1 4614 138 NERVE EXCITABILITY AND NEUROPATHIC PAIN IS REDUCED BY BET PROTEIN INHIBITION AFTER SPARED NERVE INJURY. NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE PATHOPHYSIOLOGICAL CHANGES THAT UNDERLIE THE GENERATION AND MAINTENANCE OF NEUROPATHIC PAIN REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. IN PARTICULAR, THERE IS AN INDUCTION OF PRO-INFLAMMATORY NEUROMODULATORS LEVELS, AND CHANGES IN THE EXPRESSION OF ION CHANNELS AND OTHER FACTORS INTERVENING IN THE DETERMINATION OF THE MEMBRANE POTENTIAL IN NEURONAL CELLS. WE HAVE PREVIOUSLY FOUND THAT INHIBITION OF THE BET PROTEINS EPIGENETIC READERS REDUCED NEUROINFLAMMATION AFTER SPINAL CORD INJURY. WITHIN THE PRESENT STUDY WE AIMED TO DETERMINE IF BET PROTEIN INHIBITION MAY ALSO AFFECT NEUROINFLAMMATION AFTER A PERIPHERAL NERVE INJURY, AND IF THIS WOULD BENEFICIALLY ALTER NEURONAL EXCITABILITY AND NEUROPATHIC PAIN. FOR THIS PURPOSE, C57BL/6 FEMALE MICE UNDERWENT SPARED NERVE INJURY (SNI), AND WERE TREATED WITH THE BET INHIBITOR JQ1, OR VEHICLE. ELECTROPHYSIOLOGICAL AND ALGESIMETRY TESTS WERE PERFORMED ON THESE MICE. WE ALSO DETERMINED THE EFFECTS OF JQ1 TREATMENT AFTER INJURY ON NEUROINFLAMMATION, AND THE EXPRESSION OF NEURONAL COMPONENTS IMPORTANT FOR THE MAINTENANCE OF AXON MEMBRANE POTENTIAL. WE FOUND THAT TREATMENT WITH JQ1 AFFECTED NEURONAL EXCITABILITY AND MECHANICAL HYPERALGESIA AFTER SNI IN MICE. BET PROTEIN INHIBITION REGULATED CYTOKINE EXPRESSION AND REDUCED MICROGLIAL REACTIVITY AFTER INJURY. IN ADDITION, JQ1 TREATMENT ALTERED THE EXPRESSION OF SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 AND HCN2 ION CHANNELS, AS WELL AS THE EXPRESSION OF THE NA(+)/K(+) ATPASE PUMP SUBUNITS. IN CONCLUSION, BOTH, ALTERATION OF INFLAMMATION, AND NEURONAL TRANSCRIPTION, COULD BE THE RESPONSIBLE EPIGENETIC MECHANISMS FOR THE REDUCTION OF EXCITABILITY AND HYPERALGESIA OBSERVED AFTER BET INHIBITION. INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. PERSPECTIVE: NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE UNDERLYING PATHOPHYSIOLOGICAL CHANGES REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. THIS STUDY NOTES THAT INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. 2021 2 3194 38 HDAC INHIBITORS ATTENUATE THE DEVELOPMENT OF HYPERSENSITIVITY IN MODELS OF NEUROPATHIC PAIN. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER THESE COMPOUNDS COULD ALSO AFFECT NEUROPATHIC PAIN. DIFFERENT CLASS I HDACIS WERE DELIVERED INTRATHECALLY INTO RAT SPINAL CORD IN MODELS OF TRAUMATIC NERVE INJURY AND ANTIRETROVIRAL DRUG-INDUCED PERIPHERAL NEUROPATHY (STAVUDINE, D4T). MECHANICAL AND THERMAL HYPERSENSITIVITY WAS ATTENUATED BY 40% TO 50% AS A RESULT OF HDACI TREATMENT, BUT ONLY IF STARTED BEFORE ANY INSULT. THE DRUGS GLOBALLY INCREASED HISTONE ACETYLATION IN THE SPINAL CORD, BUT APPEARED TO HAVE NO MEASURABLE EFFECTS IN RELEVANT DORSAL ROOT GANGLIA IN THIS TREATMENT PARADIGM, SUGGESTING THAT ANY POTENTIAL MECHANISM SHOULD BE SOUGHT IN THE CENTRAL NERVOUS SYSTEM. MICROARRAY ANALYSIS OF DORSAL CORD RNA REVEALED THE SIGNATURE OF THE SPECIFIC COMPOUND USED (MS-275) AND SUGGESTED THAT ITS MAIN EFFECT WAS MEDIATED THROUGH HDAC1. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE ACETYLATION IN THE EMERGENCE OF NEUROPATHIC PAIN. 2013 3 710 37 C-TERMINAL DOMAIN SMALL PHOSPHATASE 1 (CTDSP1) REGULATES GROWTH FACTOR EXPRESSION AND AXONAL REGENERATION IN PERIPHERAL NERVE TISSUE. PERIPHERAL NERVE INJURY (PNI) REPRESENTS A MAJOR CLINICAL AND ECONOMIC BURDEN. DESPITE THE ABILITY OF PERIPHERAL NEURONS TO REGENERATE THEIR AXONS AFTER AN INJURY, PATIENTS ARE OFTEN LEFT WITH MOTOR AND/OR SENSORY DISABILITY AND MAY DEVELOP CHRONIC PAIN. SUCCESSFUL REGENERATION AND TARGET ORGAN REINNERVATION REQUIRE COMPREHENSIVE TRANSCRIPTIONAL CHANGES IN BOTH INJURED NEURONS AND SUPPORT CELLS LOCATED AT THE SITE OF INJURY. THE EXPRESSION OF MOST OF THE GENES REQUIRED FOR AXON GROWTH AND GUIDANCE AND FOR SYNAPSIS FORMATION IS REPRESSED BY A SINGLE MASTER TRANSCRIPTIONAL REGULATOR, THE REPRESSOR ELEMENT 1 SILENCING TRANSCRIPTION FACTOR (REST). SUSTAINED INCREASE OF REST LEVELS AFTER INJURY INHIBITS AXON REGENERATION AND LEADS TO CHRONIC PAIN. AS TARGETING OF TRANSCRIPTION FACTORS IS CHALLENGING, WE TESTED WHETHER MODULATION OF REST ACTIVITY COULD BE ACHIEVED THROUGH KNOCKDOWN OF CARBOXY-TERMINAL DOMAIN SMALL PHOSPHATASE 1 (CTDSP1), THE ENZYME THAT STABILIZES REST BY PREVENTING ITS TARGETING TO THE PROTEASOME. TO TEST WHETHER KNOCKDOWN OF CTDSP1 PROMOTES NEUROTROPHIC FACTOR EXPRESSION IN BOTH SUPPORT CELLS LOCATED AT THE SITE OF INJURY AND IN PERIPHERAL NEURONS, WE TRANSFECTED MESENCHYMAL PROGENITOR CELLS (MPCS), A TYPE OF SUPPORT CELLS THAT ARE PRESENT AT HIGH CONCENTRATIONS AT THE SITE OF INJURY, AND DORSAL ROOT GANGLION (DRG) NEURONS WITH REST OR CTDSP1 SPECIFIC SIRNA. WE QUANTIFIED NEUROTROPHIC FACTOR EXPRESSION BY RT-QPCR AND WESTERN BLOT, AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) RELEASE IN THE CELL CULTURE MEDIUM BY ELISA, AND WE MEASURED NEURITE OUTGROWTH OF DRG NEURONS IN CULTURE. OUR RESULTS SHOW THAT CTDSP1 KNOCKDOWN PROMOTES NEUROTROPHIC FACTOR EXPRESSION IN BOTH DRG NEURONS AND THE SUPPORT CELLS MPCS, AND PROMOTES DRG NEURON REGENERATION. THERAPEUTICS TARGETING CTDSP1 ACTIVITY MAY, THEREFORE, REPRESENT A NOVEL EPIGENETIC STRATEGY TO PROMOTE PERIPHERAL NERVE REGENERATION AFTER PNI BY PROMOTING THE REGENERATIVE PROGRAM REPRESSED BY INJURY-INDUCED INCREASED LEVELS OF REST IN BOTH NEURONS AND SUPPORT CELLS. 2021 4 1105 49 COMBINED INHIBITION OF HISTONE DEACETYLASES AND BET FAMILY PROTEINS AS EPIGENETIC THERAPY FOR NERVE INJURY-INDUCED NEUROPATHIC PAIN. CURRENT TREATMENTS FOR NEUROPATHIC PAIN HAVE OFTEN MODERATE EFFICACY AND PRESENT UNWANTED EFFECTS SHOWING THE NEED TO DEVELOP EFFECTIVE THERAPIES. ACCUMULATING EVIDENCE SUGGESTS THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN CHRONIC PAIN AND THE ANALGESIC ACTIVITY OF HISTONE DEACETYLASES (HDACS) INHIBITORS IS DOCUMENTED. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT INTERACT WITH ACETYLATED LYSINE RESIDUES ON HISTONES, BUT LITTLE IS KNOWN ABOUT THEIR IMPLICATION IN NEUROPATHIC PAIN. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE EFFECT OF THE COMBINATION OF HDAC AND BET INHIBITORS IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE. INTRANASAL ADMINISTRATION OF I-BET762 (BET INHIBITOR) OR SAHA (HDAC INHIBITOR) ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY AND THIS ANTIALLODYNIC ACTIVITY WAS IMPROVED BY CO-ADMINISTRATION OF BOTH DRUGS. SPINAL CORD SECTIONS OF SNI MICE SHOWED AN INCREASED EXPRESSION OF HDAC1 AND BRD4 PROTEINS AND COMBINATION PRODUCED A STRONGER REDUCTION COMPARED TO EACH EPIGENETIC AGENT ALONE. SAHA AND I-BET762, ADMINISTERED ALONE OR IN COMBINATION, COUNTERACTED THE SNI-INDUCED MICROGLIA ACTIVATION BY INHIBITING THE EXPRESSION OF IBA1, CD11B, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS), THE ACTIVATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1) WITH COMPARABLE EFFICACY. CONVERSELY, THE EPIGENETIC INHIBITORS SHOWED A MODEST EFFECT ON SPINAL PROINFLAMMATORY CYTOKINES CONTENT THAT WAS SIGNIFICANTLY POTENTIATED BY THEIR COMBINATION. PRESENT RESULTS INDICATE A KEY ROLE OF ACETYLATED HISTONES AND THEIR RECRUITMENT BY BET PROTEINS ON MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION. TARGETING NEUROPATHIC PAIN WITH THE COMBINATION OF HDAC AND BET INHIBITORS MAY REPRESENT A PROMISING NEW THERAPEUTIC OPTION. 2021 5 3319 34 HISTONE ACETYLATION AND HISTONE DEACETYLATION IN NEUROPATHIC PAIN: AN UNRESOLVED PUZZLE? CHRONIC PAIN IS BROADLY CLASSIFIED INTO SOMATIC, VISCERAL OR NEUROPATHIC PAIN DEPENDING UPON THE LOCATION AND EXTENT OF PAIN PERCEPTION. EVIDENCES FROM DIFFERENT ANIMAL STUDIES SUGGEST THAT INFLAMMATORY OR NEUROPATHIC PAIN IS ASSOCIATED WITH ALTERED ACETYLATION AND DEACETYLATION OF HISTONE PROTEINS, WHICH RESULT IN ABNORMAL TRANSCRIPTION OF NOCICEPTIVE PROCESSING GENES. THERE HAVE BEEN A NUMBER OF STUDIES INDICATING THAT NERVE INJURY UP-REGULATES HISTONE DEACETYLASE ENZYMES, WHICH LEADS TO INCREASED HISTONE DEACETYLATION AND INDUCE CHRONIC PAIN. TREATMENT WITH HISTONE DEACETYLASE INHIBITORS RELIEVES PAIN BY NORMALIZING NERVE INJURY-INDUCED DOWN REGULATION OF METABOTROPIC GLUTAMATE RECEPTORS, GLUTAMATE TRANSPORTERS, GLUTAMIC ACID DECARBOXYLASE 65, NEURON RESTRICTIVE SILENCER FACTOR AND SERUM AND GLUCOCORTICOID INDUCIBLE KINASE 1. ON THE OTHER HAND, A FEW STUDIES REFER TO INCREASED EXPRESSION OF HISTONE ACETYLASE ENZYMES IN RESPONSE TO NERVE INJURY THAT PROMOTES HISTONE ACETYLATION LEADING TO PAIN INDUCTION. TREATMENT WITH HISTONE ACETYL TRANSFERASE INHIBITORS HAVE BEEN REPORTED TO RELIEVE CHRONIC PAIN BY BLOCKING THE UP-REGULATION OF CHEMOKINES AND CYCLOOXYGENASE-2, THE CRITICAL FACTORS ASSOCIATED WITH HISTONE ACETYLATION-INDUCED PAIN. THE PRESENT REVIEW DESCRIBES THE DUAL ROLE OF HISTONE ACETYLATION/DEACETYLATION IN DEVELOPMENT OR ATTENUATION OF NEUROPATHIC PAIN ALONG WITH THE UNDERLYING MECHANISMS. 2017 6 2179 38 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 7 4619 38 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 8 3141 36 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 9 2214 53 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 10 764 31 CBP/P300 ACTIVATION PROMOTES AXON GROWTH, SPROUTING, AND SYNAPTIC PLASTICITY IN CHRONIC EXPERIMENTAL SPINAL CORD INJURY WITH SEVERE DISABILITY. THE INTERRUPTION OF SPINAL CIRCUITRY FOLLOWING SPINAL CORD INJURY (SCI) DISRUPTS NEURAL ACTIVITY AND IS FOLLOWED BY A FAILURE TO MOUNT AN EFFECTIVE REGENERATIVE RESPONSE RESULTING IN PERMANENT NEUROLOGICAL DISABILITY. FUNCTIONAL RECOVERY REQUIRES THE ENHANCEMENT OF AXONAL AND SYNAPTIC PLASTICITY OF SPARED AS WELL AS INJURED FIBRES, WHICH NEED TO SPROUT AND/OR REGENERATE TO FORM NEW CONNECTIONS. HERE, WE HAVE INVESTIGATED WHETHER THE EPIGENETIC STIMULATION OF THE REGENERATIVE GENE EXPRESSION PROGRAM CAN OVERCOME THE CURRENT INABILITY TO PROMOTE NEUROLOGICAL RECOVERY IN CHRONIC SCI WITH SEVERE DISABILITY. WE DELIVERED THE CBP/P300 ACTIVATOR CSP-TTK21 OR VEHICLE CSP WEEKLY BETWEEN WEEK 12 AND 22 FOLLOWING A TRANSECTION MODEL OF SCI IN MICE HOUSED IN AN ENRICHED ENVIRONMENT. DATA ANALYSIS SHOWED THAT CSP-TTK21 ENHANCED CLASSICAL REGENERATIVE SIGNALLING IN DORSAL ROOT GANGLIA SENSORY BUT NOT CORTICAL MOTOR NEURONS, STIMULATED MOTOR AND SENSORY AXON GROWTH, SPROUTING, AND SYNAPTIC PLASTICITY, BUT FAILED TO PROMOTE NEUROLOGICAL SENSORIMOTOR RECOVERY. THIS WORK PROVIDES DIRECT EVIDENCE THAT CLINICALLY SUITABLE PHARMACOLOGICAL CBP/P300 ACTIVATION CAN PROMOTE THE EXPRESSION OF REGENERATION-ASSOCIATED GENES AND AXONAL GROWTH IN A CHRONIC SCI WITH SEVERE NEUROLOGICAL DISABILITY. 2022 11 2783 37 EZH2 METHYLTRANSFERASE REGULATES NEUROINFLAMMATION AND NEUROPATHIC PAIN. RECENT STUDIES BY US AND OTHERS HAVE SHOWN THAT ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A HISTONE METHYLTRANSFERASE, IN GLIAL CELLS REGULATES THE GENESIS OF NEUROPATHIC PAIN BY MODULATING THE PRODUCTION OF PROINFLAMMATORY CYTOKINES AND CHEMOKINES. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THIS RESEARCH AREA. EZH2 IS A SUBUNIT OF POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH PRIMARILY SERVES AS A HISTONE METHYLTRANSFERASE TO CATALYZE METHYLATION OF HISTONE 3 ON LYSINE 27 (H3K27), ULTIMATELY RESULTING IN TRANSCRIPTIONAL REPRESSION. ANIMALS WITH NEUROPATHIC PAIN EXHIBIT INCREASED EZH2 ACTIVITY AND NEUROINFLAMMATION OF THE INJURED NERVE, SPINAL CORD, AND ANTERIOR CINGULATE CORTEX. INHIBITION OF EZH2 WITH DZNEP OR GSK-126 AMELIORATES NEUROINFLAMMATION AND NEUROPATHIC PAIN. EZH2 PROTEIN EXPRESSION INCREASES UPON ACTIVATION OF TOLL-LIKE RECEPTOR 4 AND CALCITONIN GENE-RELATED PEPTIDE RECEPTORS, DOWNREGULATION OF MIR-124-3P AND MIR-378 MICRORNAS, OR UPREGULATION OF LNCENC1 AND MALAT1 LONG NONCODING RNAS. GENES SUPPRESSED BY EZH2 INCLUDE SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3), NUCLEAR FACTOR (ERYTHROID-DERIVED 2)-LIKE-2 FACTOR (NRF2), MIR-29B-3P, MIR-146A-5P, AND BRAIN-SPECIFIC ANGIOGENESIS INHIBITOR 1 (BAI1). PRO-INFLAMMATORY MEDIATORS FACILITATE NEURONAL ACTIVATION ALONG PAIN-SIGNALING PATHWAYS BY SENSITIZING NOCICEPTORS IN THE PERIPHERY, AS WELL AS ENHANCING EXCITATORY SYNAPTIC ACTIVITIES AND SUPPRESSING INHIBITORY SYNAPTIC ACTIVITIES IN THE CNS. THESE STUDIES COLLECTIVELY REVEAL THAT EZH2 IS IMPLICATED IN SIGNALING PATHWAYS KNOWN TO BE KEY PLAYERS IN THE PROCESS OF NEUROINFLAMMATION AND GENESIS OF NEUROPATHIC PAIN. THEREFORE, TARGETING THE EZH2 SIGNALING PATHWAY MAY OPEN A NEW AVENUE TO MITIGATE NEUROINFLAMMATION AND NEUROPATHIC PAIN. 2023 12 2061 35 EPIGENETIC CONTROL OF HYPERSENSITIVITY IN CHRONIC INFLAMMATORY PAIN BY THE DE NOVO DNA METHYLTRANSFERASE DNMT3A2. CHRONIC PAIN IS A PATHOLOGICAL MANIFESTATION OF NEURONAL PLASTICITY SUPPORTED BY ALTERED GENE TRANSCRIPTION IN SPINAL CORD NEURONS THAT RESULTS IN LONG-LASTING HYPERSENSITIVITY. RECENTLY, THE CONCEPT THAT EPIGENETIC REGULATORS MIGHT BE IMPORTANT IN PATHOLOGICAL PAIN HAS EMERGED, BUT A CLEAR UNDERSTANDING OF THE MOLECULAR PLAYERS INVOLVED IN THE PROCESS IS STILL LACKING. IN THIS STUDY, WE LINKED DNMT3A2, A SYNAPTIC ACTIVITY-REGULATED DE NOVO DNA METHYLTRANSFERASE, TO CHRONIC INFLAMMATORY PAIN. WE OBSERVED THAT DNMT3A2 LEVELS ARE INCREASED IN THE SPINAL CORD OF ADULT MICE FOLLOWING PLANTAR INJECTION OF COMPLETE FREUND'S ADJUVANT, AN IN VIVO MODEL OF CHRONIC INFLAMMATORY PAIN. IN VIVO KNOCKDOWN OF DNMT3A2 EXPRESSION IN DORSAL HORN NEURONS BLUNTED THE INDUCTION OF GENES TRIGGERED BY COMPLETE FREUND'S ADJUVANT INJECTION. AMONG THE GENES WHOSE TRANSCRIPTION WAS FOUND TO BE INFLUENCED BY DNMT3A2 EXPRESSION IN THE SPINAL CORD IS PTGS2, ENCODING FOR COX-2, A PRIME MEDIATOR OF PAIN PROCESSING. LOWERING THE LEVELS OF DNMT3A2 PREVENTED THE ESTABLISHMENT OF LONG-LASTING INFLAMMATORY HYPERSENSITIVITY. THESE RESULTS IDENTIFY DNMT3A2 AS AN IMPORTANT EPIGENETIC REGULATOR NEEDED FOR THE ESTABLISHMENT OF CENTRAL SENSITIZATION. TARGETING EXPRESSION OR FUNCTION OF DNMT3A2 MAY BE SUITABLE FOR THE TREATMENT OF CHRONIC PAIN. 2019 13 345 44 ALTERED BRAIN EXPRESSION OF DNA METHYLATION AND HYDROXYMETHYLATION EPIGENETIC ENZYMES IN A RAT MODEL OF NEUROPATHIC PAIN. THE ROLE OF EPIGENETICS IN CHRONIC PAIN AT THE SUPRASPINAL LEVEL IS YET TO BE FULLY CHARACTERIZED. DNA HISTONE METHYLATION IS CRUCIALLY REGULATED BY DE NOVO METHYLTRANSFERASES (DNMT1-3) AND TEN-ELEVEN TRANSLOCATION DIOXYGENASES (TET1-3). EVIDENCE HAS SHOWN THAT METHYLATION MARKERS ARE ALTERED IN DIFFERENT CNS REGIONS RELATED TO NOCICEPTION, NAMELY THE DORSAL ROOT GANGLIA, THE SPINAL CORD, AND DIFFERENT BRAIN AREAS. DECREASED GLOBAL METHYLATION WAS FOUND IN THE DRG, THE PREFRONTAL CORTEX, AND THE AMYGDALA, WHICH WAS ASSOCIATED WITH DECREASED DNMT1/3A EXPRESSION. IN CONTRAST, INCREASED METHYLATION LEVELS AND MRNA LEVELS OF TET1 AND TET3 WERE LINKED TO AUGMENTED PAIN HYPERSENSITIVITY AND ALLODYNIA IN INFLAMMATORY AND NEUROPATHIC PAIN MODELS. SINCE EPIGENETIC MECHANISMS MAY BE RESPONSIBLE FOR THE REGULATION AND COORDINATION OF VARIOUS TRANSCRIPTIONAL MODIFICATIONS DESCRIBED IN CHRONIC PAIN STATES, WITH THIS STUDY, WE AIMED TO EVALUATE THE FUNCTIONAL ROLE OF TET1-3 AND DNMT1/3A GENES IN NEUROPATHIC PAIN IN SEVERAL BRAIN AREAS. IN A SPARED NERVE INJURY RAT MODEL OF NEUROPATHIC PAIN, 21 DAYS AFTER SURGERY, WE FOUND INCREASED TET1 EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX AND DECREASED EXPRESSION IN THE CAUDATE-PUTAMEN AND THE AMYGDALA; TET2 WAS UPREGULATED IN THE MEDIAL THALAMUS; TET3 MRNA LEVELS WERE REDUCED IN THE MEDIAL PREFRONTAL CORTEX AND THE CAUDATE-PUTAMEN; AND DNMT1 WAS DOWNREGULATED IN THE CAUDATE-PUTAMEN AND THE MEDIAL THALAMUS. NO STATISTICALLY SIGNIFICANT CHANGES IN EXPRESSION WERE OBSERVED WITH DNMT3A. OUR RESULTS SUGGEST A COMPLEX FUNCTIONAL ROLE FOR THESE GENES IN DIFFERENT BRAIN AREAS IN THE CONTEXT OF NEUROPATHIC PAIN. THE NOTION OF DNA METHYLATION AND HYDROXYMETHYLATION BEING CELL-TYPE SPECIFIC AND NOT TISSUE SPECIFIC, AS WELL AS THE POSSIBILITY OF CHRONOLOGICALLY DIFFERENTIAL GENE EXPRESSION AFTER THE ESTABLISHMENT OF NEUROPATHIC OR INFLAMMATORY PAIN MODELS, OUGHT TO BE ADDRESSED IN FUTURE STUDIES. 2023 14 2785 43 EZH2 REGULATES SPINAL NEUROINFLAMMATION IN RATS WITH NEUROPATHIC PAIN. ALTERATION IN GENE EXPRESSION ALONG THE PAIN SIGNALING PATHWAY IS A KEY MECHANISM CONTRIBUTING TO THE GENESIS OF NEUROPATHIC PAIN. ACCUMULATING STUDIES HAVE SHOWN THAT EPIGENETIC REGULATION PLAYS A CRUCIAL ROLE IN NOCICEPTIVE PROCESS IN THE SPINAL DORSAL HORN. IN THIS PRESENT STUDY, WE INVESTIGATED THE ROLE OF ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A SUBUNIT OF THE POLYCOMB REPRESSIVE COMPLEX 2, IN THE SPINAL DORSAL HORN IN THE GENESIS OF NEUROPATHIC PAIN IN RATS INDUCED BY PARTIAL SCIATIC NERVE LIGATION. EZH2 IS A HISTONE METHYLTRANSFERASE, WHICH CATALYZES THE METHYLATION OF HISTONE H3 ON K27 (H3K27), RESULTING IN GENE SILENCING. WE FOUND THAT LEVELS OF EZH2 AND TRI-METHYLATED H3K27 (H3K27TM) IN THE SPINAL DORSAL HORN WERE INCREASED IN RATS WITH NEUROPATHIC PAIN ON DAY 3 AND DAY 10 POST NERVE INJURIES. EZH2 WAS PREDOMINANTLY EXPRESSED IN NEURONS IN THE SPINAL DORSAL HORN UNDER NORMAL CONDITIONS. THE NUMBER OF NEURONS WITH EZH2 EXPRESSION WAS INCREASED AFTER NERVE INJURY. MORE STRIKINGLY, NERVE INJURY DRASTICALLY INCREASED THE NUMBER OF MICROGLIA WITH EZH2 EXPRESSION BY MORE THAN SEVENFOLD. INTRATHECAL INJECTION OF THE EZH2 INHIBITOR ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF MECHANICAL AND THERMAL HYPERALGESIA IN RATS WITH NERVE INJURY. SUCH ANALGESIC EFFECTS WERE CONCURRENTLY ASSOCIATED WITH THE REDUCED LEVELS OF EZH2, H3K27TM, IBA1, GFAP, TNF-ALPHA, IL-1BETA, AND MCP-1 IN THE SPINAL DORSAL HORN IN RATS WITH NERVE INJURY. OUR RESULTS HIGHLY SUGGEST THAT TARGETING THE EZH2 SIGNALING PATHWAY COULD BE AN EFFECTIVE APPROACH FOR THE MANAGEMENT OF NEUROPATHIC PAIN. 2017 15 6139 38 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 16 5007 40 PERIPHERAL NERVE INJURY IS ASSOCIATED WITH CHRONIC, REVERSIBLE CHANGES IN GLOBAL DNA METHYLATION IN THE MOUSE PREFRONTAL CORTEX. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ARE ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS INCLUDING LOW BACK PAIN AND FIBROMYALGIA. THE MAGNITUDE OF THESE CHANGES CORRELATES WITH THE DURATION AND/OR THE INTENSITY OF CHRONIC PAIN. MOST STUDIES REPORT CHANGES IN COMMON AREAS INVOLVED IN PAIN MODULATION, INCLUDING THE PREFRONTAL CORTEX (PFC), AND PAIN-RELATED PATHOLOGICAL CHANGES IN THE PFC CAN BE REVERSED WITH EFFECTIVE TREATMENT. WHILE THE MECHANISMS UNDERLYING THESE CHANGES ARE UNKNOWN, THEY MUST BE DYNAMICALLY REGULATED. EPIGENETIC MODULATION OF GENE EXPRESSION IN RESPONSE TO EXPERIENCE AND ENVIRONMENT IS REVERSIBLE AND DYNAMIC. EPIGENETIC MODULATION BY DNA METHYLATION IS ASSOCIATED WITH ABNORMAL BEHAVIOR AND PATHOLOGICAL GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM. DNA METHYLATION MIGHT ALSO BE INVOLVED IN MEDIATING THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN IN THE BRAIN. WE THEREFORE TESTED A) WHETHER ALTERATIONS IN DNA METHYLATION ARE FOUND IN THE BRAIN LONG AFTER CHRONIC NEUROPATHIC PAIN IS INDUCED IN THE PERIPHERY USING THE SPARED NERVE INJURY MODAL AND B) WHETHER THESE INJURY-ASSOCIATED CHANGES ARE REVERSIBLE BY INTERVENTIONS THAT REVERSE THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN. SIX MONTHS FOLLOWING PERIPHERAL NERVE INJURY, ABNORMAL SENSORY THRESHOLDS AND INCREASED ANXIETY WERE ACCOMPANIED BY DECREASED GLOBAL METHYLATION IN THE PFC AND THE AMYGDALA BUT NOT IN THE VISUAL CORTEX OR THE THALAMUS. ENVIRONMENTAL ENRICHMENT ATTENUATED NERVE INJURY-INDUCED HYPERSENSITIVITY AND REVERSED THE CHANGES IN GLOBAL PFC METHYLATION. FURTHERMORE, GLOBAL PFC METHYLATION CORRELATED WITH MECHANICAL AND THERMAL SENSITIVITY IN NEUROPATHIC MICE. IN SUMMARY, INDUCTION OF CHRONIC PAIN BY PERIPHERAL NERVE INJURY IS ASSOCIATED WITH EPIGENETIC CHANGES IN THE BRAIN. THESE CHANGES ARE DETECTED LONG AFTER THE ORIGINAL INJURY, AT A LONG DISTANCE FROM THE SITE OF INJURY AND ARE REVERSIBLE WITH ENVIRONMENTAL MANIPULATION. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION THAT ARE ASSOCIATED WITH CHRONIC PAIN CONDITIONS MAY THEREFORE BE MEDIATED BY EPIGENETIC MECHANISMS. 2013 17 5006 45 PERIPHERAL NERVE INJURY IS ACCOMPANIED BY CHRONIC TRANSCRIPTOME-WIDE CHANGES IN THE MOUSE PREFRONTAL CORTEX. BACKGROUND: PERIPHERAL NERVE INJURY CAN HAVE LONG-TERM CONSEQUENCES INCLUDING PAIN-RELATED MANIFESTATIONS, SUCH AS HYPERSENSITIVITY TO CUTANEOUS STIMULI, AS WELL AS AFFECTIVE AND COGNITIVE DISTURBANCES, SUGGESTING THE INVOLVEMENT OF SUPRASPINAL MECHANISMS. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS HAVE BEEN REPORTED IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPLICATED IN PAIN-RELATED CO-MORBIDITIES SUCH AS DEPRESSION, ANXIETY AND IMPAIRED EMOTIONAL DECISION-MAKING ABILITY. WE RECENTLY REPORTED THAT THIS REGION IS SUBJECT TO SIGNIFICANT EPIGENETIC REPROGRAMMING FOLLOWING PERIPHERAL NERVE INJURY, AND NORMALIZATION OF PAIN-RELATED STRUCTURAL, FUNCTIONAL AND EPIGENETIC ABNORMALITIES IN THE PFC ARE ALL ASSOCIATED WITH EFFECTIVE PAIN REDUCTION. IN THIS STUDY, WE USED THE SPARED NERVE INJURY (SNI) MODEL OF NEUROPATHIC PAIN TO TEST THE HYPOTHESIS THAT PERIPHERAL NERVE INJURY TRIGGERS PERSISTENT LONG-LASTING CHANGES IN GENE EXPRESSION IN THE PFC, WHICH ALTER FUNCTIONAL GENE NETWORKS, THUS PROVIDING A POSSIBLE EXPLANATION FOR CHRONIC PAIN ASSOCIATED BEHAVIORS. RESULTS: SNI OR SHAM SURGERY WHERE PERFORMED IN MALE CD1 MICE AT THREE MONTHS OF AGE. SIX MONTHS AFTER INJURY, WE PERFORMED TRANSCRIPTOME-WIDE SEQUENCING (RNASEQ), WHICH REVEALED 1147 DIFFERENTIALLY REGULATED TRANSCRIPTS IN THE PFC IN NERVE-INJURED VS. CONTROL MICE. CHANGES IN GENE EXPRESSION OCCURRED ACROSS A NUMBER OF FUNCTIONAL GENE CLUSTERS ENCODING CARDINAL BIOLOGICAL PROCESSES AS REVEALED BY INGENUITY PATHWAY ANALYSIS. SIGNIFICANTLY ALTERED BIOLOGICAL PROCESSES INCLUDED NEUROLOGICAL DISEASE, SKELETAL MUSCULAR DISORDERS, BEHAVIOR, AND PSYCHOLOGICAL DISORDERS. SEVERAL OF THE CHANGES DETECTED BY RNASEQ WERE VALIDATED BY RT-QPCR AND INCLUDED TRANSCRIPTS WITH KNOWN ROLES IN CHRONIC PAIN AND/OR NEURONAL PLASTICITY INCLUDING THE NMDA RECEPTOR (GLUTAMATE RECEPTOR, IONOTROPIC, NMDA; GRIN1), NEURITE OUTGROWTH (ROUNDABOUT 3; ROBO3), GLIOSIS (GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP), VESICULAR RELEASE (SYNAPTOTAGMIN 2; SYT2), AND NEURONAL EXCITABILITY (VOLTAGE-GATED SODIUM CHANNEL, TYPE I; SCN1A). CONCLUSIONS: THIS STUDY USED AN UNBIASED APPROACH TO DOCUMENT LONG-TERM ALTERATIONS IN GENE EXPRESSION IN THE BRAIN FOLLOWING PERIPHERAL NERVE INJURY. WE PROPOSE THAT THESE CHANGES ARE MAINTAINED AS A MEMORY OF AN INSULT THAT IS TEMPORALLY AND SPATIALLY DISTANT FROM THE INITIAL INJURY. 2013 18 2176 31 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 19 2310 36 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 20 2736 43 EXPLORING THE TRANSCRIPTOME OF RESIDENT SPINAL MICROGLIA AFTER COLLAGEN ANTIBODY-INDUCED ARTHRITIS. RECENT STUDIES HAVE SUGGESTED A SEXUALLY DIMORPHIC ROLE OF SPINAL GLIAL CELLS IN THE MAINTENANCE OF MECHANICAL HYPERSENSITIVITY IN RODENT MODELS OF CHRONIC PAIN. WE HAVE USED THE COLLAGEN ANTIBODY-INDUCED ARTHRITIS (CAIA) MOUSE MODEL TO EXAMINE DIFFERENCES BETWEEN MALES AND FEMALES IN THE CONTEXT OF SPINAL REGULATION OF ARTHRITIS-INDUCED PAIN. WE HAVE FOCUSED ON THE LATE PHASE OF THIS MODEL WHEN JOINT INFLAMMATION HAS RESOLVED, BUT MECHANICAL HYPERSENSITIVITY PERSISTS. ALTHOUGH THE INTENSITY OF SUBSTANCE P, CALCITONIN GENE-RELATED PEPTIDE, AND GALANIN IMMUNOREACTIVITY IN THE SPINAL CORD WAS NOT DIFFERENT FROM CONTROLS, THE INTENSITY OF MICROGLIA (IBA-1) AND ASTROCYTE (GLIAL FIBRILLARY ACIDIC PROTEIN) MARKERS WAS ELEVATED IN BOTH MALES AND FEMALES. INTRATHECAL ADMINISTRATION OF THE GLIAL INHIBITORS MINOCYCLINE AND PENTOXIFYLLINE REVERSED MECHANICAL THRESHOLDS IN MALE, BUT NOT IN FEMALE MICE. WE ISOLATED RESIDENT MICROGLIA FROM THE LUMBAR DORSAL HORNS AND OBSERVED A SIGNIFICANTLY LOWER NUMBER OF MICROGLIAL CELLS IN FEMALES BY FLOW CYTOMETRY ANALYSIS. HOWEVER, ALTHOUGH GENOME-WIDE RNA SEQUENCING RESULTS POINTED TO SEVERAL TRANSCRIPTIONAL DIFFERENCES BETWEEN MALE AND FEMALE MICROGLIA, NO CONVINCING DIFFERENCES WERE IDENTIFIED BETWEEN CONTROL AND CAIA GROUPS. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THERE ARE SUBTLE SEX DIFFERENCES IN MICROGLIAL EXPRESSION PROFILES INDEPENDENT OF ARTHRITIS. OUR EXPERIMENTS FAILED TO IDENTIFY THE UNDERLYING MRNA CORRELATES OF MICROGLIAL ACTIONS IN THE LATE PHASE OF THE CAIA MODEL. IT IS LIKELY THAT TRANSCRIPTIONAL CHANGES ARE EITHER SUBTLE AND HIGHLY LOCALISED AND THEREFORE DIFFICULT TO IDENTIFY WITH BULK ISOLATION TECHNIQUES OR THAT OTHER FACTORS, SUCH AS CHANGES IN PROTEIN EXPRESSION OR EPIGENETIC MODIFICATIONS, ARE AT PLAY. 2019