGICAL MECHANISMS. IT IS LIKELY THAT STRESS-INDUCED MALADAPTIVE TRANSCRIPTIONAL REGULATION IN LIMBIC NEURAL CIRCUITS CONTRIBUTES TO THE DEVELOPMENT OF MDD, POSSIBLY THROUGH EPIGENETIC FACTORS THAT REGULATE CHROMATIN STRUCTURE. WE ESTABLISH THAT PERSISTENT UPREGULATION OF THE ACF (ATP-UTILIZING CHROMATIN ASSEMBLY AND REMODELING FACTOR) ATP-DEPENDENT CHROMATIN-REMODELING COMPLEX, OCCURRING IN THE NUCLEUS ACCUMBENS OF STRESS-SUSCEPTIBLE MICE AND DEPRESSED HUMANS, IS NECESSARY FOR STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS. WE FOUND THAT ALTERED ACF BINDING AFTER CHRONIC STRESS WAS CORRELATED WITH ALTERED NUCLEOSOME POSITIONING, PARTICULARLY AROUND THE TRANSCRIPTION START SITES OF AFFECTED GENES. THESE ALTERATIONS IN ACF BINDING AND NUCLEOSOME POSITIONING WERE ASSOCIATED WITH REPRESSED EXPRESSION OF GENES IMPLICATED IN SUSCEPTIBILITY TO STRESS. TOGETHER, OUR FINDINGS IDENTIFY THE ACF CHROMATIN-REMODELING COMPLEX AS A CRITICAL COMPONENT IN THE DEVELOPMENT OF SUSCEPTIBILITY TO DEPRESSION AND IN REGULATING STRESS-RELATED BEHAVIORS. 2015 9 984 31 CHRONIC PSYCHOLOGICAL STRESS ALTERS GENE EXPRESSION IN RAT COLON EPITHELIAL CELLS PROMOTING CHROMATIN REMODELING, BARRIER DYSFUNCTION AND INFLAMMATION. CHRONIC STRESS IS COMMONLY ASSOCIATED WITH ENHANCED ABDOMINAL PAIN (VISCERAL HYPERSENSITIVITY), BUT THE CELLULAR MECHANISMS UNDERLYING HOW CHRONIC STRESS INDUCES VISCERAL HYPERSENSITIVITY ARE POORLY UNDERSTOOD. IN THIS STUDY, WE EXAMINED CHANGES IN GENE EXPRESSION IN COLON EPITHELIAL CELLS FROM A RAT MODEL USING RNA-SEQUENCING TO EXAMINE STRESS-INDUCED CHANGES TO THE TRANSCRIPTOME. FOLLOWING CHRONIC STRESS, THE MOST SIGNIFICANTLY UP-REGULATED GENES INCLUDED ATG16L1, COQ10B, DCAF13, NAT2, PTBP2, RRAS2, SPINK4 AND DOWN-REGULATED GENES INCLUDING ABAT, CITED2, CNNM2, DAB2IP, PLEKHM1, SCD2, AND TAB2. THE PRIMARY ALTERED BIOLOGICAL PROCESSES REVEALED BY NETWORK ENRICHMENT ANALYSIS WERE INFLAMMATION/IMMUNE RESPONSE, TISSUE MORPHOGENESIS AND DEVELOPMENT, AND NUCLEOSOME/CHROMATIN ASSEMBLY. THE MOST SIGNIFICANTLY DOWN-REGULATED PROCESS WAS THE DIGESTIVE SYSTEM DEVELOPMENT/FUNCTION, WHEREAS THE MOST SIGNIFICANTLY UP-REGULATED PROCESSES WERE INFLAMMATORY RESPONSE, ORGANISMAL INJURY, AND CHROMATIN REMODELING MEDIATED BY H3K9 METHYLATION. FURTHERMORE, A SUBPOPULATION OF STRESSED RATS DEMONSTRATED VERY SIGNIFICANTLY ALTERED GENE EXPRESSION AND TRANSCRIPT ISOFORMS, ENRICHED FOR THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY RESPONSE, INCLUDING UPREGULATION OF CYTOKINE AND CHEMOKINE RECEPTOR GENE EXPRESSION COUPLED WITH DOWNREGULATION OF EPITHELIAL ADHERENS AND TIGHT JUNCTION MRNAS. IN SUMMARY, THESE FINDINGS SUPPORT THAT CHRONIC STRESS IS ASSOCIATED WITH INCREASED LEVELS OF CYTOKINES AND CHEMOKINES, THEIR DOWNSTREAM SIGNALING PATHWAYS COUPLED TO DYSREGULATION OF INTESTINAL CELL DEVELOPMENT AND FUNCTION. EPIGENETIC REGULATION OF CHROMATIN REMODELING LIKELY PLAYS A PROMINENT ROLE IN THIS PROCESS. RESULTS ALSO SUGGEST THAT SUPER ENHANCERS PLAY A PRIMARY ROLE IN CHRONIC STRESS-ASSOCIATED INTESTINAL BARRIER DYSFUNCTION. 2022 10 4742 26 NOVEL HISTONE MODIFICATIONS IN MICROGLIA DERIVED FROM A MOUSE MODEL OF CHRONIC PAIN. AS THE RESIDENT IMMUNE CELLS IN THE CENTRAL NERVOUS SYSTEM, MICROGLIA PLAY AN IMPORTANT ROLE IN THE MAINTENANCE OF ITS HOMEOSTASIS. DYSREGULATION OF MICROGLIA HAS BEEN ASSOCIATED WITH THE DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, THE RELEVANT MOLECULAR PATHWAYS REMAIN POORLY DEFINED. IN THIS STUDY, WE USED A MASS SPECTROMETRY-BASED PROTEOMIC APPROACH TO SCREEN POTENTIAL CHANGES OF HISTONE PROTEIN MODIFICATIONS IN MICROGLIA ISOLATED FROM THE BRAIN OF CONTROL AND CISPLATIN-INDUCED NEUROPATHIC PAIN ADULT C57BL/6J MALE MICE. WE IDENTIFIED SEVERAL NOVEL MICROGLIAL HISTONE MODIFICATIONS ASSOCIATED WITH PAIN, INCLUDING STATISTICALLY SIGNIFICANTLY DECREASED HISTONE H3.1 LYSINE 27 MONO-METHYLATION (H3.1K27ME1, 54.8% OF CONTROL) AND H3 LYSINE 56 TRI-METHYLATION (7.5% OF CONTROL), AS WELL AS A TREND SUGGESTING INCREASED H3 TYROSINE 41 NITRATION. WE FURTHER INVESTIGATED THE FUNCTIONAL ROLE OF H3.1K27ME1 AND FOUND THAT TREATMENT OF CULTURED MICROGLIAL CELLS FOR 4 CONSECUTIVE DAYS WITH 1-10 MUM OF NCDM-64, A POTENT AND SELECTIVE INHIBITOR OF LYSINE DEMETHYLASE 7A, AN ENZYME RESPONSIBLE FOR THE DEMETHYLATION OF H3K27ME1, DOSE-DEPENDENTLY ELEVATED ITS LEVELS WITH A GREATER THAN A TWO-FOLD INCREASE OBSERVED AT 10 MUM COMPARED TO VEHICLE-TREATED CONTROL CELLS. MOREOVER, PRETREATMENT OF MICE WITH NCDM-64 (10 OR 25 MG/KG/DAY, I.P.) PRIOR TO CISPLATIN TREATMENT PREVENTED THE DEVELOPMENT OF NEUROPATHIC PAIN IN MICE. THE IDENTIFICATION OF SPECIFIC CHROMATIN MARKS IN MICROGLIA ASSOCIATED WITH CHRONIC PAIN MAY YIELD CRITICAL INSIGHT INTO THE CONTRIBUTION OF MICROGLIA TO THE DEVELOPMENT AND MAINTENANCE OF PAIN, AND OPENS NEW AVENUES FOR THE DEVELOPMENT OF NOVEL NONOPIOID THERAPEUTICS FOR THE EFFECTIVE MANAGEMENT OF CHRONIC PAIN. 2022 11 3002 25 GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS FOR TREATMENT OF MAJOR DEPRESSION: THE 5-HT1A RECEPTOR GENE AS A PARADIGM. MAJOR DEPRESSION AND ANXIETY ARE HIGHLY PREVALENT AND INVOLVE CHRONIC DYSREGULATION OF SEROTONIN, BUT THEY REMAIN POORLY UNDERSTOOD. HERE, WE REVIEW NOVEL TRANSCRIPTIONAL (GENETIC, EPIGENETIC) AND POSTTRANSCRIPTIONAL (MICRORNA, ALTERNATIVE SPLICING) MECHANISMS IMPLICATED IN MENTAL ILLNESS, FOCUSING ON A KEY SEROTONIN-RELATED REGULATOR, THE SEROTONIN 1A (5-HT1A) RECEPTOR. FUNCTIONAL SINGLE-NUCLEOTIDE POLYMORPHISMS AND STRESS-INDUCED DNA METHYLATION OF THE 5-HT1A PROMOTER CONVERGE TO DIFFERENTIALLY ALTER PRE- AND POSTSYNAPTIC 5-HT1A RECEPTOR EXPRESSION ASSOCIATED WITH MAJOR DEPRESSION AND REDUCED THERAPEUTIC RESPONSE TO SEROTONERGIC ANTIDEPRESSANTS. MAJOR DEPRESSION IS ALSO ASSOCIATED WITH ALTERED LEVELS OF SPLICE FACTORS AND MICRORNA, POSTTRANSCRIPTIONAL MECHANISMS THAT REGULATE RNA STABILITY. THE HUMAN 5-HT1A 3'-UNTRANSLATED REGION IS ALTERNATIVELY SPLICED, REMOVING MICRORNA SITES AND INCREASING 5-HT1A EXPRESSION, WHICH IS REDUCED IN MAJOR DEPRESSION AND MAY BE GENOTYPE-DEPENDENT. THUS, THE 5-HT1A RECEPTOR GENE ILLUSTRATES THE CONVERGENCE OF GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS IN GENE EXPRESSION, NEURODEVELOPMENT AND NEUROPLASTICITY, AND MAJOR DEPRESSION. UNDERSTANDING GENE REGULATORY MECHANISMS COULD ENHANCE THE DETECTION, CATEGORIZATION AND PERSONALIZED TREATMENT OF MAJOR DEPRESSION. 2019 12 6226 19 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 13 3141 32 GLOBAL GENE EXPRESSION AND CHROMATIN ACCESSIBILITY OF THE PERIPHERAL NERVOUS SYSTEM IN ANIMAL MODELS OF PERSISTENT PAIN. BACKGROUND: EFFORTS TO UNDERSTAND GENETIC VARIABILITY INVOLVED IN AN INDIVIDUAL'S SUSCEPTIBILITY TO CHRONIC PAIN SUPPORT A ROLE FOR UPSTREAM REGULATION BY EPIGENETIC MECHANISMS. METHODS: TO EXAMINE THE TRANSCRIPTOMIC AND EPIGENETIC BASIS OF CHRONIC PAIN THAT RESIDES IN THE PERIPHERAL NERVOUS SYSTEM, WE USED RNA-SEQ AND ATAC-SEQ OF THE RAT DORSAL ROOT GANGLION (DRG) TO IDENTIFY NOVEL MOLECULAR PATHWAYS ASSOCIATED WITH PAIN HYPERSENSITIVITY IN TWO WELL-STUDIED PERSISTENT PAIN MODELS INDUCED BY CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE AND INTRA-PLANTAR INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN RATS. RESULTS: OUR RNA-SEQ STUDIES IDENTIFY A VARIETY OF BIOLOGICAL PROCESS RELATED TO SYNAPSE ORGANIZATION, MEMBRANE POTENTIAL, TRANSMEMBRANE TRANSPORT, AND ION BINDING. INTERESTINGLY, GENES THAT ENCODE TRANSCRIPTIONAL REGULATORS WERE DISPROPORTIONATELY DOWNREGULATED IN BOTH MODELS. OUR ATAC-SEQ DATA PROVIDE A COMPREHENSIVE MAP OF CHROMATIN ACCESSIBILITY CHANGES IN THE DRG. A TOTAL OF 1123 REGIONS SHOWED CHANGES IN CHROMATIN ACCESSIBILITY IN ONE OR BOTH MODELS WHEN COMPARED TO THE NAIVE AND 31 SHARED DIFFERENTIALLY ACCESSIBLE REGIONS (DAR)S. FUNCTIONAL ANNOTATION OF THE DARS IDENTIFIED DISPARATE MOLECULAR FUNCTIONS ENRICHED FOR EACH PAIN MODEL WHICH SUGGESTS THAT CHROMATIN STRUCTURE MAY BE ALTERED DIFFERENTLY FOLLOWING SCIATIC NERVE INJURY AND HIND PAW INFLAMMATION. MOTIF ANALYSIS IDENTIFIED 17 DNA SEQUENCES KNOWN TO BIND TRANSCRIPTION FACTORS IN THE CCI DARS AND 33 IN THE CFA DARS. TWO MOTIFS WERE SIGNIFICANTLY ENRICHED IN BOTH MODELS. CONCLUSIONS: OUR IMPROVED UNDERSTANDING OF THE CHANGES IN CHROMATIN ACCESSIBILITY THAT OCCUR IN CHRONIC PAIN STATES MAY IDENTIFY REGULATORY GENOMIC ELEMENTS THAT PLAY ESSENTIAL ROLES IN MODULATING GENE EXPRESSION IN THE DRG. 2021 14 5832 25 STRESS-INDUCED EPIGENETIC CHANGES IN HIPPOCAMPAL MKP-1 PROMOTE PERSISTENT DEPRESSIVE BEHAVIORS. CHRONIC STRESS INDUCES PERSISTENT DEPRESSIVE BEHAVIORS. STRESS-INDUCED TRANSCRIPTIONAL ALTERATION OVER THE HOMEOSTATIC RANGE IN STRESS HORMONE-SENSITIVE BRAIN REGIONS IS BELIEVED TO UNDERLIE LONG-LASTING DEPRESSIVE BEHAVIORS. HOWEVER, THE DETAILED MECHANISMS BY WHICH CHRONIC STRESS CAUSES THOSE ADAPTIVE CHANGES ARE NOT CLEARLY UNDERSTOOD. IN THE PRESENT STUDY, WE INVESTIGATED WHETHER EPIGENETIC CHANGES REGULATE STRESS-INDUCED DEPRESSIVE BEHAVIORS. WE FOUND THAT CHRONIC STRESS IN MICE DOWNREGULATES THE EPIGENETIC FACTORS HDAC2 AND SUV39H1 IN THE HIPPOCAMPUS. A SERIES OF FOLLOW-UP ANALYSES INCLUDING CHIP ASSAY AND SIRNA-MEDIATED FUNCTIONAL ANALYSES REVEAL THAT GLUCOCORTICOIDS RELEASED BY STRESS CUMULATIVELY INCREASE MKP-1 EXPRESSION IN THE HIPPOCAMPUS, AND INCREASED MKP-1 THEN DEBILITATES P-CREB AND PPARGAMMA, WHICH IN TURN SUPPRESS THE EPIGENETIC FACTORS HDAC2 AND SUV39H1. FURTHERMORE, HDAC2 AND SUV39H1 NORMALLY SUPPRESS THE TRANSCRIPTION OF THE MKP-1, AND THEREFORE THE REDUCED EXPRESSION OF HDAC2 AND SUV39H1 INCREASES MKP-1 EXPRESSION. ACCORDINGLY, REPEATED STRESS PROGRESSIVELY STRENGTHENS A VICIOUS CYCLE OF THE MKP-1 SIGNALING CASCADE THAT FACILITATES DEPRESSIVE BEHAVIORS. THESE RESULTS SUGGEST THAT THE HIPPOCAMPAL STRESS ADAPTATION SYSTEM COMPRISING HDAC2/SUV39H1-REGULATED MKP-1 SIGNALING NETWORK DETERMINES THE VULNERABILITY TO CHRONIC STRESS AND THE MAINTENANCE OF DEPRESSIVE BEHAVIORS. 2019 15 6895 27 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 16 2886 20 GABA-AALPHA5 MIGHT BE INVOLVED IN LEARNING-MEMORY DYSFUNCTION IN THE OFFSPRINGS OF CHRONIC ETHANOL-TREATED RATS VIA GABA-AALPHA5 HISTONE H3K9 ACETYLATION. RECENTLY, NUMEROUS STUDIES HAVE BEEN FOCUSED ON THE RELATIONSHIP BETWEEN GABA-A RECEPTORS AND ALCOHOL-INDUCED SPATIAL LEARNING AND MEMORY DEFICITS. GABA-AALPHA5, A SUBUNIT OF GABA-A RECEPTORS, IS CONSIDERED TO PLAY AN IMPORTANT ROLE IN ALCOHOL-INDUCED COGNITIVE IMPAIRMENT, HOWEVER, THE MECHANISM REMAINS OBSCURE. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF GABA-AALPHA5 INCREASED IN RATS TREATED WITH CHRONIC ETHANOL VIA HISTONE H3K9 ACETYLATION. FURTHERMORE, THIS EPIGENETIC MODIFICATION COULD BE INHERITED BY THE NEXT GENERATIONS, WHICH EVENTUALLY EXHIBIT SIMILAR SPATIAL LEARNING AND MEMORY DEFICITS IN THE OFFSPRINGS. IN SUMMARY, OUR RESULTS SUGGESTED THAT GABA-AALPHA5 MIGHT BE INVOLVED IN CHRONIC ETHANOL TREATMENT-INDUCED LEARNING-MEMORY DYSFUNCTION AND FOR THE FIRST TIME PROVED THAT LEARNING-MEMORY DYSFUNCTION COULD BE INHERITED BY THE OFFSPRINGS VIA HISTONE H3K9 ACETYLATION. HOPEFULLY, IN THE NEAR FUTURE, GABA-AALPHA5 INHIBITORS WOULD BE AN EFFECTIVE WAY TO TREAT ALCOHOL-INDUCED COGNITION IMPAIRMENT. 2019 17 1902 30 ENHANCED EXPRESSION OF THE NUCLEAR ENVELOPE LAP2 TRANSCRIPTIONAL REPRESSORS IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. EXTENSIVE RESEARCH IN RECENT YEARS HAS BROADENED THE FUNCTIONS OF NUCLEAR ENVELOPE PROTEINS BEYOND SIMPLY STABILIZING THE NUCLEUS ARCHITECTURE. PARTICULARLY, INTEGRAL NUCLEAR MEMBRANE PROTEINS, SUCH AS THE ALTERNATIVE SPLICED ISOFORMS OF LAMINA-ASSOCIATED POLYPEPTIDE 2 (LAP2), HAVE BEEN SHOWN TO BE IMPORTANT FOR THE INITIATION OF REPLICATION AND REPRESSION OF TRANSCRIPTION. THE LATTER IS REGULATED BY EPIGENETIC CHANGES, INDUCED BY THE BINDING OF LAP2BETA TO HISTONE DEACETYLASE-3 (HDAC3), RESULTING IN HISTONE H4 DEACETYLATION. INVOLVEMENT OF NUCLEAR ENVELOPE PROTEINS IN PATHOLOGICAL PROLIFERATIVE CONDITIONS, MAINLY THOSE INVOLVING ABNORMAL RECRUITMENT AND ACTIVATION OF HDACS, IS STILL UNKNOWN. IN THIS PAPER, WE SHOW THAT VARIOUS NUCLEAR ENVELOPE PROTEINS ARE HIGHLY EXPRESSED IN NORMAL AND MALIGNANT ACTIVATED LYMPHOCYTES. SPECIFICALLY, RAPIDLY REPLICATING CELLS OF VARIOUS HEMATOLOGICAL MALIGNANCIES HIGHLY EXPRESS LAP2BETA, WHILE SLOWLY PROLIFERATING MALIGNANT CELLS OF CHRONIC MALIGNANT HEMATOLOGICAL DISEASES DO NOT. TAKING TOGETHER THE ELEVATED EXPRESSION OF LAP2BETA IN HIGHLY PROLIFERATIVE MALIGNANT CELLS WITH ITS KNOWN ABILITY TO MODIFY HISTONES THROUGH BINDING WITH HDAC3 RAISES THE POSSIBILITY OF ITS ROLE IN HEMATOLOGICAL MALIGNANCIES INVOLVING ABERRANT ACTIVITY OF HDAC3. BASED ON OUR PRESENTED RESULTS, WE BELIEVE THAT THE LAP2-HDAC REGULATORY PATHWAY SHOULD BE STUDIED AS A NEW TARGET FOR RATIONAL THERAPY. 2007 18 4297 33 MICRORNA-1224 SPLICING CIRCULARRNA-FILIP1L IN AN AGO2-DEPENDENT MANNER REGULATES CHRONIC INFLAMMATORY PAIN VIA TARGETING UBR5. DYSFUNCTIONS OF GENE TRANSCRIPTION AND TRANSLATION IN THE NOCICEPTIVE PATHWAYS PLAY THE CRITICAL ROLE IN DEVELOPMENT AND MAINTENANCE OF CHRONIC PAIN. CIRCULAR RNAS (CIRCRNAS) ARE EMERGING AS NEW PLAYERS IN REGULATION OF GENE EXPRESSION, BUT WHETHER AND HOW CIRCRNAS ARE INVOLVED IN CHRONIC PAIN REMAIN ELUSIVE. WE SHOWED HERE THAT COMPLETE FREUND'S ADJUVANT-INDUCED CHRONIC INFLAMMATION PAIN SIGNIFICANTLY INCREASED CIRCRNA-FILIP1L (FILAMIN A INTERACTING PROTEIN 1-LIKE) EXPRESSION IN SPINAL NEURONS OF MICE. BLOCKAGE OF THIS INCREASE ATTENUATED COMPLETE FREUND'S ADJUVANT-INDUCED NOCICEPTIVE BEHAVIORS, AND OVEREXPRESSION OF SPINAL CIRCRNA-FILIP1L IN NAIVE MICE MIMICKED THE NOCICEPTIVE BEHAVIORS AS EVIDENCED BY DECREASED THERMAL AND MECHANICAL NOCICEPTIVE THRESHOLD. FURTHERMORE, WE FOUND THAT MATURE CIRCRNA-FILIP1L EXPRESSION WAS NEGATIVELY REGULATED BY MIRNA-1224 VIA BINDING AND SPLICING OF PRECURSOR OF CIRCRNA-FILIP1L (PRE-CIRCRNA-FILIP1L) IN THE ARGONAUTE-2 (AGO2)-DEPENDENT MANNER. INCREASE OF SPINAL CIRCRNA-FILIP1L EXPRESSION RESULTED FROM THE DECREASE OF MIRNA-1224 EXPRESSION UNDER CHRONIC INFLAMMATION PAIN STATE. MIRNA-1224 KNOCKDOWN OR AGO2 OVEREXPRESSION INDUCED NOCICEPTIVE BEHAVIORS IN NAIVE MICE, WHICH WAS PREVENTED BY THE KNOCKDOWN OF SPINAL CIRCRNA-FILIP1L. FINALLY, WE DEMONSTRATED THAT A UBIQUITIN PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 5 (UBR5), VALIDATED AS A TARGET OF CIRCRNA-FILIP1L, PLAYS A PIVOTAL ROLE IN REGULATION OF NOCICEPTION BY SPINAL CIRCRNA-FILIP1L. THESE DATA SUGGEST THAT MIRNA-1224-MEDIATED AND AGO2-DEPENDENT MODULATION OF SPINAL CIRCRNA-FILIP1L EXPRESSION REGULATES NOCICEPTION VIA TARGETING UBR5, REVEALING A NOVEL EPIGENETIC MECHANISM OF INTERACTION BETWEEN MIRNA AND CIRCRNA IN CHRONIC INFLAMMATION PAIN.SIGNIFICANCE STATEMENT CIRCRNAS ARE EMERGING AS NEW PLAYERS IN REGULATION OF GENE EXPRESSION. HERE, WE FOUND THAT THE INCREASE OF CIRCRNA-FILIP1L MEDIATED BY MIRNA-1224 IN AN AGO2-DEPENDENT WAY IN THE SPINAL CORD IS INVOLVED IN REGULATION OF NOCICEPTION VIA TARGETING UBR5 OUR STUDY REVEALS A NOVEL EPIGENETIC MECHANISM OF INTERACTION BETWEEN MIRNA AND CIRCRNA IN CHRONIC INFLAMMATION PAIN. 2019 19 656 22 BLOCKADE OF THE IL-1R1/TLR4 PATHWAY MEDIATES DISEASE-MODIFICATION THERAPEUTIC EFFECTS IN A MODEL OF ACQUIRED EPILEPSY. WE RECENTLY DISCOVERED THAT FOREBRAIN ACTIVATION OF THE IL-1 RECEPTOR/TOLL-LIKE RECEPTOR (IL-1R1/TLR4) INNATE IMMUNITY SIGNAL PLAYS A PIVOTAL ROLE IN NEURONAL HYPEREXCITABILITY UNDERLYING SEIZURES IN RODENTS. SINCE THIS PATHWAY IS ACTIVATED IN NEURONS AND GLIA IN HUMAN EPILEPTOGENIC FOCI, IT REPRESENTS A POTENTIAL TARGET FOR DEVELOPING DRUGS INTERFERING WITH THE MECHANISMS OF EPILEPTOGENESIS THAT LEAD TO SPONTANEOUS SEIZURES. THE LACK OF SUCH DRUGS REPRESENTS A MAJOR UNMET CLINICAL NEED. WE TESTED THEREFORE NOVEL THERAPIES INHIBITING THE IL-1R1/TLR4 SIGNALING IN AN ESTABLISHED MURINE MODEL OF ACQUIRED EPILEPSY. WE USED AN EPIGENETIC APPROACH BY INJECTING A SYNTHETIC MIMIC OF MICRO(MI)RNA-146A THAT IMPAIRS IL1R1/TLR4 SIGNAL TRANSDUCTION, OR WE BLOCKED RECEPTOR ACTIVATION WITH ANTIINFLAMMATORY DRUGS. BOTH INTERVENTIONS WHEN TRANSIENTLY APPLIED TO MICE AFTER EPILEPSY ONSET, PREVENTED DISEASE PROGRESSION AND DRAMATICALLY REDUCED CHRONIC SEIZURE RECURRENCE, WHILE THE ANTICONVULSANT DRUG CARBAMAZEPINE WAS INEFFECTIVE. WE CONCLUDE THAT IL-1R1/TLR4 IS A NOVEL POTENTIAL THERAPEUTIC TARGET FOR ATTAINING DISEASE-MODIFICATIONS IN PATIENTS WITH DIAGNOSED EPILEPSY. 2017 20 78 23 A NEW MECHANISTIC APPROACH FOR THE TREATMENT OF CHRONIC NEUROPATHIC PAIN WITH NITROUS OXIDE INTEGRATED FROM A SYSTEMS BIOLOGY NARRATIVE REVIEW. THE LIMITATIONS OF THE CURRENTLY AVAILABLE TREATMENTS FOR CHRONIC NEUROPATHIC PAIN HIGHLIGHT THE NEED FOR SAFER AND MORE EFFECTIVE ALTERNATIVES. THE AUTHORS CARRIED OUT A FOCUSED REVIEW USING A SYSTEMS BIOLOGY APPROACH TO INTEGRATE THE COMPLEX MECHANISMS OF NOCICEPTION AND NEUROPATHIC PAIN, AND TO DECIPHER THE EFFECTS OF NITROUS OXIDE (N(2)O) ON THOSE PATHWAYS, BEYOND THE KNOWN EFFECT OF N(2)O ON N-METHYL-D-ASPARTATE RECEPTORS. THIS REVIEW IDENTIFIED A NUMBER OF POTENTIAL MECHANISMS BY WHICH N(2)O COULD IMPACT THE PROCESSES INVOLVED IN PERIPHERAL AND CENTRAL SENSITIZATION. IN THE ASCENDING PATHWAY, THE EFFECTS OF N(2)O INCLUDE ACTIVATING TWIK-RELATED K(+) CHANNEL 1 POTASSIUM CHANNELS ON FIRST-ORDER NEURONS, BLOCKING VOLTAGE-DEPENDENT CALCIUM CHANNELS TO ATTENUATE NEURONAL EXCITABILITY, ATTENUATING POSTSYNAPTIC GLUTAMATERGIC RECEPTOR ACTIVATION, AND POSSIBLY BLOCKING VOLTAGE-DEPENDENT SODIUM CHANNELS. IN THE DESCENDING PATHWAY, N(2)O INDUCES THE RELEASE OF ENDOGENOUS OPIOID LIGANDS AND STIMULATES NOREPINEPHRINE RELEASE. IN ADDITION, N(2)O MAY MEDIATE EPIGENETIC CHANGES BY INHIBITING METHIONINE SYNTHASE, A KEY ENZYME INVOLVED IN DNA AND RNA METHYLATION. THIS COULD EXPLAIN WHY THIS SHORT-ACTING ANALGESIC HAS SHOWN LONG-LASTING ANTI-PAIN SENSITIZATION EFFECTS IN ANIMAL MODELS OF CHRONIC PAIN. THESE NEW HYPOTHESES SUPPORT THE RATIONALE FOR INVESTIGATING N(2)O, EITHER ALONE OR IN COMBINATION WITH OTHER ANALGESICS, FOR THE MANAGEMENT OF CHRONIC NEUROPATHIC PAIN. 2021