1 78 126 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 2 4861 23 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 3 5347 22 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 4 6226 13 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 5 2246 23 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 6 55 29 A GAIN-OF-FUNCTION SODIUM CHANNEL BETA2-SUBUNIT MUTATION IN PAINFUL DIABETIC NEUROPATHY. DIABETES MELLITUS IS A GLOBAL CHALLENGE WITH MANY DIVERSE HEALTH SEQUELAE, OF WHICH DIABETIC PERIPHERAL NEUROPATHY IS ONE OF THE MOST COMMON. A SUBSTANTIAL NUMBER OF PATIENTS WITH DIABETIC PERIPHERAL NEUROPATHY DEVELOP CHRONIC PAIN, BUT THE GENETIC AND EPIGENETIC FACTORS THAT PREDISPOSE DIABETIC PERIPHERAL NEUROPATHY PATIENTS TO DEVELOP NEUROPATHIC PAIN ARE POORLY UNDERSTOOD. RECENT TARGETED GENETIC STUDIES HAVE IDENTIFIED MUTATIONS IN ALPHA-SUBUNITS OF VOLTAGE-GATED SODIUM CHANNELS (NA(V)S) IN PATIENTS WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY. MUTATIONS IN PROTEINS THAT REGULATE TRAFFICKING OR FUNCTIONAL PROPERTIES OF NA(V)S COULD EXPAND THE SPECTRUM OF PATIENTS WITH NA(V)-RELATED PERIPHERAL NEUROPATHIES. THE AUXILIARY SODIUM CHANNEL BETA-SUBUNITS (BETA1-4) HAVE BEEN REPORTED TO INCREASE CURRENT DENSITY, ALTER INACTIVATION KINETICS, AND MODULATE SUBCELLULAR LOCALIZATION OF NA(V). MUTATIONS IN BETA-SUBUNITS HAVE BEEN ASSOCIATED WITH SEVERAL DISEASES, INCLUDING EPILEPSY, CANCER, AND DISEASES OF THE CARDIAC CONDUCTING SYSTEM. HOWEVER, MUTATIONS IN BETA-SUBUNITS HAVE NEVER BEEN SHOWN PREVIOUSLY TO CONTRIBUTE TO NEUROPATHIC PAIN. WE REPORT HERE A PATIENT WITH PAINFUL DIABETIC PERIPHERAL NEUROPATHY AND NEGATIVE GENETIC SCREENING FOR MUTATIONS IN SCN9A, SCN10A, AND SCN11A-GENES ENCODING SODIUM CHANNEL ALPHA-SUBUNIT THAT HAVE BEEN PREVIOUSLY LINKED TO THE DEVELOPMENT OF NEUROPATHIC PAIN. GENETIC ANALYSIS REVEALED AN ASPARTIC ACID TO ASPARAGINE MUTATION, D109N, IN THE BETA2-SUBUNIT. FUNCTIONAL ANALYSIS USING CURRENT-CLAMP REVEALED THAT THE BETA2-D109N RENDERED DORSAL ROOT GANGLION NEURONS HYPEREXCITABLE, ESPECIALLY IN RESPONSE TO REPETITIVE STIMULATION. UNDERLYING THE HYPEREXCITABILITY INDUCED BY THE BETA2-SUBUNIT MUTATION, AS EVIDENCED BY VOLTAGE-CLAMP ANALYSIS, WE FOUND A DEPOLARIZING SHIFT IN THE VOLTAGE DEPENDENCE OF NA(V)1.7 FAST INACTIVATION AND REDUCED USE-DEPENDENT INHIBITION OF THE NA(V)1.7 CHANNEL. 2019 7 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 8 6895 23 [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 9 889 23 CHRONIC DIETARY ADMINISTRATION OF VALPROIC ACID PROTECTS NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS FROM IBOTENIC ACID NEUROTOXICITY. VALPROIC ACID (VPA) HAS BEEN USED FOR MANY YEARS AS A DRUG OF CHOICE FOR EPILEPSY AND MOOD DISORDERS. RECENTLY, EVIDENCE HAS BEEN PROPOSED FOR A WIDE SPECTRUM OF ACTIONS OF THIS DRUG, INCLUDING ANTITUMORAL AND NEUROPROTECTIVE PROPERTIES. VALPROIC ACID-MEDIATED NEUROPROTECTION IN VIVO HAS BEEN SO FAR DEMONSTRATED IN A LIMITED NUMBER OF EXPERIMENTAL MODELS. IN THIS STUDY, WE HAVE TESTED THE NEUROPROTECTIVE POTENTIAL OF CHRONIC (4 + 1 WEEKS) DIETARY ADMINISTRATION OF VPA ON DEGENERATION OF CHOLINERGIC AND GABAERGIC NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS (NBM), INJECTED WITH THE EXCITOTOXIN, IBOTENIC ACID (IBO), AN ANIMAL MODELS THAT IS RELEVANT FOR ALZHEIMER'S DISEASE-LIKE NEURODEGENERATION. WE SHOW THAT VPA TREATMENT SIGNIFICANTLY PROTECTS BOTH CHOLINERGIC AND GABAERGIC NEURONS PRESENT IN THE INJECTED AREA FROM THE EXCITOTOXIC INSULT. A SIGNIFICANT LEVEL OF NEUROPROTECTION, IN PARTICULAR, IS EXERTED TOWARDS THE CHOLINERGIC NEURONS OF THE NBM PROJECTING TO THE CORTEX, AS DEMONSTRATED BY THE SUBSTANTIALLY HIGHER LEVELS OF CHOLINERGIC MARKERS MAINTAINED IN THE TARGET CORTICAL AREA OF VPA-TREATED RATS AFTER IBO INJECTION IN THE NBM. WE FURTHER SHOW THAT CHRONIC VPA ADMINISTRATION RESULTS IN INCREASED ACETYLATION OF HISTONE H3 IN BRAIN, CONSISTENT WITH THE HISTONE DEACETYLASE INHIBITORY ACTION OF VPA AND PUTATIVELY LINKED TO A NEUROPROTECTIVE ACTION OF THE DRUG MEDIATED AT THE EPIGENETIC LEVEL. 2009 10 5474 20 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 11 6130 27 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 12 2176 19 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 13 656 23 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 14 2886 22 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 15 2993 29 GENETIC PAIN LOSS DISORDERS. GENETIC PAIN LOSS INCLUDES CONGENITAL INSENSITIVITY TO PAIN (CIP), HEREDITARY SENSORY NEUROPATHIES AND, IF AUTONOMIC NERVES ARE INVOLVED, HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY (HSAN). THIS HETEROGENEOUS GROUP OF DISORDERS HIGHLIGHTS THE ESSENTIAL ROLE OF NOCICEPTION IN PROTECTING AGAINST TISSUE DAMAGE. PATIENTS WITH GENETIC PAIN LOSS HAVE RECURRENT INJURIES, BURNS AND POORLY HEALING WOUNDS AS DISEASE HALLMARKS. CIP AND HSAN ARE CAUSED BY PATHOGENIC GENETIC VARIANTS IN >20 GENES THAT LEAD TO DEVELOPMENTAL DEFECTS, NEURODEGENERATION OR ALTERED NEURONAL EXCITABILITY OF PERIPHERAL DAMAGE-SENSING NEURONS. THESE GENETIC VARIANTS LEAD TO HYPERACTIVITY OF SODIUM CHANNELS, DISTURBED HAEM METABOLISM, ALTERED CLATHRIN-MEDIATED TRANSPORT AND IMPAIRED GENE REGULATORY MECHANISMS AFFECTING EPIGENETIC MARKS, LONG NON-CODING RNAS AND REPETITIVE ELEMENTS. THERAPIES FOR PAIN LOSS DISORDERS ARE MAINLY SYMPTOMATIC BUT THE FIRST TARGETED THERAPIES ARE BEING TESTED. CONVERSELY, CHRONIC PAIN REMAINS ONE OF THE GREATEST UNRESOLVED MEDICAL CHALLENGES, AND THE GENES AND MECHANISMS ASSOCIATED WITH PAIN LOSS OFFER NEW TARGETS FOR ANALGESICS. GIVEN THE PROGRESS THAT HAS BEEN MADE, THE COMING YEARS ARE PROMISING BOTH IN TERMS OF TARGETED TREATMENTS FOR PAIN LOSS DISORDERS AND THE DEVELOPMENT OF INNOVATIVE PAIN MEDICINES BASED ON KNOWLEDGE OF THESE GENETIC DISEASES. 2022 16 195 16 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 17 980 20 CHRONIC PAIN: EMERGING EVIDENCE FOR THE INVOLVEMENT OF EPIGENETICS. EPIGENETIC PROCESSES, SUCH AS HISTONE MODIFICATIONS AND DNA METHYLATION, HAVE BEEN ASSOCIATED WITH MANY NEURAL FUNCTIONS INCLUDING SYNAPTIC PLASTICITY, LEARNING, AND MEMORY. HERE, WE CRITICALLY EXAMINE EMERGING EVIDENCE LINKING EPIGENETIC MECHANISMS TO THE DEVELOPMENT OR MAINTENANCE OF CHRONIC PAIN STATES. ALTHOUGH IN ITS INFANCY, RESEARCH IN THIS AREA POTENTIALLY UNIFIES SEVERAL PATHOPHYSIOLOGICAL PROCESSES UNDERPINNING ABNORMAL PAIN PROCESSING AND OPENS UP A DIFFERENT AVENUE FOR THE DEVELOPMENT OF NOVEL ANALGESICS. 2012 18 3833 25 INVOLVEMENT OF THE DYNORPHIN/KOR SYSTEM ON THE NOCICEPTIVE, EMOTIONAL AND COGNITIVE MANIFESTATIONS OF JOINT PAIN IN MICE. JOINT PAIN IS A MAJOR CLINICAL PROBLEM MAINLY ASSOCIATED TO OSTEOARTHRITIS, AND CHARACTERIZED BY ARTICULAR CARTILAGE DEGRADATION RESULTING IN A COMPLEX CHRONIC PAIN STATE THAT INCLUDES NOCICEPTIVE, EMOTIONAL AND COGNITIVE MANIFESTATIONS. MEMORY IMPAIRMENT, DEPRESSIVE- AND ANXIETY-LIKE SYMPTOMS HAVE BEEN REPORTED TO BE ASSOCIATED WITH CHRONIC PAIN, LEADING TO A DECREASE OF LIFE QUALITY. IN THIS STUDY, WE EVALUATED THE INVOLVEMENT OF THE ENDOGENOUS DYNORPHIN/KAPPA OPIOID RECEPTOR (KOR) SYSTEM ON THE NOCICEPTIVE, EMOTIONAL, COGNITIVE, NEUROCHEMICAL AND EPIGENETIC MANIFESTATIONS OF JOINT PAIN. THE MURINE MODEL OF MONOSODIUM IODOACETATE (MIA) WAS USED TO INDUCE JOINT PAIN IN KNOCKOUT MICE FOR KOR (KOR-KO), PRODYNORPHIN (PDYN-KO) AND THEIR WILD-TYPE (WT) LITTERMATES. KOR-KO AND PDYN-KO MICE DEVELOPED MECHANICAL ALLODYNIA AFTER INTRA-ARTICULAR INJECTION OF MIA. THIS ALLODYNIA WAS SIGNIFICANTLY INCREASED IN BOTH KOR-KO AND PDYN-KO WHEN COMPARED TO WT MICE. ACCORDINGLY, BOTH MUTANTS SHOWED INCREASED MICROGLIAL ACTIVATION ON THE LUMBAR SECTION OF THE SPINAL CORD AFTER MIA. THE EMOTIONAL RESPONSES WERE EVALUATED BY MEASURING ANXIETY-LIKE BEHAVIOUR IN THE ELEVATED PLUS MAZE AND ANHEDONIA AS DEPRESSIVE-LIKE BEHAVIOUR, AND COGNITIVE ALTERATIONS IN THE OBJECT RECOGNITION PARADIGM. EMOTIONAL AND COGNITIVE IMPAIRMENTS AFTER JOINT PAIN WERE DIFFERENTLY MODIFIED IN KOR-KO AND PDYN-KO MICE. ALTERATIONS OF CORTICOTROPIN-RELEASING FACTOR (CRF) ON THE AMYGDALA AND HIPPOCAMPUS AND DOWN REGULATION OF HISTONE 3 ACETYLATION ON THE AMYGDALA SUGGEST A POSSIBLE MECHANISM TO EXPLAIN THESE EMOTIONAL AND COGNITIVE MANIFESTATIONS. OUR RESULTS REVEAL A SPECIFIC INVOLVEMENT OF THE DYNORPHIN/KOR SYSTEM ON JOINT PAIN MANIFESTATIONS THAT ARE USUALLY ASSOCIATED TO OSTEOARTHRITIS. 2017 19 1162 30 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018 20 5599 31 ROLES OF THE NEURON-RESTRICTIVE SILENCER FACTOR IN THE PATHOPHYSIOLOGICAL PROCESS OF THE CENTRAL NERVOUS SYSTEM. THE NEURON-RESTRICTIVE SILENCER FACTOR (NRSF), ALSO KNOWN AS REPRESSOR ELEMENT 1 (RE-1) SILENCING TRANSCRIPTION FACTOR (REST) OR X2 BOX REPRESSOR (XBR), IS A ZINC FINGER TRANSCRIPTION FACTOR THAT IS WIDELY EXPRESSED IN NEURONAL AND NON-NEURONAL CELLS. IT IS A MASTER REGULATOR OF THE NERVOUS SYSTEM, AND THE FUNCTION OF NRSF IS THE BASIS OF NEURONAL DIFFERENTIATION, DIVERSITY, PLASTICITY, AND SURVIVAL. NRSF CAN BIND TO THE NEURON-RESTRICTIVE SILENCER ELEMENT (NRSE), RECRUIT SOME CO-REPRESSORS, AND THEN INHIBIT TRANSCRIPTION OF NRSE DOWNSTREAM GENES THROUGH EPIGENETIC MECHANISMS. IN NEUROGENESIS, NRSF FUNCTIONS NOT ONLY AS A TRANSCRIPTIONAL SILENCER THAT CAN MEDIATE THE TRANSCRIPTIONAL INHIBITION OF NEURON-SPECIFIC GENES IN NON-NEURONAL CELLS AND THUS GIVE NEURON CELLS SPECIFICITY, BUT ALSO AS A TRANSCRIPTIONAL ACTIVATOR TO INDUCE NEURONAL DIFFERENTIATION. MANY STUDIES HAVE CONFIRMED THE ASSOCIATION BETWEEN NRSF AND BRAIN DISORDERS, SUCH AS BRAIN INJURY AND NEURODEGENERATIVE DISEASES. OVEREXPRESSION, UNDEREXPRESSION, OR MUTATION MAY LEAD TO NEUROLOGICAL DISORDERS. IN TUMORIGENESIS, NRSF FUNCTIONS AS AN ONCOGENE IN NEURONAL TUMORS, SUCH AS NEUROBLASTOMAS, MEDULLOBLASTOMAS, AND PHEOCHROMOCYTOMAS, STIMULATING THEIR PROLIFERATION, WHICH RESULTS IN POOR PROGNOSIS. ADDITIONALLY, NRSF-MEDIATED SELECTIVE TARGETS GENE REPRESSION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN CAUSED BY NERVE INJURY, CANCER, AND DIABETES. AT PRESENT, SEVERAL COMPOUNDS THAT TARGET NRSF OR ITS CO-REPRESSORS, SUCH AS REST-VP16 AND X5050, HAVE BEEN SHOWN TO BE CLINICALLY EFFECTIVE AGAINST MANY BRAIN DISEASES, SUCH AS SEIZURES, IMPLYING THAT NRSF AND ITS CO-REPRESSORS MAY BE POTENTIAL AND PROMISING THERAPEUTIC TARGETS FOR NEURAL DISORDERS. IN THE PRESENT REVIEW, WE INTRODUCED THE BIOLOGICAL CHARACTERISTICS OF NRSF; REVIEWED THE PROGRESS TO DATE IN UNDERSTANDING THE ROLES OF NRSF IN THE PATHOPHYSIOLOGICAL PROCESSES OF THE NERVOUS SYSTEM, SUCH AS NEUROGENESIS, BRAIN DISORDERS, NEURAL TUMORIGENESIS, AND NEUROPATHIC PAIN; AND SUGGESTED NEW THERAPEUTIC APPROACHES TO SUCH BRAIN DISEASES. 2022