1 4338 123 MICROVASCULAR BARRIER PROTECTION BY MICRORNA-183 VIA FOXO1 REPRESSION: A PATHWAY DISTURBED IN NEUROPATHY AND COMPLEX REGIONAL PAIN SYNDROME. BLOOD NERVE BARRIER DISRUPTION AND EDEMA ARE COMMON IN NEUROPATHIC PAIN AS WELL AS IN COMPLEX REGIONAL PAIN SYNDROME (CRPS). MICRORNAS (MIRNA) ARE EPIGENETIC MULTITARGET SWITCHES CONTROLLING NEURONAL AND NON-NEURONAL CELLS IN PAIN. THE MIR-183 COMPLEX ATTENUATES HYPEREXCITABILITY IN NOCICEPTORS, BUT ADDITIONAL NON-NEURONAL EFFECTS VIA TRANSCRIPTION FACTORS COULD CONTRIBUTE AS WELL. THIS STUDY EXPLORED EXOSOMAL MIR-183 IN CRPS AND MURINE NEUROPATHY, ITS EFFECT ON THE MICROVASCULAR BARRIER VIA TRANSCRIPTION FACTOR FOXO1 AND TIGHT JUNCTION PROTEIN CLAUDIN-5, AND ITS ANTIHYPERALGESIC POTENTIAL. SCIATIC MIR-183 DECREASED AFTER CCI. SUBSTITUTION WITH PERINEURAL MIR-183 MIMIC ATTENUATED MECHANICAL HYPERSENSITIVITY AND RESTORED BLOOD NERVE BARRIER FUNCTION. IN VITRO, SERUM FROM CCI MICE UND CRPS PATIENTS WEAKENED THE MICROVASCULAR BARRIER OF MURINE CEREBELLAR ENDOTHELIAL CELLS, INCREASED ACTIVE FOXO1 AND REDUCED CLAUDIN-5, CONCOMITANT WITH A LACK OF EXOSOMAL MIR-183 IN CRPS PATIENTS. CELLULAR STRESS ALSO COMPROMISED THE MICROVASCULAR BARRIER WHICH WAS RESCUED EITHER BY MIR-183 MIMIC VIA FOXO1 REPRESSION OR BY PRIOR SILENCING OF FOXO1. PERSPECTIVE: LOW MIR-183 LEADING TO BARRIER IMPAIRMENT VIA FOXO1 AND SUBSEQUENT CLAUDIN-5 SUPPRESSION IS A NEW ASPECT IN THE PATHOPHYSIOLOGY OF CRPS AND NEUROPATHIC PAIN. THIS PATHWAY MIGHT HELP UNTANGLE THE WIDE SYMPTOMATIC RANGE OF CRPS AND NURTURE FURTHER RESEARCH INTO MIRNA MIMICS OR FOXO1 INHIBITORS. 2022 2 2198 35 EPIGENETIC MODIFICATION OF DRG NEURONAL GENE EXPRESSION SUBSEQUENT TO NERVE INJURY: ETIOLOGICAL CONTRIBUTION TO COMPLEX REGIONAL PAIN SYNDROMES (PART I). DRG IS OF IMPORTANCE IN RELAYING PAINFUL STIMULATION TO THE HIGHER PAIN CENTERS AND THEREFORE COULD BE A CRUCIAL TARGET FOR EARLY INTERVENTION AIMED AT SUPPRESSING PRIMARY AFFERENT STIMULATION. COMPLEX REGIONAL PAIN SYNDROME (CRPS) IS A COMMON PAIN CONDITION WITH AN UNKNOWN ETIOLOGY. RECENTLY ADDED NEW INFORMATION ENRICHES OUR UNDERSTANDING OF CRPS PATHOPHYSIOLOGY. RESEARCHES ON GENETICS, BIOGENIC AMINES, NEUROTRANSMITTERS, AND MECHANISMS OF PAIN MODULATION, CENTRAL SENSITIZATION, AND AUTONOMIC FUNCTIONS IN CRPS REVEALED VARIOUS ABNORMALITIES INDICATING THAT MULTIPLE FACTORS AND MECHANISMS ARE INVOLVED IN THE PATHOGENESIS OF CRPS. EPIGENETICS REFERS TO MITOTICALLY AND MEIOTICALLY HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT AFFECT THE DNA SEQUENCE. AS EPIGENETIC MODIFICATIONS POTENTIALLY PLAY AN IMPORTANT ROLE IN INFLAMMATORY CYTOKINE METABOLISM, NEUROTRANSMITTER RESPONSIVENESS, AND ANALGESIC SENSITIVITY, THEY ARE LIKELY KEY FACTORS IN THE DEVELOPMENT OF CHRONIC PAIN. IN THIS DYAD REVIEW SERIES, WE SYSTEMATICALLY EXAMINE THE NERVE INJURY-RELATED CHANGES IN THE NEUROLOGICAL SYSTEM AND THEIR CONTRIBUTION TO CRPS. IN THIS PART, WE FIRST REVIEWED AND SUMMARIZED THE ROLE OF NEURAL SENSITIZATION IN DRG NEURONS IN PERFORMING FUNCTION IN THE CONTEXT OF PAIN PROCESSING. PARTICULAR EMPHASIS IS PLACED ON THE CELLULAR AND MOLECULAR CHANGES AFTER NERVE INJURY AS WELL AS DIFFERENT MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN. THESE WERE CONSIDERED AS THE POTENTIAL MOLECULAR BASES THAT UNDERLIE NERVE INJURY-ASSOCIATED PATHOGENESIS OF CRPS. 2014 3 1580 27 DNA METHYLATION PROFILES ARE ASSOCIATED WITH COMPLEX REGIONAL PAIN SYNDROME AFTER TRAUMATIC INJURY. FACTORS CONTRIBUTING TO DEVELOPMENT OF COMPLEX REGIONAL PAIN SYNDROME (CRPS) ARE NOT FULLY UNDERSTOOD. THIS STUDY EXAMINED POSSIBLE EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO CRPS AFTER TRAUMATIC INJURY. DNA METHYLATION PROFILES WERE COMPARED BETWEEN INDIVIDUALS DEVELOPING CRPS (N = 9) AND THOSE DEVELOPING NON-CRPS NEUROPATHIC PAIN (N = 38) AFTER UNDERGOING AMPUTATION FOLLOWING MILITARY TRAUMA. LINEAR MODELS FOR MICROARRAY (LIMMA) ANALYSES REVEALED 48 DIFFERENTIALLY METHYLATED CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES BETWEEN GROUPS (UNADJUSTED P'S < 0.005), WITH THE TOP GENE COL11A1 MEETING BONFERRONI-ADJUSTED P < 0.05. THE SECOND LARGEST DIFFERENTIAL METHYLATION WAS OBSERVED FOR THE HLA-DRB6 GENE, AN IMMUNE-RELATED GENE LINKED PREVIOUSLY TO CRPS IN A SMALL GENE EXPRESSION STUDY. FOR ALL BUT 7 OF THE SIGNIFICANT CPG SITES, THE CRPS GROUP WAS HYPOMETHYLATED. NUMEROUS FUNCTIONAL GENE ONTOLOGY-BIOLOGICAL PROCESS CATEGORIES WERE SIGNIFICANTLY ENRICHED (FALSE DISCOVERY RATE-ADJUSTED Q VALUE <0.15), INCLUDING MULTIPLE IMMUNE-RELATED CATEGORIES (EG, ACTIVATION OF IMMUNE RESPONSE, IMMUNE SYSTEM DEVELOPMENT, REGULATION OF IMMUNE SYSTEM PROCESSES, AND ANTIGEN PROCESSING AND PRESENTATION). DIFFERENTIALLY METHYLATED GENES WERE MORE HIGHLY CONNECTED IN HUMAN PROTEIN-PROTEIN NETWORKS THAN EXPECTED BY CHANCE (P < 0.05), SUPPORTING THE BIOLOGICAL RELEVANCE OF THE FINDINGS. RESULTS WERE VALIDATED IN AN INDEPENDENT SAMPLE LINKING A DNA BIOBANK WITH ELECTRONIC HEALTH RECORDS (N = 126 CRPS PHENOTYPE, N = 19,768 NON-CRPS CHRONIC PAIN PHENOTYPE). ANALYSES USING PREDIXCAN METHODOLOGY INDICATED DIFFERENCES IN THE GENETICALLY DETERMINED COMPONENT OF GENE EXPRESSION IN 7 OF 48 GENES IDENTIFIED IN METHYLATION ANALYSES (P'S < 0.02). RESULTS SUGGEST THAT IMMUNE- AND INFLAMMATORY-RELATED FACTORS MIGHT CONFER RISK OF DEVELOPING CRPS AFTER TRAUMATIC INJURY. VALIDATION FINDINGS DEMONSTRATE THE POTENTIAL OF USING ELECTRONIC HEALTH RECORDS LINKED TO DNA FOR GENOMIC STUDIES OF CRPS. 2019 4 2199 28 EPIGENETIC MODIFICATION OF DRG NEURONAL GENE EXPRESSION SUBSEQUENT TO NERVE INJURY: ETIOLOGICAL CONTRIBUTION TO COMPLEX REGIONAL PAIN SYNDROMES (PART II). CUMULATING EVIDENCE INDICATED THAT NERVE INJURY-ASSOCIATED CELLULAR AND MOLECULAR CHANGES PLAY AN ESSENTIAL ROLE IN CONTRIBUTING TO THE DEVELOPMENT OF PATHOLOGICAL PAIN, AND MORE RECENT FINDINGS IMPLICATED THE CRITICAL ROLE OF EPIGENETIC MECHANISMS IN PAIN-RELATED SENSITIZATION IN THE DRG SUBSEQUENT TO NERVE INJURY. IN THIS PART OF THE DYAD REVIEW (PART II), WE REVIEWED AND PAID SPECIAL ATTENTION ON THE ETIOLOGICAL CONTRIBUTION OF DGR GENE EXPRESSION MODULATED BY EPIGENETIC MECHANISMS OF CRPS. AS ESSENTIAL EFFECTORS TO DIFFERENT MOLECULAR ACTIVATION, WE FIRST DISCUSSED THE ACTIVATION OF VARIOUS SIGNALING PATHWAYS THAT SUBSEQUENTLY FROM NERVE INJURY, AND IN FURTHER ILLUSTRATED THE FUNDAMENTAL AND FUNCTIONAL UNDERPINNINGS OF NERVE INJURY-INDUCED PAIN, IN WHICH WE ARGUED FOR THE POTENTIAL EPIGENETIC MECHANISMS IN RESPONSE TO SENSITIZING STIMULI OR INJURY. THEREFORE, UNDERSTANDING THE SPECIFIC MEDIATING FACTORS THAT INFLUENCE INDIVIDUAL EPIGENETIC DIFFERENCES CONTRIBUTING TO PAIN SENSITIVITY AND RESPONSIVENESS TO ANALGESICS POSSESSES CRUCIAL CLINICAL IMPLICATIONS. 2014 5 1998 33 EPIGENETIC AND MIRNA EXPRESSION CHANGES IN PEOPLE WITH PAIN: A SYSTEMATIC REVIEW. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS MAY HOLD GREAT POTENTIAL IN THE FIELD OF PAIN. WE SYSTEMATICALLY REVIEWED THE LITERATURE EXPLORING EPIGENETIC MECHANISMS IN PEOPLE WITH PAIN. FOUR DATABASES HAVE BEEN INTERROGATED: MEDLINE, THE COCHRANE CENTRAL REGISTER OF CONTROLLED TRIAL, SCOPUS, AND WEB OF SCIENCE, FOLLOWING PRISMA GUIDELINES IN CONDUCTING STUDY SELECTION AND ASSESSMENT. THIRTY-SEVEN STUDIES WERE INCLUDED. STUDIES EXPLORED EPIGENETICS IN CONDITIONS SUCH AS FIBROMYALGIA, CRPS, NEUROPATHIES, OR OSTEOARTHRITIS. RESEARCH FOCUSSED ON GENOME-WIDE AND GENE-SPECIFIC DNA METHYLATION, AND MIRNA EXPRESSION. BIOINFORMATICS ANALYSES EXPLORING MIRNA-ASSOCIATED MOLECULAR PATHWAYS WERE ALSO PERFORMED. SEVERAL GENES ALREADY KNOWN FOR THEIR ROLE IN PAIN (BDNF, HDAC4, PRKG1, IL-17, TNFRSF13B, ETC.), AND SEVERAL MIRNAS LINKED TO INFLAMMATORY REGULATION, NOCICEPTIVE SIGNALLING AND PROTEIN KINASES FUNCTIONS HAVE BEEN FOUND TO DIFFER SIGNIFICANTLY BETWEEN PEOPLE WITH CHRONIC PAIN AND HEALTHY CONTROLS. ALTHOUGH THE STUDIES INCLUDED WERE CROSS-SECTIONAL IN NATURE, AND NO CONCLUSION ON CAUSAL LINKS BETWEEN EPIGENETIC CHANGES AND PAIN COULD BE DRAWN, WE SUMMARISED THE LARGE AMOUNT OF DATA AVAILABLE IN LITERATURE ON THE TOPIC, HIGHLIGHTING RESULTS THAT HAVE BEEN REPLICATED BY INDEPENDENT INVESTIGATIONS. THE FIELD OF PAIN EPIGENETICS APPEARS VERY EXCITING AND HAS ALL THE POTENTIAL TO LEAD TO REMARKABLE SCIENTIFIC ADVANCES. HOWEVER, HIGH-QUALITY, WELL-POWERED, LONGITUDINAL STUDIES ARE WARRANTED. PERSPECTIVE: THOUGH MORE HIGH-QUALITY RESEARCH IS NEEDED, AVAILABLE RESEARCH EXPLORING EPIGENETIC MECHANISMS OR MIRNAS IN PEOPLE WITH PAIN SHOWS THAT GENES REGULATING SYNAPTIC PLASTICITY AND EXCITABILITY, PROTEIN KINASES, AND ELEMENTS OF THE IMMUNE SYSTEM MIGHT HOLD GREAT POTENTIAL IN UNDERSTANDING THE PATHOPHYSIOLOGY OF DIFFERENT CONDITIONS. 2020 6 3397 24 HOW ADVANCED ARE WE ON THE CONSEQUENCES OF ORAL EXPOSURE TO FOOD CONTAMINANTS ON THE OCCURRENCE OF CHRONIC NON COMMUNICABLE DISEASES? THE DEVELOPMENT OF AN INDIVIDUAL DURING FETAL LIFE AND CHILDHOOD IS CHARACTERIZED BY RAPID GROWTH AS WELL AS GRADUAL MATURATION OF ORGANS AND SYSTEMS. BEYOND THE NUTRITIONAL INTAKE IN ESSENTIAL NUTRIENTS, FOOD CONTAMINANTS CAN PERMANENTLY INFLUENCE THE WAY ORGANS MATURE AND FUNCTION. THESE PROCESSES ARE CALLED "PROGRAMMING" AND PLAY AN ESSENTIAL ROLE IN THE OCCURRENCE OF NON-COMMUNICABLE CHRONIC DISEASES THROUGHOUT THE LIFESPAN. POPULATIONS AS PREGNANT WOMEN, FETUSES AND YOUNG CHILDREN ARE VULNERABLE AND PARTICULARLY SENSITIVE TO FOOD CONTAMINANTS WHICH CAN INDUCE EPIGENETIC MODIFICATIONS TRANSMISSIBLE TO FUTURE GENERATIONS. AMONG THESE CONTAMINANTS, PESTICIDES ARE FOUND IN MOST FOOD MATRICES EXPOSING HUMANS TO COCKTAILS OF MOLECULES THROUGH VARIABLE CONCENTRATIONS AND DURATION OF EXPOSURE. THE MAILLARD REACTION PRODUCTS (MRPS) REPRESENT OTHER FOOD CONTAMINANTS RESULTING FROM HEAT TREATMENT OF FOOD. MODERN DIET, RICH IN FATS AND SUGARS, IS ALSO RICH IN NEOFORMED PATHOGENIC COMPOUNDS, ADVANCED GLYCATION END PRODUCTS (AGES), THE LEVELS OF WHICH DEPEND ON THE HEAT TREATMENT OF FOODS AND EATING HABITS AND WHOSE EFFECTS ON HEALTH ARE CONTROVERSIAL. IN THIS REVIEW, WE HAVE CHOSEN TO PRESENT THE CURRENT KNOWLEDGE ON THE IMPACTS OF SELECTED PESTICIDES AND MRPS, ON THE RISK OF DEVELOPING DURING LIFE NON-COMMUNICABLE CHRONIC DISEASES SUCH AS IBD, METABOLIC DISORDERS OR ALLERGIES. A LARGE REVIEW OF LITERATURE WAS PERFORMED VIA PUBMED, AND THE MOST APPROPRIATE STUDIES WERE SUMMARISED. 2022 7 4713 25 NON-CODING RNA AND N6-METHYLADENOSINE MODIFICATION PLAY CRUCIAL ROLES IN NEUROPATHIC PAIN. AFTER PERIPHERAL NERVE INJURY, PAIN SIGNALS ARE TRANSMITTED FROM PRIMARY SENSORY NEURONS IN THE DORSAL ROOT GANGLION (DRG) TO THE CENTRAL NERVOUS SYSTEM. EPIGENETIC MODIFICATION AFFECTS NEUROPATHIC PAIN THROUGH ALTERATIONS IN THE GENE EXPRESSION IN PAIN-RELATED AREAS AND GLIAL CELL ACTIVATION. RECENT STUDIES HAVE SHOWN THAT NON-CODING RNA AND N6-METHYLADENOSINE (M6A) METHYLATION MODIFICATION PLAY PIVOTAL REGULATORY ROLES IN THE OCCURRENCE AND MAINTENANCE OF NEUROPATHIC PAIN. DYSREGULATION OF THE RNA M6A LEVEL VIA DYNAMIC CHANGES IN METHYLTRANSFERASE AND DEMETHYLASE AFTER CENTRAL OR PERIPHERAL NERVE INJURY COMMONLY REGULATES PAIN-ASSOCIATED GENES, CONTRIBUTING TO THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. THE DYNAMIC PROCESS HAS SIGNIFICANT IMPLICATIONS FOR THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. HOWEVER, THE UNDERLYING MECHANISMS BY WHICH NON-CODING RNA AND M6A RNA MODIFICATION REGULATE NEUROPATHIC PAIN ARE NOT WELL-CHARACTERIZED. THIS ARTICLE ELUCIDATES THE MULTIPLE MECHANISMS OF NON-CODING RNA AND M6A METHYLATION IN THE CONTEXT OF NEUROPATHIC PAIN, AND SUMMARIZES ITS POTENTIAL FUNCTIONS AS WELL AS RECENT ADVANCES. 2022 8 6139 33 THE ETIOLOGICAL CONTRIBUTION OF GABAERGIC PLASTICITY TO THE PATHOGENESIS OF NEUROPATHIC PAIN. NEUROPATHIC PAIN DEVELOPING AFTER PERIPHERAL OR CENTRAL NERVE INJURY IS THE RESULT OF PATHOLOGICAL CHANGES GENERATED THROUGH COMPLEX MECHANISMS. DISRUPTION IN THE HOMEOSTASIS OF EXCITATORY AND INHIBITORY NEURONS WITHIN THE CENTRAL NERVOUS SYSTEM IS A CRUCIAL FACTOR IN THE FORMATION OF HYPERALGESIA OR ALLODYNIA OCCURRING WITH NEUROPATHIC PAIN. THE CENTRAL GABAERGIC PATHWAY HAS RECEIVED ATTENTION FOR ITS EXTENSIVE DISTRIBUTION AND FUNCTION IN NEURAL CIRCUITS, INCLUDING THE GENERATION AND DEVELOPMENT OF NEUROPATHIC PAIN. GABAERGIC INHIBITORY CHANGES THAT OCCUR IN THE INTERNEURONS ALONG DESCENDING MODULATORY AND NOCICEPTIVE PATHWAYS IN THE CENTRAL NERVOUS SYSTEM ARE BELIEVED TO GENERATE NEURONAL PLASTICITY, SUCH AS SYNAPTIC PLASTICITY OR FUNCTIONAL PLASTICITY OF THE RELATED GENES OR PROTEINS, THAT IS THE FOUNDATION OF PERSISTENT NEUROPATHIC PAIN. THE PRIMARY GABAERGIC PLASTICITY OBSERVED IN NEUROPATHIC PAIN INCLUDES GABAERGIC SYNAPSE HOMO- AND HETEROSYNAPTIC PLASTICITY, DECREASED SYNTHESIS OF GABA, DOWN-EXPRESSION OF GLUTAMIC ACID DECARBOXYLASE AND GABA TRANSPORTER, ABNORMAL EXPRESSION OF NKCC1 OR KCC2, AND DISTURBED FUNCTION OF GABA RECEPTORS. IN THIS REVIEW, WE DESCRIBE POSSIBLE MECHANISMS ASSOCIATED WITH GABAERGIC PLASTICITY, SUCH AS CENTRAL SENSITIZATION AND GABAERGIC INTERNEURON APOPTOSIS, AND THE EPIGENETIC ETIOLOGIES OF GABAERGIC PLASTICITY IN NEUROPATHIC PAIN. MOREOVER, WE SUMMARIZE POTENTIAL THERAPEUTIC TARGETS OF GABAERGIC PLASTICITY THAT MAY ALLOW FOR SUCCESSFUL RELIEF OF HYPERALGESIA FROM NERVE INJURY. FINALLY, WE COMPARE THE EFFECTS OF THE GABAERGIC SYSTEM IN NEUROPATHIC PAIN TO OTHER TYPES OF CHRONIC PAIN TO UNDERSTAND THE CONTRIBUTION OF GABAERGIC PLASTICITY TO NEUROPATHIC PAIN. 2019 9 4616 32 NERVE INJURY INCREASES BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS TO SUPPRESS BK CHANNEL ACTIVITY IN PRIMARY SENSORY NEURONS. ABNORMAL HYPEREXCITABILITY OF PRIMARY SENSORY NEURONS CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT AFTER NERVE INJURY. NERVE INJURY PROFOUNDLY REDUCES THE EXPRESSION OF BIG CONDUCTANCE CA(2+) -ACTIVATED K(+) (BK) CHANNELS IN THE DORSAL ROOT GANGLION (DRG). HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY AFFECTS BK CHANNEL ACTIVITY IN DRG NEURONS. IN THIS STUDY, WE DETERMINED THE CHANGES IN BK CHANNEL ACTIVITY IN DRG NEURONS IN A RAT MODEL OF NEUROPATHIC PAIN AND THE CONTRIBUTION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) TO REDUCED BK CHANNEL ACTIVITY. THE BK CHANNEL ACTIVITY WAS PRESENT PREDOMINANTLY IN SMALL AND MEDIUM DRG NEURONS, AND LIGATION OF L5 AND L6 SPINAL NERVES PROFOUNDLY DECREASED THE BK CURRENT DENSITY IN THESE NEURONS. BLOCKING BK CHANNELS SIGNIFICANTLY INCREASED NEURONAL EXCITABILITY IN SHAM CONTROL, BUT NOT IN NERVE-INJURED, RATS. THE BDNF CONCENTRATION IN THE DRG WAS SIGNIFICANTLY GREATER IN NERVE-INJURED RATS THAN IN CONTROL RATS. BDNF TREATMENT LARGELY REDUCED BK CURRENTS IN DRG NEURONS IN CONTROL RATS, WHICH WAS BLOCKED BY EITHER ANTI-BDNF ANTIBODY OR K252A, A TRK RECEPTOR INHIBITOR. FURTHERMORE, EITHER ANTI-BDNF ANTIBODY OR K252A REVERSED REDUCTION IN BK CURRENTS IN INJURED DRG NEURONS. BDNF TREATMENT REDUCED THE MRNA LEVELS OF BKALPHA1 SUBUNIT IN DRG NEURONS, AND ANTI-BDNF ANTIBODY ATTENUATED THE REDUCTION IN THE BKALPHA1 MRNA LEVEL IN INJURED DRG NEURONS. THESE FINDINGS SUGGEST THAT NERVE INJURY PRIMARILY DIMINISHES THE BK CHANNEL ACTIVITY IN SMALL AND MEDIUM DRG NEURONS. INCREASED BDNF LEVELS CONTRIBUTE TO REDUCED BK CHANNEL ACTIVITY IN DRG NEURONS THROUGH EPIGENETIC AND TRANSCRIPTIONAL MECHANISMS IN NEUROPATHIC PAIN. 2012 10 2179 24 EPIGENETIC MECHANISMS OF NEURAL PLASTICITY IN CHRONIC NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A CHALLENGING CLINICAL PROBLEM AND REMAINS DIFFICULT TO TREAT. ALTERED GENE EXPRESSION IN PERIPHERAL SENSORY NERVES AND NEURONS DUE TO NERVE INJURY IS WELL DOCUMENTED AND CONTRIBUTES CRITICALLY TO THE SYNAPTIC PLASTICITY IN THE SPINAL CORD AND THE INITIATION AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS REGULATING THE TRANSCRIPTION OF PRO-NOCICEPTIVE (E.G., NMDA RECEPTORS AND ALPHA2DELTA-1) AND ANTINOCICEPTIVE (E.G., POTASSIUM CHANNELS AND OPIOID AND CANNABINOID RECEPTORS) GENES ARE STILL LIMITED. IN THIS REVIEW, WE SUMMARIZE RECENT STUDIES DETERMINING THE ROLES OF HISTONE MODIFICATIONS (INCLUDING METHYLATION, ACETYLATION, AND UBIQUITINATION), DNA METHYLATION, AND NONCODING RNAS IN NEUROPATHIC PAIN DEVELOPMENT. WE REVIEW THE EPIGENETIC WRITER, READER, AND ERASER PROTEINS THAT PARTICIPATE IN THE TRANSCRIPTIONAL CONTROL OF THE EXPRESSION OF KEY ION CHANNELS AND NEUROTRANSMITTER RECEPTORS IN THE DORSAL ROOT GANGLION AFTER TRAUMATIC NERVE INJURY, WHICH IS COMMONLY USED AS A PRECLINICAL MODEL OF NEUROPATHIC PAIN. A BETTER UNDERSTANDING OF EPIGENETIC REPROGRAMMING INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN COULD LEAD TO THE DEVELOPMENT OF NEW TREATMENTS FOR NEUROPATHIC PAIN. 2022 11 5369 25 RECENT ADVANCES IN UNDERSTANDING NEUROPATHIC PAIN: GLIA, SEX DIFFERENCES, AND EPIGENETICS. NEUROPATHIC PAIN RESULTS FROM DISEASES OR TRAUMA AFFECTING THE NERVOUS SYSTEM. THIS PAIN CAN BE DEVASTATING AND IS POORLY CONTROLLED. THE PATHOPHYSIOLOGY IS COMPLEX, AND IT IS ESSENTIAL TO UNDERSTAND THE UNDERLYING MECHANISMS IN ORDER TO IDENTIFY THE RELEVANT TARGETS FOR THERAPEUTIC INTERVENTION. IN THIS ARTICLE, WE FOCUS ON THE RECENT RESEARCH INVESTIGATING NEURO-IMMUNE COMMUNICATION AND EPIGENETIC PROCESSES, WHICH GAIN PARTICULAR ATTENTION IN THE CONTEXT OF NEUROPATHIC PAIN. SPECIFICALLY, WE ANALYZE THE ROLE OF GLIAL CELLS, INCLUDING MICROGLIA, ASTROCYTES, AND OLIGODENDROCYTES, IN THE MODULATION OF THE CENTRAL NERVOUS SYSTEM INFLAMMATION TRIGGERED BY NEUROPATHY. CONSIDERING EPIGENETICS, WE ADDRESS DNA METHYLATION, HISTONE MODIFICATIONS, AND THE NON-CODING RNAS IN THE REGULATION OF ION CHANNELS, G-PROTEIN-COUPLED RECEPTORS, AND TRANSMITTERS FOLLOWING NEURONAL DAMAGE. THE GOAL WAS NOT ONLY TO HIGHLIGHT THE EMERGING CONCEPTS BUT ALSO TO DISCUSS CONTROVERSIES, METHODOLOGICAL COMPLICATIONS, AND INTRIGUING OPINIONS. 2016 12 4619 28 NERVE TRAUMA-CAUSED DOWNREGULATION OF OPIOID RECEPTORS IN PRIMARY AFFERENT NEURONS: MOLECULAR MECHANISMS AND POTENTIAL MANAGEMENTS. NEUROPATHIC PAIN IS THE MOST COMMON CLINICAL DISORDER DESTROYING THE QUALITY OF PATIENT LIFE AND LEADING TO A MARKED ECONOMIC AND SOCIAL BURDEN. OPIOIDS ARE STILL LAST OPTION FOR PHARMACOLOGICAL TREATMENT OF THIS DISORDER, BUT THEIR ANTINOCICEPTIVE EFFECTS ARE LIMITED IN PART DUE TO THE DOWNREGULATION OF OPIOID RECEPTORS IN THE PRIMARY AFFERENT NEURONS AFTER PERIPHERAL NERVE TRAUMA. HOW THIS DOWNREGULATION OCCURS IS NOT COMPLETELY UNDERSTOOD, BUT RECENT STUDIES HAVE DEMONSTRATED THAT PERIPHERAL NERVE TRAUMA DRIVES THE ALTERATIONS IN EPIGENETIC MODIFICATIONS (INCLUDING DNA METHYLATION, HISTONE METHYLATION AND MCIRORNAS), EXPRESSION OF TRANSCRIPTION FACTORS, POST-TRANSCRIPTIONAL MODIFICATIONS (E.G., RNA METHYLATION) AND PROTEIN TRANSLATION INITIATION IN THE NEURONS OF NERVE TRAUMA-RELATED DORSAL ROOT GANGLION (DRG) AND THAT THESE ALTERNATIONS MAY BE ASSOCIATED WITH NERVE TRAUMA-CAUSED DOWNREGULATION OF DRG OPIOID RECEPTORS. THIS REVIEW PRESENTS HOW OPIOID RECEPTORS ARE DOWNREGULATED IN THE DRG AFTER PERIPHERAL NERVE TRAUMA, SPECIFICALLY FOCUSING ON DISTINCT MOLECULAR MECHANISMS UNDERLYING TRANSCRIPTIONAL AND TRANSLATIONAL PROCESSES. THIS REVIEW ALSO DISCUSSES HOW THIS DOWNREGULATION CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. A DEEPER UNDERSTANDING OF THESE MOLECULAR MECHANISMS LIKELY PROVIDES A NOVEL AVENUE FOR PREVENTION AND/OR TREATMENT OF NEUROPATHIC PAIN. 2021 13 1166 33 CONTRIBUTION OF DNMT1 TO NEUROPATHIC PAIN GENESIS PARTIALLY THROUGH EPIGENETICALLY REPRESSING KCNA2 IN PRIMARY AFFERENT NEURONS. EXPRESSIONAL CHANGES OF PAIN-ASSOCIATED GENES IN PRIMARY SENSORY NEURONS OF DRG ARE CRITICAL FOR NEUROPATHIC PAIN GENESIS. DNA METHYLTRANSFERASE (DNMT)-TRIGGERED DNA METHYLATION SILENCES GENE EXPRESSION. WE SHOW HERE THAT DNMT1, A CANONICAL MAINTENANCE METHYLTRANSFERASE, ACTS AS THE DE NOVO DNMT AND IS REQUIRED FOR NEUROPATHIC PAIN GENESIS LIKELY THROUGH REPRESSING AT LEAST DRG KCNA2 GENE EXPRESSION IN MALE MICE. PERIPHERAL NERVE INJURY UPREGULATED DNMT1 EXPRESSION IN THE INJURED DRG THROUGH THE TRANSCRIPTION FACTOR CAMP RESPONSE ELEMENT BINDING PROTEIN-TRIGGERED TRANSCRIPTIONAL ACTIVATION OF DNMT1 GENE. BLOCKING THIS UPREGULATION PREVENTED NERVE INJURY-INDUCED DNA METHYLATION WITHIN THE PROMOTER AND 5'-UNTRANSLATED REGION OF KCNA2 GENE, RESCUED KCNA2 EXPRESSION AND TOTAL KV CURRENT, ATTENUATED HYPEREXCITABILITY IN THE INJURED DRG NEURONS, AND ALLEVIATED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. GIVEN THAT KCNA2 IS A KEY PLAYER IN NEUROPATHIC PAIN, OUR FINDINGS SUGGEST THAT DRG DNMT1 MAY BE A POTENTIAL TARGET FOR NEUROPATHIC PAIN MANAGEMENT.SIGNIFICANCE STATEMENT IN THE PRESENT STUDY, WE REPORTED THAT DNMT1, A CANONICAL DNA MAINTENANCE METHYLTRANSFERASE, IS UPREGULATED VIA THE ACTIVATION OF THE TRANSCRIPTION FACTOR CREB IN THE INJURED DRG AFTER PERIPHERAL NERVE INJURY. THIS UPREGULATION WAS RESPONSIBLE FOR NERVE INJURY-INDUCED DE NOVO DNA METHYLATION WITHIN THE PROMOTER AND 5'-UNTRANSLATED REGION OF THE KCNA2 GENE, REDUCTIONS IN KCNA2 EXPRESSION AND KV CURRENT AND INCREASES IN NEURONAL EXCITABILITY IN THE INJURED DRG. SINCE PHARMACOLOGICAL INHIBITION OR GENETIC KNOCKDOWN OF DRG DNMT1 ALLEVIATED NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES, DRG DNMT1 CONTRIBUTES TO NEUROPATHIC PAIN GENESIS PARTIALLY THROUGH REPRESSION OF DRG KCNA2 GENE EXPRESSION. 2019 14 2214 32 EPIGENETIC MODIFICATIONS ASSOCIATED TO NEUROINFLAMMATION AND NEUROPATHIC PAIN AFTER NEURAL TRAUMA. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS LIE BEHIND THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. NEUROPATHIC PAIN IS USUALLY A CHRONIC CONDITION CAUSED BY A LESION, OR PATHOLOGICAL CHANGE, WITHIN THE NERVOUS SYSTEM. NEUROPATHIC PAIN APPEARS FREQUENTLY AFTER NERVE AND SPINAL CORD INJURIES OR DISEASES, PRODUCING A DEBILITATION OF THE PATIENT AND A DECREASE OF THE QUALITY OF LIFE. AT THE CELLULAR LEVEL, NEUROPATHIC PAIN IS THE RESULT OF NEURONAL PLASTICITY SHAPED BY AN INCREASE IN THE SENSITIVITY AND EXCITABILITY OF SENSORY NEURONS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. ONE OF THE MECHANISMS THOUGHT TO CONTRIBUTE TO HYPEREXCITABILITY AND THEREFORE TO THE ONTOGENY OF NEUROPATHIC PAIN IS THE ALTERED EXPRESSION, TRAFFICKING, AND FUNCTIONING OF RECEPTORS AND ION CHANNELS EXPRESSED BY PRIMARY SENSORY NEURONS. BESIDES, NEURONAL AND GLIAL CELLS, SUCH AS MICROGLIA AND ASTROCYTES, TOGETHER WITH BLOOD BORNE MACROPHAGES, PLAY A CRITICAL ROLE IN THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN BY RELEASING POWERFUL NEUROMODULATORS SUCH AS PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, WHICH ENHANCE NEURONAL EXCITABILITY. ALTERED GENE EXPRESSION OF NEURONAL RECEPTORS, ION CHANNELS, AND PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, HAVE BEEN ASSOCIATED TO EPIGENETIC ADAPTATIONS OF THE INJURED TISSUE. WITHIN THIS REVIEW, WE DISCUSS THE INVOLVEMENT OF THESE EPIGENETIC CHANGES, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNAS, AND ALTERATION OF CHROMATIN MODIFIERS, THAT HAVE BEEN SHOWN TO TRIGGER MODIFICATION OF NOCICEPTION AFTER NEURAL LESIONS. IN PARTICULAR, THE FUNCTION ON THESE PROCESSES OF EZH2, JMJD3, MECP2, SEVERAL HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYL TRANSFERASES (HATS), G9A, DNMT, REST AND DIVERSE NON-CODING RNAS, ARE DESCRIBED. DESPITE THE EFFORT ON DEVELOPING NEW THERAPIES, CURRENT TREATMENTS HAVE ONLY PRODUCED LIMITED RELIEF OF THIS PAIN IN A PORTION OF PATIENTS. THUS, THE PRESENT REVIEW AIMS TO CONTRIBUTE TO FIND NOVEL TARGETS FOR CHRONIC NEUROPATHIC PAIN TREATMENT. 2018 15 2885 29 G9A PARTICIPATES IN NERVE INJURY-INDUCED KCNA2 DOWNREGULATION IN PRIMARY SENSORY NEURONS. NERVE INJURY-INDUCED DOWNREGULATION OF VOLTAGE-GATED POTASSIUM CHANNEL SUBUNIT KCNA2 IN THE DORSAL ROOT GANGLION (DRG) IS CRITICAL FOR DRG NEURONAL EXCITABILITY AND NEUROPATHIC PAIN GENESIS. HOWEVER, HOW NERVE INJURY CAUSES THIS DOWNREGULATION IS STILL ELUSIVE. EUCHROMATIC HISTONE-LYSINE N-METHYLTRANSFERASE 2, ALSO KNOWN AS G9A, METHYLATES HISTONE H3 ON LYSINE RESIDUE 9 TO PREDOMINANTLY PRODUCE A DYNAMIC HISTONE DIMETHYLATION, RESULTING IN CONDENSED CHROMATIN AND GENE TRANSCRIPTIONAL REPRESSION. WE SHOWED HERE THAT BLOCKING NERVE INJURY-INDUCED INCREASE IN G9A RESCUED KCNA2 MRNA AND PROTEIN EXPRESSION IN THE AXOTOMIZED DRG AND ATTENUATED THE DEVELOPMENT OF NERVE INJURY-INDUCED PAIN HYPERSENSITIVITY. MIMICKING THIS INCREASE DECREASED KCNA2 MRNA AND PROTEIN EXPRESSION, REDUCED KV CURRENT, AND INCREASED EXCITABILITY IN THE DRG NEURONS AND LED TO SPINAL CORD CENTRAL SENSITIZATION AND NEUROPATHIC PAIN-LIKE SYMPTOMS. G9A MRNA IS CO-LOCALIZED WITH KCNA2 MRNA IN THE DRG NEURONS. THESE FINDINGS INDICATE THAT G9A CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT THROUGH EPIGENETIC SILENCING OF KCNA2 IN THE AXOTOMIZED DRG. 2016 16 2053 30 EPIGENETIC CONNECTIONS OF THE TRPA1 ION CHANNEL IN PAIN TRANSMISSION AND NEUROGENIC INFLAMMATION - A THERAPEUTIC PERSPECTIVE IN MIGRAINE? PERSISTENT REPROGRAMMING OF EPIGENETIC PATTERN LEADS TO CHANGES IN GENE EXPRESSION OBSERVED IN MANY NEUROLOGICAL DISORDERS. TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL SUBFAMILY A MEMBER 1 (TRPA1), A MEMBER OF THE TRP CHANNELS SUPERFAMILY, IS ACTIVATED BY MANY MIGRAINE TRIGGERS AND EXPRESSED IN TRIGEMINAL NEURONS AND BRAIN REGIONS THAT ARE IMPORTANT IN MIGRAINE PATHOGENESIS. TRP CHANNELS CHANGE NOXIOUS STIMULI INTO PAIN SIGNALS WITH THE INVOLVEMENT OF EPIGENETIC REGULATION. THE EXPRESSION OF THE TRPA1 ENCODING GENE, TRPA1, IS MODULATED IN PAIN-RELATED SYNDROMES BY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND EFFECTS OF NON-CODING RNAS: MICRO RNAS (MIRNAS), LONG NON-CODING RNAS, AND CIRCULAR RNAS. TRPA1 MAY CHANGE EPIGENETIC PROFILE OF MANY PAIN-RELATED GENES AS IT MAY MODIFY ENZYMES RESPONSIBLE FOR EPIGENETIC MODIFICATIONS AND EXPRESSION OF NON-CODING RNAS. TRPA1 MAY INDUCE THE RELEASE OF CALCITONIN GENE RELATED PEPTIDE (CGRP), FROM TRIGEMINAL NEURONS AND DURAL TISSUE. THEREFORE, EPIGENETIC REGULATION OF TRPA1 MAY PLAY A ROLE IN EFFICACY AND SAFETY OF ANTI-MIGRAINE THERAPIES TARGETING TRP CHANNELS AND CGRP. TRPA1 IS ALSO INVOLVED IN NEUROGENIC INFLAMMATION, IMPORTANT IN MIGRAINE PATHOGENESIS. THE FUNDAMENTAL ROLE OF TRPA1 IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF TRPA1 MAY PLAY A ROLE IN EFFICACY AND SAFETY OF ANTI-MIGRAINE THERAPY TARGETING TRP CHANNELS OR CGRP AND THEY SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE TREATMENT. THIS NARRATIVE/PERSPECTIVE REVIEW PRESENTS INFORMATION ON THE STRUCTURE AND FUNCTIONS OF TRPA1 AS WELL AS ROLE OF ITS EPIGENETIC CONNECTIONS IN PAIN TRANSMISSION AND POTENTIAL IN MIGRAINE THERAPY. 2023 17 2310 24 EPIGENETIC REGULATION OF CHRONIC PAIN. CHRONIC PAIN ARISING FROM PERIPHERAL INFLAMMATION AND TISSUE OR NERVE INJURY IS A COMMON CLINICAL SYMPTOM. ALTHOUGH INTENSIVE RESEARCH ON THE NEUROBIOLOGICAL MECHANISMS OF CHRONIC PAIN HAS BEEN CARRIED OUT DURING PREVIOUS DECADES, THIS DISORDER IS STILL POORLY MANAGED BY CURRENT DRUGS SUCH AS OPIOIDS AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. INFLAMMATION, TISSUE INJURY AND/OR NERVE INJURY-INDUCED CHANGES IN GENE EXPRESSION IN SENSORY NEURONS OF THE DORSAL ROOT GANGLION, SPINAL CORD DORSAL HORN AND PAIN-ASSOCIATED BRAIN REGIONS ARE THOUGHT TO PARTICIPATE IN CHRONIC PAIN GENESIS; HOWEVER, HOW THESE CHANGES OCCUR IS STILL ELUSIVE. EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION AND COVALENT HISTONE MODIFICATIONS CONTROL GENE EXPRESSION. RECENT STUDIES HAVE SHOWN THAT PERIPHERAL NOXIOUS STIMULATION CHANGES DNA METHYLATION AND HISTONE MODIFICATIONS AND THAT THESE CHANGES MAY BE RELATED TO THE INDUCTION OF PAIN HYPERSENSITIVITY UNDER CHRONIC PAIN CONDITIONS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE AND PROGRESS IN EPIGENETIC RESEARCH IN CHRONIC PAIN AND DISCUSSES THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS AS THERAPEUTIC ANTINOCICEPTIVE TARGETS IN THIS DISORDER. 2015 18 189 29 ACETYL-L-CARNITINE IN CHRONIC PAIN: A NARRATIVE REVIEW. ACETYL-L-CARNITINE (ALC) IS AN ENDOGENOUS MOLECULE THAT NOT ONLY PLAYS A ROLE IN ENERGY METABOLISM, BUT ALSO HAS ANTIOXIDANT PROPERTIES, PROTECTS FROM OXIDATIVE STRESS, MODULATES BRAIN NEUROTRANSMITTERS SUCH AS ACETYLCHOLINE, SEROTONIN AND DOPAMINE, AND ACTS ON NEUROTROPHIC FACTORS SUCH AS NERVE GROWTH FACTOR (NGF) AND METABOTROPIC GLUTAMATE (MGLU) RECEPTORS BY MEANS OF EPIGENETIC MECHANISMS. IMPORTANTLY, IT INDUCES MGLU2 EXPRESSION AT NERVE TERMINALS, THUS GIVING RISE TO ANALGESIA AND PREVENTING SPINAL SENSITISATION. IT HAS ALSO BEEN FOUND TO HAVE EVEN LONG-TERM NEUROTROPHIC AND ANALGESIC ACTIVITY IN EXPERIMENTAL MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN. THE AIM OF THIS NARRATIVE REVIEW IS TO SUMMARISE THE CURRENT EVIDENCE REGARDING THE USE OF ALC IN PATIENTS WITH CHRONIC PAIN, AND COGNITIVE AND MOOD DISORDERS, AND INVESTIGATE THE RATIONALE UNDERLYING ITS USE IN PATIENTS WITH FIBROMYALGIA SYNDROME, WHICH IS CHARACTERISED BY NOCIPLASTIC CHANGES THAT INCREASE THE SENSITIVITY OF THE NERVOUS SYSTEM TO PAIN. 2021 19 5600 23 ROLES OF VOLTAGE-DEPENDENT SODIUM CHANNELS IN NEURONAL DEVELOPMENT, PAIN, AND NEURODEGENERATION. BESIDES INITIATING AND PROPAGATING ACTION POTENTIALS IN ESTABLISHED NEURONAL CIRCUITS, VOLTAGE-DEPENDENT SODIUM CHANNELS SCULPT AND BOLSTER THE FUNCTIONAL NEURONAL NETWORK FROM EARLY IN EMBRYONIC DEVELOPMENT THROUGH ADULTHOOD (E.G., DIFFERENTIATION OF OLIGODENDROCYTE PRECURSOR CELLS INTO OLIGODENDROCYTES, MYELINATING AXON; COMPETITION BETWEEN NEIGHBORING EQUIPOTENTIAL NEURITES FOR DEVELOPMENT INTO A SINGLE AXON; ENHANCING AND OPPOSING FUNCTIONAL INTERACTIONS WITH ATTRACTIVE AND REPULSIVE MOLECULES FOR AXON PATHFINDING; EXTENDING AND RETRACTING TERMINAL ARBORIZATION OF AXON FOR CORRECT SYNAPSE FORMATION; EXPERIENCE-DRIVEN COGNITION; NEURONAL SURVIVAL; AND REMYELINATION OF DEMYELINATED AXONS). SURPRISINGLY, DIFFERENT PATTERNS OF ACTION POTENTIALS DIRECT HOMEOSTASIS-BASED EPIGENETIC SELECTION FOR NEUROTRANSMITTER PHENOTYPE, THUS EXCITABILITY BY SODIUM CHANNELS SPECIFYING EXPRESSION OF INHIBITORY NEUROTRANSMITTERS. MECHANISMS FOR THESE PLEIOTROPIC EFFECTS OF SODIUM CHANNELS INCLUDE RECIPROCAL INTERACTIONS BETWEEN NEURONS AND GLIA VIA NEUROTRANSMITTERS, GROWTH FACTORS, AND CYTOKINES AT SYNAPSES AND AXONS. SODIUM CHANNELOPATHIES CAUSING PAIN (E.G., ALLODYNIA) AND NEURODEGENERATION (E.G., MULTIPLE SCLEROSIS) DERIVE FROM 1) ELECTROPHYSIOLOGICAL DISTURBANCES BY INSULTS (E.G., ISCHEMIA/HYPOXIA, TOXINS, AND ANTIBODIES); 2) LOSS-OF-PHYSIOLOGICAL FUNCTION OR GAIN-OF-PATHOLOGICAL FUNCTION OF MUTANT SODIUM CHANNEL PROTEINS; 3) SPATIOTEMPORAL INAPPROPRIATE EXPRESSION OF NORMAL SODIUM CHANNEL PROTEINS; OR 4) DE-REPRESSED EXPRESSION OF OTHERWISE SILENT SODIUM CHANNEL GENES. NA(V)1.7 PROVED TO ACCOUNT FOR PAIN IN HUMAN ERYTHERMALGIA AND INFLAMMATION, BEING THE CONVINCING MOLECULAR TARGET OF PAIN TREATMENT. 2006 20 2646 21 EPIGENOMIC LINKS BETWEEN SOCIAL DETERMINANTS OF HEALTH AND SYMPTOMS: A SCOPING REVIEW. SOCIAL DETERMINANTS OF HEALTH (SDOH) IMPACT HEALTH AND WELLNESS. THE LINK BETWEEN SDOH AND ADVERSE HEALTH OUTCOMES, INCLUDING SYMPTOM OCCURRENCE AND SEVERITY, MAY BE EXPLAINED BY AN INDIVIDUAL'S PHYSIOLOGIC RESPONSE TO ONE OR MORE SDOH. ONE POTENTIAL MECHANISM UNDERLYING THIS PHYSIOLOGIC RESPONSE LINKING SDOH AND SYMPTOMS IS THE DYNAMIC EPIGENOME. THE PURPOSE OF THIS SCOPING REVIEW OF THE LITERATURE WAS TO EXAMINE DIFFERENTIAL SUSCEPTIBILITY FOR SYMPTOMS BY IDENTIFYING AND SUMMARIZING RESEARCH LINKING SDOH AND SYMPTOMS THROUGH EPIGENOMIC MECHANISMS. PUBMED WAS SEARCHED TO IDENTIFY EMPIRICAL RESEARCH WHERE AT LEAST ONE SDOH WAS AN INDEPENDENT OR DEPENDENT VARIABLE, AT LEAST ONE SYMPTOM WAS INVESTIGATED, AND THE INVESTIGATION INCLUDED AN EPIGENOMIC MEASURE. OF THE 484 ARTICLES INITIALLY RETRIEVED, AFTER THOROUGH VETTING, 41 ARTICLES MET ELIGIBILITY. THE MOST STUDIED SYMPTOM WAS DEPRESSIVE SYMPTOMS FOLLOWED BY ANXIETY, COGNITIVE FUNCTION, SLEEP DYSFUNCTION, AND PAIN. THE MOST FREQUENTLY STUDIED SDOH WERE: 1) STRESS, PARTICULARLY EARLY LIFE STRESS AND ACCULTURATIVE STRESS; AND 2) TRAUMA, PREDOMINANTLY CHILDHOOD TRAUMA. DNA METHYLATION AND TELOMERE LENGTH WERE THE MOST STUDIED EPIGENOMIC MEASURES. FOUR GENES (SLC6A4, BDNF, NR3C1, OXTR) HAD EVIDENCE FROM MULTIPLE STUDIES AND ACROSS METHODOLOGICAL APPROACHES LINKING SDOH TO SYMPTOMS. THIS REVIEW SUPPORTS THE INCLUSION OF EPIGENOMIC APPROACHES TO BETTER UNDERSTAND THE LINK BETWEEN SDOH AND SYMPTOMS AND PROVIDES EVIDENCE THAT SDOH IMPACT TELOMERE LENGTH AND THE METHYLATION OF GENES INVOLVED IN NEUROTRANSMITTER SIGNALING, NEURONAL SURVIVAL, BEHAVIOR, INFLAMMATION AND STRESS RESPONSE. 2023