1 5007 129 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 2 6427 51 THE TRANSITION FROM ACUTE TO CHRONIC PAIN: DYNAMIC EPIGENETIC REPROGRAMMING OF THE MOUSE PREFRONTAL CORTEX UP TO 1 YEAR AFTER NERVE INJURY. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT STRUCTURAL AND FUNCTIONAL CHANGES THROUGHOUT THE NEUROAXIS, INCLUDING IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPORTANT IN THE INTEGRATION OF SENSORY, COGNITIVE, AND EMOTIONAL INFORMATION AND IN CONDITIONED PAIN MODULATION. WE PREVIOUSLY REPORTED WIDESPREAD EPIGENETIC REPROGRAMMING IN THE PFC MANY MONTHS AFTER NERVE INJURY IN RODENTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, CAN DRIVE CHANGES IN GENE EXPRESSION WITHOUT MODIFYING DNA SEQUENCES. TO DATE, LITTLE IS KNOWN ABOUT EPIGENETIC DYSREGULATION AT THE ONSET OF ACUTE PAIN OR HOW IT PROGRESSES AS PAIN TRANSITIONS FROM ACUTE TO CHRONIC. WE HYPOTHESIZE THAT ACUTE PAIN AFTER INJURY RESULTS IN RAPID AND PERSISTENT EPIGENETIC REMODELLING IN THE PFC THAT EVOLVES AS PAIN BECOMES CHRONIC. WE FURTHER PROPOSE THAT UNDERSTANDING EPIGENETIC REMODELLING WILL PROVIDE INSIGHTS INTO THE MECHANISMS DRIVING PAIN-RELATED CHANGES IN THE BRAIN. EPIGENOME-WIDE ANALYSIS WAS PERFORMED IN THE MOUSE PFC 1 DAY, 2 WEEKS, 6 MONTHS, AND 1 YEAR AFTER PERIPHERAL INJURY USING THE SPARED NERVE INJURY IN MICE. SPARED NERVE INJURY RESULTED IN RAPID AND PERSISTENT CHANGES IN DNA METHYLATION, WITH ROBUST DIFFERENTIAL METHYLATION OBSERVED BETWEEN SPARED NERVE INJURY AND SHAM-OPERATED CONTROL MICE AT ALL TIME POINTS. HUNDREDS OF DIFFERENTIALLY METHYLATED GENES WERE IDENTIFIED, INCLUDING MANY WITH KNOWN FUNCTION IN PAIN. PATHWAY ANALYSIS REVEALED ENRICHMENT IN GENES RELATED TO STIMULUS RESPONSE AT EARLY TIME POINTS, IMMUNE FUNCTION AT LATER TIME POINTS, AND ACTIN AND CYTOSKELETAL REGULATION THROUGHOUT THE TIME COURSE. THESE RESULTS EMPHASIZE THE IMPORTANCE OF CONSIDERING PAIN CHRONICITY IN BOTH PAIN RESEARCH AND IN TREATMENT OPTIMIZATION. 2020 3 377 40 AN EPIGENETIC HYPOTHESIS FOR THE GENOMIC MEMORY OF PAIN. CHRONIC PAIN IS ACCOMPANIED WITH LONG-TERM SENSORY, AFFECTIVE AND COGNITIVE DISTURBANCES. WHAT ARE THE MECHANISMS THAT MEDIATE THE LONG-TERM CONSEQUENCES OF PAINFUL EXPERIENCES AND EMBED THEM IN THE GENOME? WE HYPOTHESIZE THAT ALTERATIONS IN DNA METHYLATION, AN ENZYMATIC COVALENT MODIFICATION OF CYTOSINE BASES IN DNA, SERVE AS A "GENOMIC" MEMORY OF PAIN IN THE ADULT CORTEX. DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR LONG-TERM REGULATION OF GENE EXPRESSION. NEURONAL PLASTICITY AT THE NEUROANATOMICAL, FUNCTIONAL, MORPHOLOGICAL, PHYSIOLOGICAL AND MOLECULAR LEVELS HAS BEEN DEMONSTRATED THROUGHOUT THE NEUROAXIS IN RESPONSE TO PERSISTENT PAIN, INCLUDING IN THE ADULT PREFRONTAL CORTEX (PFC). WE HAVE PREVIOUSLY REPORTED WIDESPREAD CHANGES IN GENE EXPRESSION AND DNA METHYLATION IN THE PFC MANY MONTHS FOLLOWING PERIPHERAL NERVE INJURY. IN SUPPORT OF THIS HYPOTHESIS, WE SHOW HERE THAT UP-REGULATION OF A GENE INVOLVED WITH SYNAPTIC FUNCTION, SYNAPTOTAGMIN II (SYT2), IN THE PFC IN A CHRONIC PAIN MODEL IS ASSOCIATED WITH LONG-TERM CHANGES IN DNA METHYLATION. THE CHALLENGES OF UNDERSTANDING THE CONTRIBUTIONS OF EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION WITHIN THE PFC TO PAIN CHRONICITY AND THEIR THERAPEUTIC IMPLICATIONS ARE DISCUSSED. 2015 4 4604 32 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 5 5199 47 PRENATAL MATERNAL STRESS IS ASSOCIATED WITH INCREASED SENSITIVITY TO NEUROPATHIC PAIN AND SEX-SPECIFIC CHANGES IN SUPRASPINAL MRNA EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES IN ADULTHOOD. EXPOSURE TO PRENATAL MATERNAL STRESS IMPACTS ADULT BEHAVIORAL OUTCOMES AND HAS BEEN SUGGESTED AS A RISK FACTOR FOR CHRONIC PAIN. HOWEVER, THE NEUROBIOLOGICAL MECHANISMS IMPLICATED ARE NOT WELL-CHARACTERIZED. IN THIS STUDY, WE ANALYZED THE EFFECT OF A PRENATAL MATERNAL STRESS ON THE DEVELOPMENT OF NEUROPATHIC PAIN-RELATED BEHAVIOURS AND GENE EXPRESSION IN THE FRONTAL CORTEX AND HIPPOCAMPUS IN ADULT OFFSPRING FOLLOWING CHRONIC CONSTRICTION INJURY OF THE SCIATIC NERVE IN MALE AND FEMALE CD1 MICE. NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY WAS AMPLIFIED IN BOTH MALE AND FEMALE PRENATALLY-STRESSED OFFSPRING, SUGGESTING THAT PRENATAL STRESS EXACERBATES PAIN AFTER INJURY. ANALYSIS OF MRNA EXPRESSION OF GENES RELATED TO EPIGENETIC REGULATION AND STRESS RESPONSES IN THE FRONTAL CORTEX AND HIPPOCAMPUS, BRAIN STRUCTURES IMPLICATED IN CHRONIC PAIN, SHOWED DISTINCT SEX AND REGION-SPECIFIC PATTERNS OF DYSREGULATION. IN GENERAL, MRNA EXPRESSION WAS MOST FREQUENTLY ALTERED IN THE MALE HIPPOCAMPUS AND EFFECTS OF PRENATAL STRESS WERE MORE PREVALENT THAN EFFECTS OF NERVE INJURY IN BOTH SUPRASPINAL AREAS. THESE FINDINGS DEMONSTRATE THE IMPACT OF PRENATAL STRESS ON BEHAVIORAL SENSITIVITY TO A PAINFUL INJURY. CHANGES IN THE EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES SUGGEST A POSSIBLE MECHANISM BY WHICH THE EARLY LIFE STRESS BECOMES EMBEDDED IN THE CENTRAL NERVOUS SYSTEM. INCREASED UNDERSTANDING OF THE INTERACTIONS AMONG EARLY-LIFE STRESS, SEX, AND PAIN MAY LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND EPIGENETIC DRUGS FOR THE TREATMENT OF CHRONIC PAIN DISORDERS. 2020 6 4879 29 OVERLAPPING SIGNATURES OF CHRONIC PAIN IN THE DNA METHYLATION LANDSCAPE OF PREFRONTAL CORTEX AND PERIPHERAL T CELLS. WE TESTED THE HYPOTHESIS THAT EPIGENETIC MECHANISMS IN THE BRAIN AND THE IMMUNE SYSTEM ARE ASSOCIATED WITH CHRONIC PAIN. GENOME-WIDE DNA METHYLATION ASSESSED IN 9 MONTHS POST NERVE-INJURY (SNI) AND SHAM RATS, IN THE PREFRONTAL CORTEX (PFC) AS WELL AS IN T CELLS REVEALED A VAST DIFFERENCE IN THE DNA METHYLATION LANDSCAPE IN THE BRAIN BETWEEN THE GROUPS AND A REMARKABLE OVERLAP (72%) BETWEEN DIFFERENTIALLY METHYLATED PROBES IN T CELLS AND PREFRONTAL CORTEX. DNA METHYLATION STATES IN THE PFC SHOWED ROBUST CORRELATION WITH PAIN SCORE OF ANIMALS IN SEVERAL GENES INVOLVED IN PAIN. FINALLY, ONLY 11 DIFFERENTIALLY METHYLATED PROBES IN T CELLS WERE SUFFICIENT TO DISTINGUISH SNI OR SHAM INDIVIDUAL RATS. THIS STUDY SUPPORTS THE PLAUSIBILITY OF DNA METHYLATION INVOLVEMENT IN CHRONIC PAIN AND DEMONSTRATES THE POTENTIAL FEASIBILITY OF DNA METHYLATION MARKERS IN T CELLS AS NONINVASIVE BIOMARKERS OF CHRONIC PAIN SUSCEPTIBILITY. 2016 7 1614 40 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES. 2021 8 5006 59 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 9 345 49 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 10 5645 34 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 11 2214 44 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 12 6445 61 THERAPEUTIC BENEFITS OF THE METHYL DONOR S-ADENOSYLMETHIONINE ON NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY AND COGNITIVE IMPAIRMENT IN MICE. DESPITE CONSIDERABLE ADVANCES IN UNDERSTANDING MECHANISMS INVOLVED IN CHRONIC PAIN, EFFECTIVE TREATMENT REMAINS ELUSIVE. COMORBID CONDITIONS INCLUDING ANXIETY, DEPRESSION, AND COGNITIVE IMPAIRMENT FURTHER IMPACT QUALITY OF LIFE. CHRONIC PAIN IS ASSOCIATED WITH REVERSIBLE CHANGES IN BRAIN ANATOMY AND FUNCTION AND WITH LONG-TERM CHANGES IN GENE EXPRESSION. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CONTRIBUTE TO WIDE-SPREAD AND LONG-LASTING REPROGRAMMING OF GENE EXPRESSION. WE PREVIOUSLY REPORTED DECREASES IN GLOBAL DNA METHYLATION IN THE MOUSE FRONTAL CORTEX 6 MONTHS AFTER INDUCTION OF NEUROPATHIC PAIN USING THE SPARED NERVE INJURY (SNI) MODEL. HERE, WE EXAMINED THE THERAPEUTIC EFFECT OF INCREASING DNA METHYLATION USING THE METHYL DONOR S-ADENOSYLMETHIONINE (SAM). S-ADENOSYLMETHIONINE IS MARKETED AS A NUTRITIONAL SUPPLEMENT FOR A RANGE OF CONDITIONS INCLUDING LIVER DISEASE, DEPRESSION, OSTEOARTHRITIS, FIBROMYALGIA, AND DEMENTIA. THREE MONTHS AFTER SNI OR SHAM SURGERY, ANIMALS WERE TREATED WITH SAM (20 MG/KG, 3X/WEEK) OR SALINE ORALLY FOR 4 MONTHS, AND THE IMPACT ON SENSORY, MOTOR, MOTIVATIONAL, AND COGNITIVE INDICES WAS MEASURED. S-ADENOSYLMETHIONINE ATTENUATED SNI-INDUCED MECHANICAL HYPERSENSITIVITY AND REDUCED ACTIVE AVOIDANCE OF MECHANICAL STIMULI BUT HAD NO EFFECT ON COLD SENSITIVITY OR MOTOR CAPACITY. S-ADENOSYLMETHIONINE COMPLETELY BLOCKED NERVE INJURY-INDUCED COGNITIVE IMPAIRMENT AND ATTENUATED SNI-INDUCED DECREASES IN GLOBAL DNA METHYLATION IN THE FRONTAL CORTEX. IN SUMMARY, CHRONIC ORAL ADMINISTRATION OF THE METHYL DONOR, SAM, ATTENUATED SENSORY AND COGNITIVE SYMPTOMS ASSOCIATED WITH NERVE INJURY IN MICE. THESE EFFECTS MAY BE MEDIATED, IN PART, THROUGH MODULATION OF DNA METHYLATION IN THE CENTRAL NERVOUS SYSTEM BY SYSTEMIC ADMINISTRATION OF THE METHYL DONOR SAM. 2017 13 5709 41 SIRT1 DECREASES EMOTIONAL PAIN VULNERABILITY WITH ASSOCIATED CAMKIIALPHA DEACETYLATION IN CENTRAL AMYGDALA. EMOTIONAL DISORDERS ARE COMMON COMORBID CONDITIONS THAT FURTHER EXACERBATE THE SEVERITY AND CHRONICITY OF CHRONIC PAIN. HOWEVER, INDIVIDUALS SHOW CONSIDERABLE VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN UNDER SIMILAR PAIN CONDITIONS. IN THIS STUDY ON MALE RAT AND MOUSE MODELS OF CHRONIC NEUROPATHIC PAIN, WE IDENTIFY THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) IN CENTRAL AMYGDALA AS A KEY EPIGENETIC REGULATOR THAT CONTROLS THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDERLYING THE INDIVIDUAL VULNERABILITY TO CHRONIC PAIN. WE FOUND THAT ANIMALS THAT WERE VULNERABLE TO DEVELOPING BEHAVIORS OF ANXIETY AND DEPRESSION UNDER THE PAIN CONDITION DISPLAYED REDUCED SIRT1 PROTEIN LEVELS IN CENTRAL AMYGDALA, BUT NOT THOSE ANIMALS RESISTANT TO THE EMOTIONAL DISORDERS. VIRAL OVEREXPRESSION OF LOCAL SIRT1 REVERSED THIS VULNERABILITY, BUT VIRAL KNOCKDOWN OF LOCAL SIRT1 MIMICKED THE PAIN EFFECT, ELICITING THE PAIN VULNERABILITY IN PAIN-FREE ANIMALS. THE SIRT1 ACTION WAS ASSOCIATED WITH CAMKIIALPHA DOWNREGULATION AND DEACETYLATION OF HISTONE H3 LYSINE 9 AT THE CAMKIIALPHA PROMOTER. THESE RESULTS SUGGEST THAT, BY TRANSCRIPTIONAL REPRESSION OF CAMKIIALPHA IN CENTRAL AMYGDALA, SIRT1 FUNCTIONS TO GUARD AGAINST THE EMOTIONAL PAIN VULNERABILITY UNDER CHRONIC PAIN CONDITIONS. THIS STUDY INDICATES THAT SIRT1 MAY SERVE AS A POTENTIAL THERAPEUTIC MOLECULE FOR INDIVIDUALIZED TREATMENT OF CHRONIC PAIN WITH VULNERABLE EMOTIONAL DISORDERS.SIGNIFICANCE STATEMENT CHRONIC PAIN IS A PREVALENT NEUROLOGICAL DISEASE WITH NO EFFECTIVE TREATMENT AT PRESENT. PAIN PATIENTS DISPLAY CONSIDERABLY VARIABLE VULNERABILITY TO DEVELOPING CHRONIC PAIN, INDICATING INDIVIDUAL-BASED MOLECULAR MECHANISMS UNDERLYING THE PAIN VULNERABILITY, WHICH IS HARDLY ADDRESSED IN CURRENT PRECLINICAL RESEARCH. IN THIS STUDY, WE HAVE IDENTIFIED THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) AS A KEY REGULATOR THAT CONTROLS THIS PAIN VULNERABILITY. THIS STUDY REVEALS THAT THE SIRT1-CAMKIIAALPHA PATHWAY IN CENTRAL AMYGDALA ACTS AS AN EPIGENETIC MECHANISM THAT GUARDS AGAINST THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDER CHRONIC PAIN, AND THAT ITS DYSFUNCTION CAUSES INCREASED VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN. THESE FINDINGS SUGGEST THAT SIRT1 ACTIVATORS MAY BE USED IN A NOVEL THERAPEUTIC APPROACH FOR INDIVIDUAL-BASED TREATMENT OF CHRONIC PAIN. 2020 14 2310 39 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 15 5019 46 PERSISTENT INFLAMMATORY PAIN IS LINKED WITH ANXIETY-LIKE BEHAVIORS, INCREASED BLOOD CORTICOSTERONE, AND REDUCED GLOBAL DNA METHYLATION IN THE RAT AMYGDALA. CHRONIC PAIN INCREASES THE RISK OF DEVELOPING ANXIETY, WITH LIMBIC AREAS BEING LIKELY NEUROLOGICAL SUBSTRATES. DESPITE HIGH CLINICAL RELEVANCE, LITTLE IS KNOWN ABOUT THE PRECISE BEHAVIORAL, HORMONAL, AND BRAIN NEUROPLASTIC CORRELATES OF ANXIETY IN THE CONTEXT OF PERSISTENT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT DECREASED NOCICEPTIVE THRESHOLDS IN CHRONIC PAIN MODELS ARE PARALLELED BY ANXIETY-LIKE BEHAVIOR IN RATS, BUT THERE ARE CONFLICTING IDEAS REGARDING ITS EFFECTS ON THE STRESS RESPONSE AND CIRCULATING CORTICOSTERONE LEVELS. EVEN LESS IS KNOWN ABOUT THE MOLECULAR MECHANISMS THROUGH WHICH THE BRAIN ENCODES PAIN-RELATED ANXIETY. THIS STUDY EXAMINES HOW PERSISTENT INFLAMMATORY PAIN IN A RAT MODEL WOULD IMPACT ANXIETY-LIKE BEHAVIORS AND CORTICOSTERONE RELEASE, AND WHETHER THESE CHANGES WOULD BE REFLECTED IN LEVELS OF GLOBAL DNA METHYLATION IN BRAIN AREAS INVOLVED IN STRESS REGULATION. COMPLETE FREUND'S ADJUVANT (CFA) OR SALINE WAS ADMINISTERED IN THE RIGHT HINDPAW OF ADULT MALE WISTAR RATS. BEHAVIORAL TESTING INCLUDED THE MEASUREMENT OF NOCICEPTIVE THRESHOLDS (DIGITAL ANESTHESIOMETER), MOTOR FUNCTION (OPEN FIELD TEST), AND ANXIETY-LIKE BEHAVIORS (ELEVATED PLUS MAZE AND THE DARK-LIGHT BOX TEST). CORTICOSTERONE WAS MEASURED VIA RADIOIMMUNOASSAY. GLOBAL DNA METHYLATION (ENZYME IMMUNOASSAY) AS WELL AS DNMT3A LEVELS (WESTERN BLOTTING) WERE QUANTIFIED IN THE AMYGDALA, PREFRONTAL CORTEX, AND VENTRAL HIPPOCAMPUS. CFA ADMINISTRATION RESULTED IN PERSISTENT REDUCTION IN NOCICEPTIVE THRESHOLD IN THE ABSENCE OF LOCOMOTOR ABNORMALITIES. INCREASED ANXIETY-LIKE BEHAVIORS WERE OBSERVED IN THE ELEVATED PLUS MAZE AND WERE ACCOMPANIED BY INCREASED BLOOD CORTICOSTERONE LEVELS 10 DAYS AFTER PAIN INDUCTION. GLOBAL DNA METHYLATION WAS DECREASED IN THE AMYGDALA, WITH NO CHANGES IN DNMT3A ABUNDANCE IN ANY OF THE REGIONS EXAMINED. PERSISTENT INFLAMMATORY PAIN PROMOTES ANXIETY -LIKE BEHAVIORS, HPA AXIS ACTIVATION, AND EPIGENETIC REGULATION THROUGH DNA METHYLATION IN THE AMYGDALA. THESE FINDINGS DESCRIBE A MOLECULAR MECHANISM THAT LINKS PAIN AND STRESS IN A WELL-CHARACTERIZED RODENT MODEL. 2022 16 4628 34 NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX OF TYPE 2 DIABETIC MICE THROUGH DNA HYPERMETHYLATION. BACKGROUND: DNA METHYLATION CHANGES HAVE KNOWN TO DOWNREGULATE SEVERAL REGULATORY PROTEINS EPIGENETICALLY DURING VARIOUS NEURODEGENERATIVE DISORDERS. OUR STUDY AIMS TO UNDERSTAND THE EFFECT OF THIS GLOBAL DNA METHYLATION ON THE CEREBRAL COMPLICATIONS OF TYPE 2 DIABETES MICE, AND ITS NOTABLE EFFECT ON MAINTAINING THE SYNAPTIC FIDELITY. METHODS AND RESULTS: CHRONIC HIGH FAT DIET AND STREPTOZOTOCIN-INDUCED DIABETIC MICE WERE STUDIED FOR THE NEUROBEHAVIORAL AND NEUROANATOMIC PARAMETERS PERTAINING TO PREFRONTAL CORTEX, SUBSEQUENTLY ELUCIDATING THE ASSOCIATED CHANGES IN DNA METHYLATION WITHIN THESE DIABETIC BRAINS. FURTHER, THE IMPACT OF THIS EPIGENETIC DYSREGULATION ON HSF1, BDNF AND PSD95 WERE STUDIED BY ASSESSING THE BINDING AFFINITY AND LEVEL OF % METHYLATION WITHIN THE PROMOTER SITE OF THEIR RESPECTIVE GENES. OUR STUDY SUGGEST INCREASED DNMT ABERRATIONS WITHIN THE PREFRONTAL CORTEX, WITH INCREASED MECP2 LEVELS, CONFIRMING DNA HYPERMETHYLATION. THIS WAS IN ACCORDANCE WITH THE ALTERED NEUROBEHAVIORAL CHANGES. FURTHER, THE HYPERMETHYLATION WAS FOUND TO PARTICIPATE IN GENE SILENCING OF HSF1, BDNF AND PSD95 PROTEINS, RESPONSIBLE FOR MAINTAINING THE SYNAPTIC FIDELITY. CONCLUSION: OVERALL, OUR STUDY CONCLUDES THE PLAUSIBLE INVOLVEMENT OF NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX (PFC) OF THE TYPE 2 DIABETES MICE, SPECIFICALLY DNA HYPERMETHYLATION. PFC PLAYS A CENTRAL ROLE IN MODULATING COGNITIVE AND OTHER EXECUTIVE FUNCTIONS THROUGH ITS CONNECTION WITH SEVERAL BRAIN REGIONS, AND THUS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC MODULATIONS IN IT, CAN PAVE A WAY IN CONTROLLING SEVERAL NEUROLOGICAL ALTERATIONS IN THE BRAIN. 2022 17 2194 37 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015 18 6246 46 THE METHYL DONOR S-ADENOSYL METHIONINE REVERSES THE DNA METHYLATION SIGNATURE OF CHRONIC NEUROPATHIC PAIN IN MOUSE FRONTAL CORTEX. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT BUT REVERSIBLE STRUCTURAL AND FUNCTIONAL CHANGES IN THE PREFRONTAL CORTEX (PFC). THIS STABLE YET MALLEABLE PLASTICITY IMPLICATES EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, AS A POTENTIAL MEDIATOR OF CHRONIC PAIN-INDUCED CORTICAL PATHOLOGY. WE PREVIOUSLY DEMONSTRATED THAT CHRONIC ORAL ADMINISTRATION OF THE METHYL DONOR S-ADENOSYL METHIONINE (SAM) ATTENUATES LONG-TERM PERIPHERAL NEUROPATHIC PAIN AND ALTERS GLOBAL FRONTAL CORTICAL DNA METHYLATION. HOWEVER, THE SPECIFIC GENES AND PATHWAYS ASSOCIATED WITH THE RESOLUTION OF CHRONIC PAIN BY SAM REMAIN UNEXPLORED. OBJECTIVE: TO DETERMINE THE EFFECT OF LONG-TERM THERAPEUTIC EXPOSURE TO SAM ON THE DNA METHYLATION OF INDIVIDUAL GENES AND PATHWAYS IN A MOUSE NEUROPATHIC PAIN MODEL. METHODS: MALE CD-1 MICE RECEIVED SPARED NERVE INJURY OR SHAM SURGERY. THREE MONTHS AFTER INJURY, ANIMALS RECEIVED SAM (20 MG/KG, ORAL, 3X A WEEK) OR VEHICLE FOR 16 WEEKS FOLLOWED BY EPIGENOME-WIDE ANALYSIS OF FRONTAL CORTEX. RESULTS: PERIPHERAL NEUROPATHIC PAIN WAS ASSOCIATED WITH 4000 DIFFERENTIALLY METHYLATED GENOMIC REGIONS THAT WERE ENRICHED IN INTRACELLULAR SIGNALING, CELL MOTILITY AND MIGRATION, CYTOSKELETAL STRUCTURE, AND CELL ADHESION PATHWAYS. A THIRD OF THESE DIFFERENTIALLY METHYLATED REGIONS WERE REVERSED BY SAM TREATMENT (1415 REGIONS REPRESENTING 1013 GENES). MORE THAN 100 GENES WITH KNOWN PAIN-RELATED FUNCTION WERE DIFFERENTIALLY METHYLATED AFTER NERVE INJURY; 29 OF THESE WERE REVERSED BY SAM TREATMENT INCLUDING SCN10A, TRPA1, NTRK1, AND GFAP. CONCLUSION: THESE RESULTS SUGGEST A ROLE FOR THE EPIGENOME IN THE MAINTENANCE OF CHRONIC PAIN AND ADVANCE EPIGENETIC MODULATORS SUCH AS SAM AS A NOVEL APPROACH TO TREAT CHRONIC PAIN. 2021 19 2003 26 EPIGENETIC AND TRANSCRIPTIONAL CONTROL OF THE OPIOID PRODYNORPHINE GENE: IN-DEPTH ANALYSIS IN THE HUMAN BRAIN. NEUROPEPTIDES SERVE AS NEUROHORMONES AND LOCAL PARACRINE REGULATORS THAT CONTROL NEURAL NETWORKS REGULATING BEHAVIOR, ENDOCRINE SYSTEM AND SENSORIMOTOR FUNCTIONS. THEIR EXPRESSION IS CHARACTERIZED BY EXCEPTIONALLY RESTRICTED PROFILES. CIRCUIT-SPECIFIC AND ADAPTIVE EXPRESSION OF NEUROPEPTIDE GENES MAY BE DEFINED BY TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS CONTROLLED BY CELL TYPE AND SUBTYPE SEQUENCE-SPECIFIC TRANSCRIPTION FACTORS, INSULATORS AND SILENCERS. THE OPIOID PEPTIDE DYNORPHINS PLAY A CRITICAL ROLE IN NEUROLOGICAL AND PSYCHIATRIC DISORDERS, PAIN PROCESSING AND STRESS, WHILE THEIR MUTATIONS CAUSE PROFOUND NEURODEGENERATION IN THE HUMAN BRAIN. IN THIS REVIEW, WE FOCUS ON THE PRODYNORPHIN GENE AS A MODEL FOR THE IN-DEPTH EPIGENETIC AND TRANSCRIPTIONAL ANALYSIS OF EXPRESSION OF THE NEUROPEPTIDE GENES. PRODYNORPHIN STUDIES MAY PROVIDE A FRAMEWORK FOR ANALYSIS OF MECHANISMS RELEVANT FOR REGULATION OF NEUROPEPTIDE GENES IN NORMAL AND PATHOLOGICAL HUMAN BRAIN. 2021 20 4643 37 NEUROPATHIC PAIN AS A TRIGGER FOR HISTONE MODIFICATIONS IN LIMBIC CIRCUITRY. CHRONIC PAIN INVOLVES BOTH CENTRAL AND PERIPHERAL NEURONAL PLASTICITY THAT ENCOMPASSES CHANGES IN THE BRAIN, SPINAL CORD, AND PERIPHERAL NOCICEPTORS. WITHIN THE FOREBRAIN, MESOCORTICOLIMBIC REGIONS ASSOCIATED WITH EMOTIONAL REGULATION HAVE RECENTLY BEEN SHOWN TO EXHIBIT LASTING GENE EXPRESSION CHANGES IN MODELS OF CHRONIC PAIN. TO BETTER UNDERSTAND HOW SUCH ENDURING TRANSCRIPTIONAL CHANGES MIGHT BE REGULATED WITHIN BRAIN STRUCTURES ASSOCIATED WITH PROCESSING OF PAIN OR AFFECT, WE EXAMINED EPIGENETIC MODIFICATIONS INVOLVED WITH ACTIVE OR PERMISSIVE TRANSCRIPTIONAL STATES (HISTONE H3 LYSINE 4 MONO AND TRIMETHYLATION, AND HISTONE H3 LYSINE 27 ACETYLATION) IN PERIAQUEDUCTAL GRAY (PAG), LATERAL HYPOTHALAMUS (LH), NUCLEUS ACCUMBENS (NAC), AND VENTRAL TEGMENTAL AREA (VTA) 5 WEEKS AFTER SCIATIC NERVE INJURY IN MICE TO MODEL CHRONIC PAIN. FOR BOTH MALE AND FEMALE MICE IN CHRONIC PAIN, WE OBSERVED AN OVERALL TREND FOR A REDUCTION OF THESE EPIGENETIC MARKERS IN PERIAQUEDUCTAL GRAY, LH, AND NAC, BUT NOT VTA. MOREOVER, WE DISCOVERED THAT SOME EPIGENETIC MODIFICATIONS EXHIBITED CHANGES ASSOCIATED WITH PAIN HISTORY, WHILE OTHERS WERE ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY. WHEN TAKEN TOGETHER, THESE RESULTS SUGGEST THAT NERVE INJURY LEADS TO CHRONIC CHROMATIN-MEDIATED SUPPRESSION OF TRANSCRIPTION IN KEY LIMBIC BRAIN STRUCTURES AND CIRCUITS, WHICH MAY UNDERLIE ENDURING CHANGES IN PAIN PROCESSING AND SENSITIVITY WITHIN THESE SYSTEMS. 2023