1 5537 122 ROLE OF CALCITONIN GENE-RELATED PEPTIDE IN LIGHT-AVERSIVE BEHAVIOR: IMPLICATIONS FOR MIGRAINE. MIGRAINE IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRENT EPISODES OF SEVERE UNILATERAL THROBBING HEAD PAIN AND ASSOCIATED SYMPTOMS, SUCH AS PHOTOPHOBIA. OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING MIGRAINE HAS BEEN HAMPERED BY LIMITATIONS IN ASCERTAINING MIGRAINE SYMPTOMS IN ANIMAL MODELS. CLINICAL STUDIES HAVE ESTABLISHED THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A KEY PLAYER IN MIGRAINE. HERE, WE ESTABLISH A GENETIC MODEL OF PHOTOPHOBIA BY ENGINEERING INCREASED SENSITIVITY TO CGRP IN MICE. THESE TRANSGENIC MICE (NESTIN/HRAMP1) DISPLAY LIGHT-AVERSIVE BEHAVIOR THAT IS GREATLY ENHANCED BY INTRACEREBROVENTRICULAR INJECTION OF CGRP AND BLOCKED BY COADMINISTRATION OF THE CGRP RECEPTOR ANTAGONIST OLCEGEPANT. THIS BEHAVIOR APPEARS TO BE AN INDICATOR OF PHOTOPHOBIA AND CANNOT BE FULLY EXPLAINED BY GROSS ABNORMALITY OF OCULAR ANATOMY OR DIFFERENCES IN GENERAL ANXIETY OR MOTOR ACTIVITY. OUR FINDINGS DEMONSTRATE THAT A SINGLE GENE, RECEPTOR ACTIVITY-MODIFYING PROTEIN 1 (RAMP1), CAN BE A MODIFIER OF PHOTOPHOBIA AND, BY EXTENSION, SUGGEST THAT GENETIC OR EPIGENETIC MODULATION OF RAMP1 LEVELS MAY CONTRIBUTE TO MIGRAINE SUSCEPTIBILITY. MOREOVER, THEY VALIDATE CGRP HYPERSENSITIVE MICE AS A TOOL FOR EXPLORING THE NEUROBIOLOGY AND NOVEL THERAPIES FOR MIGRAINE AND OTHER DISORDERS INVOLVING PHOTOPHOBIA. 2009 2 2052 32 EPIGENETIC CONNECTION OF THE CALCITONIN GENE-RELATED PEPTIDE AND ITS POTENTIAL IN MIGRAINE. THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) IS IMPLICATED IN THE PATHOGENESIS OF SEVERAL PAIN-RELATED SYNDROMES, INCLUDING MIGRAINE. TARGETING CGRP AND ITS RECEPTOR BY THEIR ANTAGONISTS AND ANTIBODIES WAS A BREAKTHROUGH IN MIGRAINE THERAPY, BUT THE NEED TO IMPROVE EFFICACY AND LIMIT THE SIDE EFFECTS OF THESE DRUGS JUSTIFY FURTHER STUDIES ON THE REGULATION OF CGRP IN MIGRAINE. THE EXPRESSION OF THE CGRP ENCODING GENE, CALCA, IS MODULATED BY EPIGENETIC MODIFICATIONS, INCLUDING THE DNA METHYLATION, HISTONE MODIFICATION, AND EFFECTS OF MICRO RNAS (MIRNAS), CIRCULAR RNAS, AND LONG-CODING RNAS (LNCRNAS). ON THE OTHER HAND, CGRP CAN CHANGE THE EPIGENETIC PROFILE OF NEURONAL AND GLIAL CELLS. THE PROMOTER OF THE CALCA GENE HAS TWO CPG ISLANDS THAT MAY BE SPECIFICALLY METHYLATED IN MIGRAINE PATIENTS. DNA METHYLATION AND LNCRNAS WERE SHOWN TO PLAY A ROLE IN THE CELL-SPECIFIC ALTERNATIVE SPLICING OF THE CALCA PRIMARY TRANSCRIPT. CGRP MAY BE INVOLVED IN CHANGES IN NEURAL CYTOARCHITECTURE THAT ARE CONTROLLED BY HISTONE DEACETYLASE 6 (HDAC6) AND CAN BE RELATED TO MIGRAINE. INHIBITION OF HDAC6 RESULTS IN REDUCED CORTICAL-SPREADING DEPRESSION AND A BLOCKADE OF THE CGRP RECEPTOR. CGRP LEVELS ARE ASSOCIATED WITH THE EXPRESSION OF SEVERAL MIRNAS IN PLASMA, MAKING THEM USEFUL PERIPHERAL MARKERS OF MIGRAINE. THE FUNDAMENTAL ROLE OF CGRP IN INFLAMMATORY PAIN TRANSMISSION MAY BE EPIGENETICALLY REGULATED. IN CONCLUSION, EPIGENETIC CONNECTIONS OF CGRP SHOULD BE FURTHER EXPLORED FOR EFFICIENT AND SAFE ANTIMIGRAINE THERAPY. 2022 3 717 37 CALCITONIN GENE-RELATED PEPTIDE REGULATES SPINAL MICROGLIAL ACTIVATION THROUGH THE HISTONE H3 LYSINE 27 TRIMETHYLATION VIA ENHANCER OF ZESTE HOMOLOG-2 IN RATS WITH NEUROPATHIC PAIN. BACKGROUND: CALCITONIN GENE-RELATED PEPTIDE (CGRP) AS A MEDIATOR OF MICROGLIAL ACTIVATION AT THE TRANSCRIPTIONAL LEVEL MAY FACILITATE NOCICEPTIVE SIGNALING. TRIMETHYLATION OF H3 LYSINE 27 (H3K27ME3) BY ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS AN EPIGENETIC MARK THAT REGULATES INFLAMMATORY-RELATED GENE EXPRESSION AFTER PERIPHERAL NERVE INJURY. IN THIS STUDY, WE EXPLORED THE RELATIONSHIP BETWEEN CGRP AND H3K27ME3 IN MICROGLIAL ACTIVATION AFTER NERVE INJURY, AND ELUCIDATED THE UNDERLYING MECHANISMS IN THE PATHOGENESIS OF CHRONIC NEUROPATHIC PAIN. METHODS: MICROGLIAL CELLS (BV2) WERE TREATED WITH CGRP AND DIFFERENTIALLY ENRICHMENTS OF H3K27ME3 ON GENE PROMOTERS WERE EXAMINED USING CHIP-SEQ. A CHRONIC CONSTRICTION INJURY (CCI) RAT MODEL WAS USED TO EVALUATE THE ROLE OF CGRP ON MICROGLIAL ACTIVATION AND EZH2/H3K27ME3 SIGNALING IN CCI-INDUCED NEUROPATHIC PAIN. RESULTS: OVEREXPRESSIONS OF EZH2 AND H3K27ME3 WERE CONFIRMED IN SPINAL MICROGLIA OF CCI RATS BY IMMUNOFLUORESCENCE. CGRP TREATMENT INDUCED THE INCREASED OF H3K27ME3 EXPRESSION IN THE SPINAL DORSAL HORN AND CULTURED MICROGLIAL CELLS (BV2) THROUGH EZH2. CHIP-SEQ DATA INDICATED THAT CGRP SIGNIFICANTLY ALTERED H3K27ME3 ENRICHMENTS ON GENE PROMOTERS IN MICROGLIA FOLLOWING CGRP TREATMENT, INCLUDING 173 GAINING H3K27ME3 AND 75 LOSING THIS MARK, WHICH MOSTLY ENRICHED IN REGULATION OF CELL GROWTH, PHAGOSOME, AND INFLAMMATION. QRT-PCR VERIFIED EXPRESSIONS OF REPRESENTATIVE CANDIDATE GENES (TRAF3IP2, BCL2L11, ITGAM, DAB2, NLRP12, WNT3, ADAM10) AND REAL-TIME CELL ANALYSIS (RTCA) VERIFIED MICROGLIAL PROLIFERATION. ADDITIONALLY, CGRP TREATMENT AND CCI INCREASED EXPRESSIONS OF ITGAM, ADAM10, MCP-1, AND CX3CR1, KEY MEDIATORS OF MICROGLIAL ACTIVATION IN SPINAL DORSAL HORN AND CULTURED MICROGLIAL CELLS. SUCH INCREASED EFFECTS INDUCED BY CCI WERE SUPPRESSED BY CGRP ANTAGONIST AND EZH2 INHIBITOR, WHICH WERE CONCURRENTLY ASSOCIATED WITH THE ATTENUATED MECHANICAL AND THERMAL HYPERALGESIA IN CCI RATS. CONCLUSION: OUR FINDINGS HIGHLY INDICATE THAT CGRP IS IMPLICATED IN THE GENESIS OF NEUROPATHIC PAIN THROUGH REGULATING MICROGLIAL ACTIVATION VIA EZH2-MEDIATED H3K27ME3 IN THE SPINAL DORSAL HORN. 2021 4 63 40 A HIGH METHYLATION LEVEL OF A NOVEL -284 BP CPG ISLAND IN THE RAMP1 GENE PROMOTER IS POTENTIALLY ASSOCIATED WITH MIGRAINE IN WOMEN. MIGRAINE IS A COMPLEX NEUROVASCULAR DISORDER AFFECTING ONE BILLION PEOPLE WORLDWIDE, MAINLY FEMALES. IT IS CHARACTERIZED BY ATTACKS OF MODERATE TO SEVERE HEADACHE PAIN, WITH ASSOCIATED SYMPTOMS. RECEPTOR ACTIVITY MODIFYING PROTEIN (RAMP1) IS PART OF THE CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR, A PHARMACOLOGICAL TARGET FOR MIGRAINE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION, PLAY A ROLE IN CLINICAL PRESENTATION OF VARIOUS DISEASES. DNA METHYLATION OCCURS MOSTLY IN THE GENE PROMOTER AND CAN CONTROL GENE EXPRESSION. WE INVESTIGATED THE METHYLATION STATE OF THE RAMP1 PROMOTER IN 104 FEMALE BLOOD DNA SAMPLES: 54 MIGRAINEURS AND 50 CONTROLS. WE TREATED DNA WITH SODIUM BISULFITE AND PERFORMED PCR, SANGER SEQUENCING, AND EPIGENETIC SEQUENCING METHYLATION (ESME) SOFTWARE ANALYSIS. WE IDENTIFIED 51 CPG DINUCLEOTIDES, AND 5 SHOWED METHYLATION VARIABILITY. MIGRAINEURS HAD A HIGHER NUMBER OF INDIVIDUALS WITH ALL FIVE CPG METHYLATED WHEN COMPARED TO CONTROLS (26% VS. 16%), ALTHOUGH NON-SIGNIFICANT (P = 0.216). WE ALSO FOUND THAT CPG -284 BP, RELATED TO THE TRANSCRIPTION START SITE (TSS), SHOWED HIGHER METHYLATION LEVELS IN CASES (P = 0.011). THIS CPG MAY POTENTIALLY PLAY A ROLE IN MIGRAINE, AFFECTING RAMP1 TRANSCRIPTION OR RECEPTOR MALFUNCTIONING AND/OR ALTERED CGRP BINDING. WE HOPE TO CONFIRM THIS FINDING IN A LARGER COHORT AND ESTABLISH AN EPIGENETIC BIOMARKER TO PREDICT FEMALE MIGRAINE RISK. 2022 5 3334 33 HISTONE DEACETYLASE INHIBITORS COUNTERACT CGRP SIGNALING AND PRONOCICEPTIVE SENSITIZATION IN A RAT MODEL OF MEDICATION OVERUSE HEADACHE. CHRONIC TRIPTAN EXPOSURE IN RODENTS RECAPITULATES MEDICATION OVERUSE HEADACHE (MOH), CAUSING CEPHALIC PAIN SENSITIZATION AND TRIGEMINAL GANGLION OVEREXPRESSION OF PRONOCICEPTIVE PROTEINS INCLUDING CGRP. BECAUSE OF THESE TRANSCRIPTIONAL DERANGEMENTS, AS WELL AS THE EMERGING ROLE OF EPIGENETICS IN CHRONIC PAIN, IN THE PRESENT STUDY, WE EVALUATED THE EFFECTS OF THE HISTONE DEACETYLASE INHIBITORS (HDACIS) PANOBINOSTAT AND GIVINOSTAT, IN RATS CHRONICALLY EXPOSED TO ELETRIPTAN FOR 1 MONTH. BOTH PANOBINOSTAT AND GIVINOSTAT COUNTERACTED OVEREXPRESSION OF GENES CODING FOR CGRP AND ITS RECEPTOR SUBUNIT RAMP1, HAVING NO EFFECTS ON CLR AND RCP RECEPTOR SUBUNITS IN THE TRIGEMINAL GANGLION (TG) OF ELETRIPTAN-EXPOSED RATS. WITHIN THE TRIGEMINAL NUCLEUS CAUDALIS (TNC), TRANSCRIPTS FOR THESE GENES WERE NEITHER UPREGULATED BY ELETRIPTAN NOR ALTERED BY CONCOMITANT TREATMENT WITH PANOBINOSTAT OR GIVINOSTAT. HDACIS COUNTERACTED HYPERSENSITIVITY TO CAPSAICIN-INDUCED VASODILATATION IN THE TRIGEMINAL TERRITORY, AS WELL AS PHOTOPHOBIC BEHAVIOR AND CEPHALIC ALLODYNIAIN ELETRIPTAN-EXPOSED RATS. ELETRIPTAN DID NOT AFFECT CGRP, CLR, AND RAMP1 EXPRESSION IN CULTURED TRIGEMINAL GANGLIA, WHEREAS BOTH INHIBITORS REDUCED TRANSCRIPTS FOR CLR AND RAMP-1. THE DRUGS, HOWEVER, INCREASED LUCIFERASE EXPRESSION DRIVEN BY CGRP PROMOTER IN CULTURED CELLS. OUR FINDINGS PROVIDE EVIDENCE FOR A KEY ROLE OF HDACS AND EPIGENETICS IN MOH PATHOGENESIS, HIGHLIGHTING THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE PREVENTION OF MIGRAINE CHRONIFICATION. PERSPECTIVE: THE PRESENT STUDY HIGHLIGHTS A KEY EPIGENETIC ROLE OF HDAC IN THE RODENT MODEL OF MEDICATION OVERUSE HEADACHE, FURTHERING OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS RESPONSIBLE FOR PRONOCICEPTIVE SENSITIZATION DURING HEADACHE CHRONIFICATION. 2022 6 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 7 1637 36 DOES DYSREGULATION OF KEY EPIGENETIC AND BIOCHEMICAL PATHWAYS OCCUR IN POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE DISORDERS? AUTOIMMUNE DYSFUNCTION OF CERTAIN VASOACTIVE NEUROPEPTIDES (VNS) HAS BEEN POSTULATED AS A CONTRIBUTING CAUSE OF SUDDEN INFANT DEATH SYNDROME (SIDS), CHRONIC FATIGUE SYNDROME (CFS), GULF WAR SYNDROME (GWS) AND OTHER FATIGUE-RELATED DISORDERS. THIS FAMILY OF VNS INCLUDES PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP), VASOACTIVE INTESTINAL PEPTIDE (VIP) AND CALCITONIN GENE RELATED PEPTIDE (CGRP). THE POSTULATED MECHANISM IS COMPROMISE OF ADENYLATE CYCLASE ACTIVATION, A VITAL AND UNIQUE STEP IN CYCLIC AMP PRODUCTION FROM ATP, THROUGH AUTOIMMUNE DYSFUNCTION OF VNS, THEIR RECEPTORS OR THEIR GENES POSSIBLY INVOLVING CYTOSINE-PHOSPHATE-GUANINE (CPG) FRAGMENTS. CPG FRAGMENTS ARE IMMUNOMODULATORY DINUCLEOTIDES SERVING AS 'FRIEND OR FOE' RECOGNITION SYSTEMS TO DIFFERENTIATE BACTERIAL AND VIRAL (HYPOMETHYLATED CPG) FROM MAMMALIAN (METHYLATED CPG) DNA. HOWEVER HYPOMETHYLATION DISORDERS AFFECTING THESE FRAGMENTS IN MAMMALS MAY CONVERT THEM TO DYSFUNCTIONAL STATES BY PROMOTING AUTOIMMUNE INFLAMMATORY REACTIONS. EPIGENETIC MECHANISMS ACTING ON GENE PROMOTER REGIONS MAY CONTRIBUTE TO THE DEVELOPMENT OF VN AUTOIMMUNE FATIGUE-RELATED DISORDERS THROUGH CPG FRAGMENTS LOCATED IN VITAL SEGMENTS OF VN/RECEPTOR GENES BY CAUSING SIGNALLING DEFECTS WITH PROFOUND IMPLICATIONS FOR VN FUNCTION. NEUROTRANSMITTER DYSFUNCTION PARTICULARLY GLUTAMATERGIC TRANSMISSION COULD ALSO RESULT WITH DISRUPTION OF NEURONAL CELLULAR BIOCHEMICAL FUNCTIONS SUCH AS AMMONIA REGULATION. ENDOSOMAL ACIDITY AND MITOCHONDRIAL MEMBRANE POTENTIAL MODIFIERS SUCH AS CHLOROQUINE, TOGETHER WITH IMMUNOREGULATORY THERAPIES, MAY HAVE THERAPEUTIC IMPLICATIONS IN PROTECTING AGAINST THESE APPARENT AUTOIMMUNE DISORDERS. THIS PAPER EXAMINES SPECIFIC EPIGENETIC AND BIOCHEMICAL MECHANISMS POSSIBLY MEDIATED BY VN OR RECEPTOR GENES RESULTING IN POSTULATED VN AUTOIMMUNE FATIGUE-RELATED DISORDERS. THESE MECHANISMS MAY HAVE IMPLICATIONS FOR TREATMENT AND PREVENTION OPTIONS FOR VN AUTOIMMUNE DISORDERS. VN AUTOIMMUNE PROCESSES HAVE IMPLICATIONS FOR MILITARY MEDICINE WHERE RADIOLOGICAL, CHEMICAL AND BIOLOGICAL AGENTS MAY PLAY AN IMPORTANT ROLE IN PATHOGENESIS. 2005 8 6323 33 THE ROLE OF A POTENTIAL BIOMARKER IN PATIENTS WITH MIGRAINE: REVIEW AND NEW INSIGHTS. INTRODUCTION: THE SEARCH FOR AN IDEAL BIOMARKER FOR MIGRAINE HAS PERSISTED FOR A LONG TIME. THERE IS PLENTIFUL EVIDENCE OF POTENTIAL BIOMARKERS FOR MIGRAINE FOUND IN CEREBROSPINAL FLUID, BLOOD, AND SALIVA.AREAS COVERED: HEREIN, THE AUTHORS HIGHLIGHT AND DISCUSS THE MOST PROMISING CANDIDATES IN THE LITERATURE. AN ELECTRONIC SEARCH WAS PERFORMED FOR STUDIES PUBLISHED BETWEEN 2010 AND 2020 IN MEDLINE, PUBMED, AND EMBASE, RELATED TO POTENTIAL BIOMARKERS IN MIGRAINE PATIENTS, FOUND IN CEREBROSPINAL FLUID, SALIVA, AND SERUM, FOCUSING ON BIOMARKERS THAT CAN BE RELATED TO TREATMENT AND CLINICAL OUTCOMES.EXPERT OPINION: AN IDEAL BIOMARKER, OR A PANEL OF BIOMARKERS, COULD REVOLUTIONIZE THE WAY WE ADDRESS AND PROPOSE TREATMENTS FOR THIS DISEASE. ONCE SEVERE PRESENTATIONS AND PHENOTYPES HAVE BEEN IDENTIFIED USING A RELIABLE BIOMARKER, PATIENTS COULD BE TREATED AT EARLIER DISEASE STAGES WITH MORE SPECIFIC MEDICATIONS. THE MOST IMPORTANT BIOMARKERS WITH THE MOST SIGNIFICANT LEVELS OF EVIDENCE COMPRISED CALCITONIN GENE-RELATED PEPTIDE (CGRP), GLUTAMATE, NERVE GROWTH FACTOR, SOME INFLAMMATORY (CRP, TNF-ALPHA, INTERLEUKINS) AND OXIDATIVE STRESS MARKERS. CGRP WAS ASSOCIATED WITH EPISODIC, CHRONIC MIGRAINE AND RESPONSE TO TREATMENT. PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE IS AN EMERGING NEUROPEPTIDE INVOLVED IN MIGRAINE DIAGNOSTICS AND SEVERITY. NEW GENETIC AND EPIGENETIC BIOMARKERS WILL BE CANDIDATES FOR FUTURE RESEARCH. 2021 9 2321 23 EPIGENETIC REGULATION OF GENES THAT MODULATE CHRONIC STRESS-INDUCED VISCERAL PAIN IN THE PERIPHERAL NERVOUS SYSTEM. BACKGROUND & AIMS: CHRONIC STRESS ALTERS THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, INCREASES GUT MOTILITY, AND INCREASES THE PERCEPTION OF VISCERAL PAIN. WE INVESTIGATED WHETHER EPIGENETIC MECHANISMS REGULATE CHRONIC STRESS-INDUCED VISCERAL PAIN IN THE PERIPHERAL NERVOUS SYSTEMS OF RATS. METHODS: MALE RATS WERE SUBJECTED TO 1 HOUR OF WATER AVOIDANCE STRESS EACH DAY, OR GIVEN DAILY SUBCUTANEOUS INJECTIONS OF CORTICOSTERONE, FOR 10 CONSECUTIVE DAYS. L4-L5 AND L6-S2 DORSAL ROOT GANGLIA (DRG) WERE COLLECTED AND COMPARED BETWEEN STRESSED AND CONTROL RATS (PLACED FOR 1 HOUR EACH DAY IN A TANK WITHOUT WATER). LEVELS OF CANNABINOID RECEPTOR 1 (CNR1), DNA (CYTOSINE-5-)-METHYLTRANSFERASE 1 (DNMT1), TRANSIENT RECEPTOR POTENTIAL VANILLOID TYPE 1 (TRPV1), AND EP300 WERE KNOCKED DOWN IN DRG NEURONS IN SITU WITH SMALL INTERFERING RNAS. WE MEASURED DNA METHYLATION AND HISTONE ACETYLATION AT GENES ENCODING THE GLUCOCORTICOID RECEPTOR (NR3C1), CNR1, AND TRPV1. VISCERAL PAIN WAS MEASURED IN RESPONSE TO COLORECTAL DISTENTION. RESULTS: CHRONIC STRESS WAS ASSOCIATED WITH INCREASED METHYLATION OF THE NR3C1 PROMOTER AND REDUCED EXPRESSION OF THIS GENE IN L6-S2, BUT NOT L4-L5, DRGS. STRESS ALSO WAS ASSOCIATED WITH UP-REGULATION IN DNMT1-ASSOCIATED METHYLATION OF THE CNR1 PROMOTER AND DOWN-REGULATION OF GLUCOCORTICOID-RECEPTOR-MEDIATED EXPRESSION OF CNR1 IN L6-S2, BUT NOT L4-L5, DRGS. CONCURRENTLY, CHRONIC STRESS INCREASED EXPRESSION OF THE HISTONE ACETYLTRANSFERASE EP300 AND INCREASED HISTONE ACETYLATION AT THE TRPV1 PROMOTER AND EXPRESSION OF THE TRPV1 RECEPTOR IN L6-S2 DRG NEURONS. KNOCKDOWN OF DNMT1 AND EP300 IN L6-S2 DRG NEURONS OF RATS REDUCED DNA METHYLATION AND HISTONE ACETYLATION, RESPECTIVELY, AND PREVENTED CHRONIC STRESS-INDUCED INCREASES IN VISCERAL PAIN. CONCLUSIONS: CHRONIC STRESS INCREASES DNA METHYLATION AND HISTONE ACETYLATION OF GENES THAT REGULATE VISCERAL PAIN SENSATION IN THE PERIPHERAL NERVOUS SYSTEM OF RATS. BLOCKING EPIGENETIC REGULATORY PATHWAYS IN SPECIFIC REGIONS OF THE SPINAL CORD MIGHT BE DEVELOPED TO TREAT PATIENTS WITH CHRONIC ABDOMINAL PAIN. 2015 10 3201 36 HDAC2 IN PRIMARY SENSORY NEURONS CONSTITUTIVELY RESTRAINS CHRONIC PAIN BY REPRESSING ALPHA2DELTA-1 EXPRESSION AND ASSOCIATED NMDA RECEPTOR ACTIVITY. ALPHA2DELTA-1 (ENCODED BY THE CACNA2D1 GENE) IS A NEWLY DISCOVERED NMDA RECEPTOR-INTERACTING PROTEIN AND IS THE THERAPEUTIC TARGET OF GABAPENTINOIDS (E.G., GABAPENTIN AND PREGABALIN) FREQUENTLY USED FOR TREATING PATIENTS WITH NEUROPATHIC PAIN. NERVE INJURY CAUSES SUSTAINED ALPHA2DELTA-1 UPREGULATION IN THE DORSAL ROOT GANGLION (DRG), WHICH PROMOTES NMDA RECEPTOR SYNAPTIC TRAFFICKING AND ACTIVATION IN THE SPINAL DORSAL HORN, A HALLMARK OF CHRONIC NEUROPATHIC PAIN. HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY INITIATES AND MAINTAINS THE HIGH EXPRESSION LEVEL OF ALPHA2DELTA-1 TO SUSTAIN CHRONIC PAIN. HERE, WE SHOW THAT NERVE INJURY CAUSED HISTONE HYPERACETYLATION AND DIMINISHED ENRICHMENT OF HISTONE DEACETYLASE-2 (HDAC2), BUT NOT HDAC3, AT THE CACNA2D1 PROMOTER IN THE DRG. STRIKINGLY, HDAC2 KNOCKDOWN OR CONDITIONAL KNOCKOUT IN DRG NEURONS IN MALE AND FEMALE MICE CONSISTENTLY INDUCED LONG-LASTING MECHANICAL PAIN HYPERSENSITIVITY, WHICH WAS READILY REVERSED BY BLOCKING NMDA RECEPTORS, INHIBITING ALPHA2DELTA-1 WITH GABAPENTIN OR DISRUPTING THE ALPHA2DELTA-1-NMDA RECEPTOR INTERACTION AT THE SPINAL CORD LEVEL. HDAC2 DELETION IN DRG NEURONS INCREASED HISTONE ACETYLATION LEVELS AT THE CACNA2D1 PROMOTER, UPREGULATED ALPHA2DELTA-1 IN THE DRG, AND POTENTIATED ALPHA2DELTA-1-DEPENDENT NMDA RECEPTOR ACTIVITY AT PRIMARY AFFERENT CENTRAL TERMINALS IN THE SPINAL DORSAL HORN. CORRESPONDINGLY, HDAC2 KNOCKDOWN-INDUCED PAIN HYPERSENSITIVITY WAS BLUNTED IN CACNA2D1 KNOCKOUT MICE. THUS, OUR FINDINGS REVEAL THAT HDAC2 FUNCTIONS AS A PIVOTAL TRANSCRIPTIONAL REPRESSOR OF NEUROPATHIC PAIN VIA CONSTITUTIVELY SUPPRESSING ALPHA2DELTA-1 EXPRESSION AND ENSUING PRESYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD. HDAC2 ENRICHMENT LEVELS AT THE CACNA2D1 PROMOTER IN DRG NEURONS CONSTITUTE A UNIQUE EPIGENETIC MECHANISM THAT GOVERNS ACUTE-TO-CHRONIC PAIN TRANSITION.SIGNIFICANCE STATEMENT EXCESS ALPHA2DELTA-1 PROTEINS PRODUCED AFTER NERVE INJURY DIRECTLY INTERACT WITH GLUTAMATE NMDA RECEPTORS TO POTENTIATE SYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD, A PROMINENT MECHANISM OF NERVE PAIN. BECAUSE ALPHA2DELTA-1 UPREGULATION AFTER NERVE INJURY IS LONG LASTING, GABAPENTINOIDS RELIEVE PAIN SYMPTOMS ONLY TEMPORARILY. OUR STUDY DEMONSTRATES FOR THE FIRST TIME THE UNEXPECTED ROLE OF INTRINSIC HDAC2 ACTIVITY AT THE ALPHA2DELTA-1 GENE PROMOTER IN LIMITING ALPHA2DELTA-1 GENE TRANSCRIPTION, NMDA RECEPTOR-DEPENDENT SYNAPTIC PLASTICITY, AND CHRONIC PAIN DEVELOPMENT AFTER NERVE INJURY. THESE FINDINGS CHALLENGE THE PREVAILING VIEW ABOUT THE ROLE OF GENERAL HDAC ACTIVITY IN PROMOTING CHRONIC PAIN. RESTORING THE REPRESSIVE HDAC2 FUNCTION AND/OR REDUCING HISTONE ACETYLATION AT THE ALPHA2DELTA-1 GENE PROMOTER IN PRIMARY SENSORY NEURONS COULD LEAD TO LONG-LASTING RELIEF OF NERVE PAIN. 2022 11 3869 25 JNK1 REGULATES HISTONE ACETYLATION IN TRIGEMINAL NEURONS FOLLOWING CHEMICAL STIMULATION. TRIGEMINAL NERVE FIBERS IN NASAL AND ORAL CAVITIES ARE SENSITIVE TO VARIOUS ENVIRONMENTAL HAZARDOUS STIMULI, WHICH TRIGGER MANY NEUROTOXIC PROBLEMS SUCH AS CHRONIC MIGRAINE HEADACHE AND TRIGEMINAL IRRITATED DISORDERS. HOWEVER, THE ROLE OF JNK KINASE CASCADE AND ITS EPIGENETIC MODULATION OF HISTONE REMODELING IN TRIGEMINAL GANGLION (TG) NEURONS ACTIVATED BY ENVIRONMENTAL NEUROTOXINS REMAINS UNKNOWN. HERE WE INVESTIGATED THE ROLE OF JNK/C-JUN CASCADE IN THE REGULATION OF ACETYLATION OF H3 HISTONE IN TG NEURONS FOLLOWING IN VITRO STIMULATION BY A NEURO-INFLAMMATORY AGENT, MUSTARD OIL (MO). WE FOUND THAT MO STIMULATION ELICITED JNK/C-JUN PATHWAY SIGNIFICANTLY BY ENHANCING PHOSPHO-JNK1, PHOSPHO-C-JUN EXPRESSION, AND C-JUN ACTIVITY, WHICH WERE CORRELATED WITH AN ELEVATED ACETYLATED H3 HISTONE IN TG NEURONS. HOWEVER, INCREASES IN PHOSPHO-C-JUN AND C-JUN ACTIVITY WERE SIGNIFICANTLY BLOCKED BY A JNK INHIBITOR, SP600125. WE ALSO FOUND THAT ALTERED H3 HISTONE REMODELING, ASSESSED BY H3 ACETYLATION IN TRIGGERED TG NEURONS, WAS REDUCED BY SP600125. THE STUDY SUGGESTS THAT THE ACTIVATED JNK SIGNALING IN REGULATION OF HISTONE REMODELING MAY CONTRIBUTE TO NEURO-EPIGENTIC CHANGES IN PERIPHERAL SENSORY NEURONS FOLLOWING ENVIRONMENTAL NEUROTOXIC EXPOSURE. 2008 12 742 26 CANNABINOID CB2 RECEPTORS ARE UPREGULATED VIA BIVALENT HISTONE MODIFICATIONS AND CONTROL PRIMARY AFFERENT INPUT TO THE SPINAL CORD IN NEUROPATHIC PAIN. TYPE-2 CANNABINOID RECEPTORS (CB2, ENCODED BY THE CNR2 GENE) ARE MAINLY EXPRESSED IN IMMUNE CELLS, AND CB2 AGONISTS NORMALLY HAVE NO ANALGESIC EFFECT. HOWEVER, NERVE INJURY UPREGULATES CB2 IN THE DORSAL ROOT GANGLION (DRG), FOLLOWING WHICH CB2 STIMULATION REDUCES NEUROPATHIC PAIN. IT IS UNCLEAR HOW NERVE INJURY INCREASES CB2 EXPRESSION OR HOW CB2 ACTIVITY IS TRANSFORMED IN NEUROPATHIC PAIN. IN THIS STUDY, IMMUNOBLOTTING SHOWED THAT SPINAL NERVE LIGATION (SNL) INDUCED A DELAYED AND SUSTAINED INCREASE IN CB2 EXPRESSION IN THE DRG AND DORSAL SPINAL CORD SYNAPTOSOMES. RNASCOPE IN SITU HYBRIDIZATION ALSO SHOWED THAT SNL SUBSTANTIALLY INCREASED CB2 MRNA LEVELS, MOSTLY IN MEDIUM AND LARGE DRG NEURONS. FURTHERMORE, WE FOUND THAT THE SPECIFIC CB2 AGONIST JWH-133 SIGNIFICANTLY INHIBITS THE AMPLITUDE OF DORSAL ROOT-EVOKED GLUTAMATERGIC EXCITATORY POSTSYNAPTIC CURRENTS IN SPINAL DORSAL HORN NEURONS IN SNL RATS, BUT NOT IN SHAM CONTROL RATS; INTRATHECAL INJECTION OF JWH-133 REVERSED PAIN HYPERSENSITIVITY IN SNL RATS, BUT HAD NO EFFECT IN SHAM CONTROL RATS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION-QPCR ANALYSIS SHOWED THAT SNL INCREASED ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME3 AND H3K9AC) AND DIMINISHED OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AT THE CNR2 PROMOTER IN THE DRG. IN CONTRAST, SNL HAD NO EFFECT ON DNA METHYLATION LEVELS AROUND THE CNR2 PROMOTER. OUR FINDINGS SUGGEST THAT PERIPHERAL NERVE INJURY PROMOTES CB2 EXPRESSION IN PRIMARY SENSORY NEURONS VIA EPIGENETIC BIVALENT HISTONE MODIFICATIONS AND THAT CB2 ACTIVATION REDUCES NEUROPATHIC PAIN BY ATTENUATING NOCICEPTIVE TRANSMISSION FROM PRIMARY AFFERENT NERVES TO THE SPINAL CORD. 2022 13 638 44 BIOMARKERS ASSOCIATED WITH MIGRAINE AND THEIR POTENTIAL ROLE IN MIGRAINE MANAGEMENT. OBJECTIVE: THE FOCUS OF THIS REVIEW IS TO REVIEW POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKERS ASSOCIATED WITH MIGRAINE. BACKGROUND: MIGRAINE HEADACHE IS A COMMON DISEASE THAT AFFECTS MILLIONS OF INDIVIDUALS WORLDWIDE. ALTHOUGH WELL-ACCEPTED DIAGNOSTIC CRITERIA EXIST FOR MIGRAINE, IT IS STILL A COMPLEX DISORDER THAT REMAINS BOTH UNDERDIAGNOSED AND MISDIAGNOSED. THE CAUSES OF MIGRAINE ARE LIKELY A MIX OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT, TOGETHER WITH THE INDIVIDUAL'S LIFE HISTORY, TRANSLATE INTO THE OBSERVED CLINICAL HETEROGENEITY. INHERENT CLINICAL HETEROGENEITY IS AN OBSTACLE IN DEVELOPING MORE EFFECTIVE TREATMENTS. THE LACK OF APPROPRIATE BIOMARKERS IS ALSO AN IMPEDIMENT TO DEVELOPING MORE EFFECTIVE THERAPEUTIC/PREVENTIVE APPROACHES. ULTIMATELY, BIOMARKERS MAY FACILITATE THE GOAL OF INDIVIDUALIZED MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER TYPES OF HEADACHE. METHODS: A COMPREHENSIVE REVIEW WAS CONDUCTED OF PUBMED CITATIONS CONTAINING THE KEY WORD "MARKER" OR "BIOMARKER" COMBINED WITH "MIGRAINE" OR "HEADACHE." OTHER KEY WORDS INCLUDED "SERUM," "SALIVA," "CEREBROSPINAL FLUID," "GENES," "BLOOD," AND "INFLAMMATION." THE ONLY RESTRICTION WAS ENGLISH-LANGUAGE PUBLICATION. THE ABSTRACTS OF ALL ARTICLES MEETING THESE CRITERIA WERE REVIEWED, AND FULL TEXT WAS RETRIEVED AND EXAMINED FOR RELEVANT REFERENCES. RESULTS: DATA FROM HUMAN STUDIES HAVE BEGUN TO IDENTIFY GENETIC MUTATIONS/POLYMORPHISMS AND ALTERED LEVELS OF SPECIFIC PROINFLAMMATORY AND NEUROMODULATORY MOLECULES THAT STRONGLY CORRELATE WITH MIGRAINE AS WELL AS SYMPTOM SEVERITY. RESULTS FROM A SMALLER NUMBER OF STUDIES HAVE IDENTIFIED PARAMETERS, SUCH AS THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP), WHICH ARE SIGNIFICANTLY ASSOCIATED WITH RESPONSE TO SPECIFIC TREATMENTS FOR ACUTE MIGRAINE ATTACKS AND PROPHYLAXIS. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MIGRAINE, AND UNDERSTANDING ENVIRONMENTALLY INDUCED GENETIC CHANGES ASSOCIATED WITH THIS DISEASE MAY EVENTUALLY GUIDE THE DEVELOPMENT OF THERAPIES CAPABLE OF REVERSING THESE PATHOPHYSIOLOGICAL CHANGES IN GENE FUNCTION. CONCLUSIONS: THE UNDERSTANDING OF THE ETIOLOGY OF MIGRAINE IS INCOMPLETE. ALTHOUGH THE IDENTIFICATION AND VALIDATION OF BIOMARKERS HAS GREATLY ADVANCED DIAGNOSTIC PRECISION AND MEASURES OF THERAPEUTIC EFFICACY IN OTHER DISEASES, THERE ARE NO CURRENTLY ACCEPTED BIOMARKERS FOR CHRONIC OR EPISODIC MIGRAINE. HOWEVER, THE CONTINUED INVESTIGATION AND IDENTIFICATION OF GENETIC, EPIGENETIC, AND MOLECULAR BIOMARKERS IS LIKELY TO FACILITATE THE GOAL OF INDIVIDUALIZING MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER HEADACHE DISORDERS. 2013 14 6916 29 [WHAT IS MIGRAINE?]. MIGRAINE IS A MULTIFACTORIAL AND HETEROGENEOUS DISORDER. DIAGNOSTIC CRITERIA HAVE BEEN ESTABLISHED BY THE INTERNATIONAL HEADACHE SOCIETY, HOWEVER THESE ARE ONLY SUPPORTIVE IN TERMS OF DEFINITION. THE PATHOPHYSIOLOGY INVOLVES NEURONAL AND VASCULAR PHENOMENA. THE FORMER IS SUPPORTED BY THE CORTICAL SPREADING DEPRESSION BEING THE AURA CORRELATE AND BY BRAINSTEM AND HYPOTHALAMIC ACTIVATION DURING THE PAIN PHASE; THE LATTER IS SUGGESTED BY THE ASSOCIATION BETWEEN MIGRAINE AND CARDIOVASCULAR DISEASE AND FINDINGS OF PATHOLOGICAL VASOREACTIVITY AND ENDOTHELIAL DYSFUNCTION. TRIPTANS AND CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONISTS SHOW ONLY A RELATIVE MIGRAINE-SPECIFIC ACTION; UP TO 30% OF PATIENTS ARE NONRESPONDERS. DESPITE A CLEAR GENETIC COMPONENT, THE DISCOVERY OF SPECIFIC GENES FOR COMMON FORMS OF MIGRAINE REMAINS ELUSIVE. ELECTROPHYSIOLOGICAL STUDIES CONSISTENTLY INDICATE A CHARACTERISTIC "DYSHABITUATION" CONCURRING WITH CLINICAL FEATURES OF ALTERED SENSORY PERCEPTION. THE AGE- AND SEX-SPECIFIC PATTERN ALONG WITH THE EFFECT OF EXTERNAL FACTORS ON THE COURSE OF MIGRAINE ARGUE IN FAVOR OF THE INVOLVEMENT OF EPIGENETIC MECHANISMS. KNOWLEDGE ABOUT MIGRAINE IS STILL LIMITED, WHICH HAMPERS A DEFINITION. 2009 15 4366 29 MIRNA-23A/CXCR4 REGULATES NEUROPATHIC PAIN VIA DIRECTLY TARGETING TXNIP/NLRP3 INFLAMMASOME AXIS. BACKGROUND: CHEMOKINE CXC RECEPTOR 4 (CXCR4) IN SPINAL GLIAL CELLS HAS BEEN IMPLICATED IN NEUROPATHIC PAIN. HOWEVER, THE REGULATORY CASCADES OF CXCR4 IN NEUROPATHIC PAIN REMAIN ELUSIVE. HERE, WE INVESTIGATED THE FUNCTIONAL REGULATORY ROLE OF MIRNAS IN THE PAIN PROCESS AND ITS INTERPLAY WITH CXCR4 AND ITS DOWNSTREAM SIGNALING. METHODS: MIRNAS AND CXCR4 AND ITS DOWNSTREAM SIGNALING MOLECULES WERE MEASURED IN THE SPINAL CORDS OF MICE WITH SCIATIC NERVE INJURY VIA PARTIAL SCIATIC NERVE LIGATION (PSNL). IMMUNOBLOTTING, IMMUNOFLUORESCENCE, IMMUNOPRECIPITATION, AND MAMMAL TWO-HYBRID AND BEHAVIORAL TESTS WERE USED TO EXPLORE THE DOWNSTREAM CXCR4-DEPENDENT SIGNALING PATHWAY. RESULTS: CXCR4 EXPRESSION INCREASED IN SPINAL GLIAL CELLS OF MICE WITH PSNL-INDUCED NEUROPATHIC PAIN. BLOCKING CXCR4 ALLEVIATED THE PAIN BEHAVIOR; CONTRARILY, OVEREXPRESSING CXCR4 INDUCED PAIN HYPERSENSITIVITY. MICRORNA-23A-3P (MIR-23A) DIRECTLY BOUNDS TO 3' UTR OF CXCR4 MRNA. PSNL-INDUCED NEUROPATHIC PAIN SIGNIFICANTLY REDUCED MRNA EXPRESSION OF MIR-23A. OVEREXPRESSION OF MIR-23A BY INTRATHECAL INJECTION OF MIR-23A MIMICS OR LENTIVIRUS REDUCED SPINAL CXCR4 AND PREVENTED PSNL-INDUCED NEUROPATHIC PAIN. IN CONTRAST, KNOCKDOWN OF MIR-23A BY INTRATHECAL INJECTION OF MIR-23A INHIBITOR OR LENTIVIRUS INDUCED PAIN-LIKE BEHAVIOR, WHICH WAS REDUCED BY CXCR4 INHIBITION. ADDITIONALLY, MIR-23A KNOCKDOWN OR CXCR4 OVEREXPRESSION IN NAIVE MICE COULD INCREASE THE THIOREDOXIN-INTERACTING PROTEIN (TXNIP), WHICH WAS ASSOCIATED WITH INDUCTION OF NOD-LIKE RECEPTOR PROTEIN 3 (NLRP3) INFLAMMASOME. INDEED, CXCR4 AND TXNIP WERE CO-EXPRESSED. THE MAMMAL TWO-HYBRID ASSAY REVEALED THE DIRECT INTERACTION BETWEEN CXCR4 AND TXNIP, WHICH WAS INCREASED IN THE SPINAL CORD OF PSNL MICE. IN PARTICULAR, INHIBITION OF TXNIP REVERSED PAIN BEHAVIOR ELICITED BY PSNL, MIR-23A KNOCKDOWN, OR CXCR4 OVEREXPRESSION. MOREOVER, MIR-23A OVEREXPRESSION OR CXCR4 KNOCKDOWN INHIBITED THE INCREASE OF TXNIP AND NLRP3 INFLAMMASOME IN PSNL MICE. CONCLUSIONS: MIR-23A, BY DIRECTLY TARGETING CXCR4, REGULATES NEUROPATHIC PAIN VIA TXNIP/NLRP3 INFLAMMASOME AXIS IN SPINAL GLIAL CELLS. EPIGENETIC INTERVENTIONS AGAINST MIR-23A, CXCR4, OR TXNIP MAY POTENTIALLY SERVE AS NOVEL THERAPEUTIC AVENUES IN TREATING PERIPHERAL NERVE INJURY-INDUCED NOCICEPTIVE HYPERSENSITIVITY. 2018 16 4160 29 MECP2 EPIGENETIC SILENCING OF OPRM1 GENE IN PRIMARY SENSORY NEURONS UNDER NEUROPATHIC PAIN CONDITIONS. OPIOIDS ARE THE LAST OPTION FOR THE PHARMACOLOGICAL TREATMENT OF NEUROPATHIC PAIN, BUT THEIR ANTINOCICEPTIVE EFFECTS ARE LIMITED. DECREASED MU OPIOID RECEPTOR (MOR) EXPRESSION IN THE PERIPHERAL NERVOUS SYSTEM MAY CONTRIBUTE TO THIS. HERE, WE SHOWED THAT NERVE INJURY INDUCED HYPERMETHYLATION OF THE OPRM1 GENE PROMOTER AND AN INCREASED EXPRESSION OF METHYL-CPG BINDING PROTEIN 2 (MECP2) IN INJURED DORSAL ROOT GANGLION (DRG). THE DOWNREGULATION OF MOR IN THE DRG IS CLOSELY RELATED TO THE AUGMENTATION OF MECP2, AN EPIGENETIC REPRESSOR, WHICH COULD RECRUIT HDAC1 AND BIND TO THE METHYLATED REGIONS OF THE OPRM1 GENE PROMOTER. MECP2 KNOCKDOWN RESTORED THE EXPRESSION OF MOR IN INJURED DRG AND ENHANCED THE ANALGESIC EFFECT OF MORPHINE, WHILE THE MIMICKING OF THIS INCREASE VIA THE INTRATHECAL INFUSION OF VIRAL VECTOR-MEDIATED MECP2 WAS SUFFICIENT TO REDUCE MOR IN THE DRG. MOREOVER, HDAC1 INHIBITION WITH SUBEROYLANILIDE HYDROXAMIC ACID, AN HDAC INHIBITOR, ALSO PREVENTED MOR REDUCTION IN THE DRG OF NEUROPATHIC PAIN MICE, CONTRIBUTING TO THE AUGMENTATION OF MORPHINE ANALGESIA EFFECTS. MECHANISTICALLY, UPREGULATED MECP2 PROMOTES THE BINDING OF A HIGH LEVEL OF HDCA1 TO HYPERMETHYLATED REGIONS OF THE OPRM1 GENE PROMOTER, REDUCES THE ACETYLATION OF HISTONE H3 (ACH3) LEVELS OF THE OPRM1 GENE PROMOTER, AND ATTENUATES OPRM1 TRANSCRIPTION IN INJURED DRG. THUS, UPREGULATED MECP2 AND HDAC1 IN OPRM1 GENE PROMOTER SITES, NEGATIVELY REGULATES MOR EXPRESSION IN INJURED DRG, MITIGATING THE ANALGESIC EFFECT OF THE OPIOIDS. TARGETING MECP2/HDAC1 MAY THUS PROVIDE A NEW SOLUTION FOR IMPROVING THE THERAPEUTIC EFFECT OF OPIOIDS IN A CLINICAL SETTING. 2021 17 2300 30 EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS KNOWN TO BE UP-REGULATED IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, AND TO CONTRIBUTE TO NEUROPATHIC PAIN. HERE, WE FOUND THAT THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AT DAY 7 POST-INJURY WERE INHIBITED ONLY WHEN ANTI-BDNF ANTIBODY WAS INTRATHECALLY ADMINISTRATED AT DAY 2 POST-INJURY. CONSISTENT WITH BEHAVIORAL RESULTS, WESTERN BLOT ANALYSIS SHOWED THAT THE EXPRESSION LEVELS OF BDNF PROTEIN IN THE SPINAL DORSAL HORN WERE MARKEDLY INDUCED DURING EARLY STAGE POST-INJURY. MOREOVER, THE MAXIMAL INCREASE IN BDNF MRNA EXPRESSION IN THE DRG WAS OBSERVED AT DAY 1 POST-INJURY, AND SIGNIFICANTLY ELEVATED LEVELS WERE SUSTAINED FOR AT LEAST 14 DAYS. FOUR OF FIVE BDNF MRNA TRANSCRIPTS WERE UP-REGULATED AFTER NERVE INJURY, AND THE MOST INDUCIBLE TRANSCRIPT WAS EXON I. USING A CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, WE FOUND THAT NERVE INJURY PROMOTES HISTONE H3 AND H4 ACETYLATION, TRANSCRIPTIONALLY ACTIVE MODIFICATIONS, AT BDNF PROMOTER I AT DAY 1 POST-INJURY, AND THE LEVELS OF HISTONE ACETYLATION REMAIN ELEVATED FOR AT LEAST 7 DAYS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT AN INITIAL INCREASE IN BDNF EXON I EXPRESSION CONTROLLED BY EPIGENETIC MECHANISMS MIGHT HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF NEUROPATHIC PAIN. 2013 18 4172 32 MELATONIN IMPEDES TET1-DEPENDENT MGLUR5 PROMOTER DEMETHYLATION TO RELIEVE PAIN. MELATONIN (N-ACETYL-5-METHOXYTRYPTAMINE)/MT2 RECEPTOR-DEPENDENT EPIGENETIC MODIFICATION REPRESENTS A NOVEL PATHWAY IN THE TREATMENT OF NEUROPATHIC PAIN. BECAUSE SPINAL TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1)-DEPENDENT EPIGENETIC DEMETHYLATION HAS RECENTLY BEEN LINKED TO PAIN HYPERSENSITIVITY, WE HYPOTHESIZED THAT MELATONIN/MT2-DEPENDENT ANALGESIA INVOLVES SPINAL TET1-DEPENDENT DEMETHYLATION. HERE, WE SHOWED THAT SPINAL TET1 GENE TRANSFER BY INTRATHECAL DELIVERY OF TET1-ENCODING VECTORS TO NAIVE RATS PRODUCED PROFOUND AND LONG-LASTING NOCICEPTIVE HYPERSENSITIVITY. IN ADDITION, ENHANCED TET1 EXPRESSION, TET1-METABOTROPIC GLUTAMATE RECEPTOR SUBTYPE 5 (MGLUR5) PROMOTER COUPLING, DEMETHYLATION AT THE MGLUR5 PROMOTER, AND MGLUR5 EXPRESSION IN DORSAL HORN NEURONS WERE OBSERVED. RATS SUBJECTED TO SPINAL NERVE LIGATION AND INTRAPLANTAR COMPLETE FREUND'S ADJUVANT INJECTION DISPLAYED TACTILE ALLODYNIA AND BEHAVIORAL HYPERALGESIA ASSOCIATED WITH SIMILAR CHANGES IN THE DORSAL HORN. NOTABLY, INTRATHECAL MELATONIN INJECTION REVERSED THE PROTEIN EXPRESSION, PROTEIN-PROMOTER COUPLING, PROMOTER DEMETHYLATION, AND PAIN HYPERSENSITIVITY INDUCED BY TET1 GENE TRANSFER, SPINAL NERVE LIGATION, AND INTRAPLANTAR COMPLETE FREUND'S ADJUVANT INJECTION. ALL THE EFFECTS CAUSED BY MELATONIN WERE BLOCKED BY PRETREATMENT WITH A MT2 RECEPTOR-SELECTIVE ANTAGONIST. IN CONCLUSION, MELATONIN RELIEVES PAIN BY IMPEDING TET1-DEPENDENT DEMETHYLATION OF MGLUR5 IN DORSAL HORN NEURONS THROUGH THE MT2 RECEPTOR. OUR FINDINGS LINK MELATONIN/MT2 SIGNALING TO TET1-DEPENDENT EPIGENETIC DEMETHYLATION OF NOCICEPTIVE GENES FOR THE FIRST TIME AND SUGGEST MELATONIN AS A PROMISING THERAPY FOR THE TREATMENT OF PAIN. 2017 19 2452 32 EPIGENETIC SUPPRESSION OF POTASSIUM-CHLORIDE CO-TRANSPORTER 2 EXPRESSION IN INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). BACKGROUND: MULTIPLE MECHANISMS CONTRIBUTE TO THE STIMULUS-EVOKED PAIN HYPERSENSITIVITY THAT MAY BE EXPERIENCED AFTER PERIPHERAL INFLAMMATION. PERSISTENT PATHOLOGICAL STIMULI IN MANY PAIN CONDITIONS AFFECT THE EXPRESSION OF CERTAIN GENES THROUGH EPIGENETIC ALTERNATIONS. THE MAIN PURPOSE OF OUR STUDY WAS TO INVESTIGATE THE ROLE OF EPIGENETIC MODIFICATION ON POTASSIUM-CHLORIDE CO-TRANSPORTER 2 (KCC2) GENE EXPRESSION IN THE PERSISTENCE OF INFLAMMATORY PAIN. METHODS: PERSISTENT INFLAMMATORY PAIN WAS INDUCED THROUGH THE INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN THE LEFT HIND PAW OF RATS. ACETYL-HISTONE H3 AND H4 LEVEL WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN THE SPINAL DORSAL HORN. PAIN BEHAVIOUR AND INHIBITORY SYNAPTIC FUNCTION OF SPINAL CORD WERE DETERMINED BEFORE AND AFTER CFA INJECTION. KCC2 EXPRESSION WAS DETERMINED BY REAL TIME RT-PCR AND WESTERN BLOT. INTRATHECAL KCC2 SIRNA (2 MUG PER 10 MUL PER RAT) OR HDAC INHIBITOR (10 MUG PER 10 MUL PER RAT) WAS INJECTED ONCE DAILY FOR 3 DAYS BEFORE CFA INJECTION. RESULTS: PERSISTENT INFLAMMATORY PAIN EPIGENETICALLY SUPPRESSED KCC2 EXPRESSION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN DECREASED INHIBITORY SIGNALLING EFFICACY. KCC2 KNOCK-DOWN CAUSED BY INTRATHECAL ADMINISTRATION OF KCC2 SIRNA IN NAIVE RATS REDUCED KCC2 EXPRESSION IN THE SPINAL CORD, LEADING TO SENSITIZED PAIN BEHAVIOURS AND IMPAIRED INHIBITORY SYNAPTIC TRANSMISSION IN THEIR SPINAL CORDS. MOREOVER, INTRATHECAL HDAC INHIBITOR INJECTION IN CFA RATS INCREASED KCC2 EXPRESSION, PARTIALLY RESTORING THE SPINAL INHIBITORY SYNAPTIC TRANSMISSION AND RELIEVING THE SENSITIZED PAIN BEHAVIOUR. CONCLUSION: THESE FINDINGS SUGGEST THAT THE TRANSCRIPTION OF SPINAL KCC2 IS REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING CFA. SIGNIFICANCE: PERSISTENT PAIN SUPPRESSES KCC2 EXPRESSION THROUGH HDAC-MEDIATED HISTONE HYPOACETYLATION AND CONSEQUENTLY IMPAIRS THE INHIBITORY FUNCTION OF INHIBITORY INTERNEURONS. DRUGS SUCH AS HDAC INHIBITORS THAT SUPPRESS THE INFLUENCES OF PERSISTENT PAIN ON THE EXPRESSION OF KCC2 MAY SERVE AS A NOVEL ANALGESIC. 2017 20 1654 33 DORSAL ROOT GANGLIA COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 CONTRIBUTES TO PERIPHERAL NERVE INJURY-INDUCED PAIN HYPERSENSITIVITIES. NEUROPATHIC PAIN IS ASSOCIATED WITH GENE EXPRESSION CHANGES WITHIN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, WHICH INVOLVES EPIGENETIC MECHANISMS. COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1), AN EPIGENETIC ACTIVATOR, REGULATES GENE TRANSCRIPTIONAL ACTIVITY BY PROTEIN POSTTRANSLATIONAL MODIFICATIONS. HOWEVER, WHETHER CARM1 PLAYS AN ESSENTIAL ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN IS UNKNOWN. WE REPORT HERE THAT PERIPHERAL NERVE INJURY INDUCED THE UPREGULATION OF THE MRNA AND PROTEIN EXPRESSION OF CARM1 IN THE INJURED DRG, AND BLOCKING ITS EXPRESSION THROUGH SMALL INTERFERING RNA (SIRNA) IN THE INJURED DRG ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF CARM1 MITIGATED PERIPHERAL NERVE INJURY-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. GIVEN THAT CARM1 INHIBITION OR KNOCKDOWN ATTENUATED THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY, OUR FINDINGS SUGGEST THAT CARM1 MAY SERVE AS A PROMISING THERAPEUTIC TARGET FOR NEUROPATHIC PAIN TREATMENT IN CLINICAL APPLICATIONS. 2018