1 5615 118 SAHA INHIBITS SOMATIC HYPERALGESIA INDUCED BY STRESS COMBINED WITH OROFACIAL INFLAMMATION THROUGH TARGETING DIFFERENT SPINAL 5-HT RECEPTOR SUBTYPES. EPIGENETIC REGULATION OF GENE EXPRESSION HAS BEEN IMPLICATED IN THE DEVELOPMENT OF CHRONIC PAIN. HOWEVER, LITTLE IS KNOWN ABOUT WHETHER THIS REGULATION IS INVOLVED IN THE DEVELOPMENT AND TREATMENT OF CHRONIC PAIN COMORBIDITIES SUCH AS FIBROMYALGIA SYNDROME (FMS) AND TEMPOROMANDIBULAR DISORDER (TMD), A COMORBIDITY PREDOMINANTLY OCCURRING AMONG WOMEN. HERE WE EXPLORED THE IMPACT OF THE HISTONE DEACETYLASE (HDAC) INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ON SOMATIC HYPERALGESIA INDUCED BY STRESS OR STRESS COMBINED WITH OROFACIAL INFLAMMATION, WHICH MIMICKED THE COMORBIDITY OF FMS AND TMD IN RATS. OUR DATA SHOWED THAT SOMATIC THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA INDUCED BY BOTH CONDITIONS WERE COMPLETELY PREVENTED BY INTRATHECAL INJECTION OF SAHA, WHICH UPREGULATED 5-HT(2C) RECEPTORS BUT DOWNREGULATED 5-HT(3) RECEPTORS IN THE SPINAL DORSAL HORN. SUBSEQUENT SPINAL ADMINISTRATION OF RS102221 TO INHIBIT 5-HT(2C) RECEPTORS OR SR57227 TO ACTIVATE 5-HT(3) RECEPTORS REVERSED THE ANALGESIC EFFECT OF SAHA UNDER BOTH CONDITIONS. THESE RESULTS INDICATE THAT SAHA ATTENUATES THE PRO-NOCICEPTIVE EFFECTS OF STRESS COMBINED WITH OROFACIAL INFLAMMATION AND THE EFFECTS OF STRESS ALONE. THIS LIKELY OCCURS THROUGH EPIGENETIC REGULATION OF SPINAL 5-HT(2C) AND 5-HT(3) RECEPTOR EXPRESSION, SUGGESTING THAT SAHA HAS POTENTIAL THERAPEUTIC VALUE IN FMS OR COMORBID FMS-TMD PATIENTS WITH SOMATIC HYPERALGESIA. 2022 2 1390 17 DIAGNOSING NOCIPLASTIC PAIN IN CANCER SURVIVORS: A MAJOR STEP FORWARD. NOCIPLASTIC PAIN SYNDROMES INCLUDE PARTICULAR FIBROMYALGIA, IRRITABLE BOWEL SYNDROME, HEADACHE, COMPLEX REGIONAL PAIN SYNDROME, AND IDIOPATHIC OROFACIAL PAIN. SEVERAL MECHANISMS HAVE BEEN PROPOSED TO ACCOUNT FOR NOCIPLASTIC PAIN INCLUDING CENTRAL SENSITISATION, ALTERATIONS OF PAIN MODULATORY CONTROLS, EPIGENETIC CHANGES, AND PERIPHERAL MECHANISMS. IMPORTANTLY, NOCIPLASTIC PAIN MIGHT ALSO BE PRESENT IN PATIENTS WITH CANCER PAIN, PARTICULARLY THOSE WITH PAIN RELATED TO COMPLICATIONS OF CANCER TREATMENT. INCREASED AWARENESS OF NOCIPLASTIC PAIN ASSOCIATED WITH CANCER SHOULD HAVE IMPORTANT IMPLICATIONS FOR MONITORING AND MANAGING SUCH PATIENTS. 2023 3 5692 31 SILENCING OF LNCRNA PKIA-AS1 ATTENUATES SPINAL NERVE LIGATION-INDUCED NEUROPATHIC PAIN THROUGH EPIGENETIC DOWNREGULATION OF CDK6 EXPRESSION. NEUROPATHIC PAIN (NP) IS AMONG THE MOST INTRACTABLE COMORBIDITIES OF SPINAL CORD INJURY. DYSREGULATION OF NON-CODING RNAS HAS ALSO BEEN IMPLICATED IN THE DEVELOPMENT OF NEUROPATHIC PAIN. HERE, WE IDENTIFIED A NOVEL LNCRNA, PKIA-AS1, BY USING LNCRNA ARRAY ANALYSIS IN SPINAL CORD TISSUE OF SPINAL NERVE LIGATION (SNL) MODEL RATS, AND INVESTIGATED THE ROLE OF PKIA-AS1 IN SNL-MEDIATED NEUROPATHIC PAIN. WE OBSERVED THAT PKIA-AS1 WAS SIGNIFICANTLY UPREGULATED IN SNL MODEL RATS AND THAT PKIA-AS1 KNOCKDOWN ATTENUATED NEUROPATHIC PAIN PROGRESSION. ALTERNATIVELY, OVEREXPRESSION OF PKIA-AS1 WAS SUFFICIENT TO INDUCE NEUROPATHIC PAIN-LIKE SYMPTOMS IN UNINJURED RATS. WE ALSO FOUND THAT PKIA-AS1 MEDIATED SNL-INDUCED NEUROPATHIC PAIN BY DIRECTLY REGULATING THE EXPRESSION AND FUNCTION OF CDK6, WHICH IS ESSENTIAL FOR THE INITIATION AND MAINTENANCE OF NEUROINFLAMMATION AND NEUROPATHIC PAIN. THEREFORE, OUR STUDY IDENTIFIES PKIA-AS1 AS A NOVEL THERAPEUTIC TARGET FOR NEUROINFLAMMATION RELATED NEUROPATHIC PAIN. 2019 4 6336 36 THE ROLE OF DNA METHYLATION IN TRANSCRIPTIONAL REGULATION OF PRO-NOCICEPTIVE GENES IN RAT TRIGEMINAL GANGLIA. EPIGENETIC MODULATION BY DNA METHYLATION IS ASSOCIATED WITH ABERRANT GENE EXPRESSION IN SENSORY NEURONS, WHICH CONSEQUENTLY LEADS TO PATHOLOGICAL PAIN RESPONSES. IN THIS STUDY, WE SOUGHT TO INVESTIGATE WHETHER PERIPHERAL INFLAMMATION ALTERS GLOBAL DNA METHYLATION IN TRIGEMINAL GANGLIA (TG) AND RESULTS IN ABNORMAL EXPRESSION OF PRO-NOCICEPTIVE GENES. OUR RESULTS SHOW THAT PERIPHERAL INFLAMMATION REMOTELY REDUCED THE LEVEL OF GLOBAL DNA METHYLATION IN RAT TG WITH A CONCURRENT REDUCTION IN DNMT1 AND DNMT3A EXPRESSION. USING UNBIASED STEPS, WE SELECTED THE FOLLOWING PRO-NOCICEPTIVE CANDIDATE GENES THAT ARE POTENTIALLY REGULATED BY DNA METHYLATION: TRPV1, TRPA1, P2X3, AND PIEZO2. INHIBITION OF DNMT WITH 5-AZA-DC IN DISSOCIATED TG CELLS PRODUCED DOSE-DEPENDENT UPREGULATION OF TRPV1, TRPA1, AND P2X3. SYSTEMIC TREATMENT OF ANIMALS WITH 5-AZA-DC SIGNIFICANTLY INCREASED THE EXPRESSION OF TRPV1, TRPA1, AND PIEZO2 IN TG. FURTHERMORE, THE OVEREXPRESSION OF DNMT3A, AS DELIVERED BY A LENTIVIRAL VECTOR, SIGNIFICANTLY DOWNREGULATED TRPV1 AND PIEZO2 EXPRESSION AND ALSO RELIABLY DECREASED TRPA1 AND P2X3 TRANSCRIPTS. MEDIP REVEALED THAT THIS OVEREXPRESSION ALSO SIGNIFICANTLY ENHANCED METHYLATION OF CGIS ASSOCIATED WITH TRPV1 AND TRPA1. IN ADDITION, BISULFITE SEQUENCING DATA INDICATED THAT THE CGI ASSOCIATED WITH TRPA1 WAS METHYLATED IN A PATTERN CATALYZED BY DNMT3A. TAKEN TOGETHER, OUR RESULTS SHOW THAT ALL 4 PRO-NOCICEPTIVE GENES ARE SUBJECT TO EPIGENETIC MODULATION VIA DNA METHYLATION, LIKELY VIA DNMT3A UNDER INFLAMMATORY CONDITIONS. THESE FINDINGS PROVIDE THE FIRST EVIDENCE FOR THE FUNCTIONAL IMPORTANCE OF DNA METHYLATION AS AN EPIGENETIC FACTOR IN THE TRANSCRIPTION OF PRO-NOCICEPTIVE GENES IN TG THAT ARE IMPLICATED IN PATHOLOGICAL OROFACIAL PAIN RESPONSES. 2020 5 5780 36 SPINAL RNF20-MEDIATED HISTONE H2B MONOUBIQUITYLATION REGULATES MGLUR5 TRANSCRIPTION FOR NEUROPATHIC ALLODYNIA. TO DATE, HISTONE H2B MONOUBIQUITINATION (H2BUB), A MARK ASSOCIATED WITH TRANSCRIPTIONAL ELONGATION AND ONGOING TRANSCRIPTION, HAS NOT BEEN LINKED TO THE DEVELOPMENT OR MAINTENANCE OF NEUROPATHIC PAIN STATES. HERE, USING MALE SPRAGUE DAWLEY RATS, WE DEMONSTRATED SPINAL NERVE LIGATION (SNL) INDUCED BEHAVIORAL ALLODYNIA AND PROVOKED RING FINGER PROTEIN 20 (RNF20)-DEPENDENT H2BUB IN DORSAL HORN. MOREOVER, SNL PROVOKED RNF20-MEDIATED H2BUB PHOSPHORYLATED RNA POLYMERASE II (RNAPII) IN THE PROMOTER FRAGMENTS OF MGLUR5, THEREBY ENHANCING MGLUR5 TRANSCRIPTION/EXPRESSION IN THE DORSAL HORN. CONVERSELY, FOCAL KNOCKDOWN OF SPINAL RNF20 EXPRESSION REVERSED NOT ONLY SNL-INDUCED ALLODYNIA BUT ALSO RNF20/H2BUB/RNAPII PHOSPHORYLATION-ASSOCIATED SPINAL MGLUR5 TRANSCRIPTION/EXPRESSION. NOTABLY, TNF-ALPHA INJECTION INTO NAIVE RATS AND SPECIFIC NEUTRALIZING ANTIBODY INJECTION INTO SNL-INDUCED ALLODYNIA RATS REVEALED THAT TNF-ALPHA-ASSOCIATED ALLODYNIA INVOLVES THE RNF20/H2BUB/RNAPII TRANSCRIPTIONAL AXIS TO UPREGULATE MGLUR5 EXPRESSION IN THE DORSAL HORN. COLLECTIVELY, OUR FINDINGS INDICATED TNF-ALPHA INDUCES RNF20-DRIVED H2B MONOUBIQUITINATION, WHICH FACILITATES PHOSPHORYLATED RNAPII-DEPENDENT MGLUR5 TRANSCRIPTION IN THE DORSAL HORN FOR THE DEVELOPMENT OF NEUROPATHIC ALLODYNIA.SIGNIFICANCE STATEMENT HISTONE H2B MONOUBIQUITINATION (H2BUB), AN EPIGENETIC POST-TRANSLATIONAL MODIFICATION, POSITIVELY CORRELATED WITH GENE EXPRESSION. HERE, TNF-ALPHA PARTICIPATED IN NEUROPATHIC PAIN DEVELOPMENT BY ENHANCING RNF20-MEDIATED H2BUB, WHICH FACILITATES PHOSPHORYLATED RNAPII-DEPENDENT MGLUR5 TRANSCRIPTION IN DORSAL HORN. OUR FINDING POTENTIALLY IDENTIFIED NEUROPATHIC ALLODYNIA PATHOPHYSIOLOGICAL PROCESSES UNDERPINNING ABNORMAL NOCICEPTION PROCESSING AND OPENS A NEW AVENUE FOR THE DEVELOPMENT OF NOVEL ANALGESICS. 2018 6 3337 37 HISTONE DEACETYLASE INHIBITORS PREVENT PERSISTENT HYPERSENSITIVITY IN AN OROFACIAL NEUROPATHIC PAIN MODEL. CHRONIC OROFACIAL PAIN IS A SIGNIFICANT HEALTH PROBLEM REQUIRING IDENTIFICATION OF REGULATING PROCESSES. INVOLVEMENT OF EPIGENETIC MODIFICATIONS THAT IS REPORTED FOR HINDLIMB NEUROPATHIC PAIN EXPERIMENTAL MODELS, HOWEVER, IS LESS WELL STUDIED IN CRANIAL NERVE PAIN MODELS. THREE INDEPENDENT OBSERVATIONS REPORTED HERE ARE THE (1) EPIGENETIC PROFILE IN MOUSE TRIGEMINAL GANGLIA (TG) AFTER TRIGEMINAL INFLAMMATORY COMPRESSION (TIC) NERVE INJURY MOUSE MODEL DETERMINED BY GENE EXPRESSION MICROARRAY, (2) H3K9 ACETYLATION PATTERN IN TG BY IMMUNOHISTOCHEMISTRY, AND (3) EFFICACY OF HISTONE DEACETYLASE (HDAC) INHIBITORS TO ATTENUATE DEVELOPMENT OF HYPERSENSITIVITY. AFTER TIC INJURY, IPSILATERAL WHISKER PAD MECHANICAL SENSITIZATION DEVELOPS BY DAY 3 AND PERSISTS WELL BEYOND DAY 21 IN CONTRAST TO SHAM SURGERY. GLOBAL ACETYLATION OF H3K9 DECREASES AT DAY 21 IN IPSILATERAL TG . THIRTY-FOUR GENES ARE SIGNIFICANTLY ( P < 0.05) OVEREXPRESSED IN THE IPSILATERAL TG BY AT LEAST TWO-FOLD AT EITHER 3 OR 21 DAYS POST-TRIGEMINAL INFLAMMATORY COMPRESSION INJURY. THE THREE GENES MOST OVEREXPRESSED THREE DAYS POST-TRIGEMINAL INFLAMMATORY COMPRESSION NERVE INJURY ARE NERVE REGENERATION-ASSOCIATED GENE ATF3, UP 6.8-FOLD, AND TWO OF ITS REGENERATION-ASSOCIATED GENE EFFECTOR GENES, SPRR1A AND GAL, UP 174- AND 25-FOLD, RESPECTIVELY. ALTHOUGH TRANSCRIPTION LEVELS OF 25 OF 32 GENES SIGNIFICANTLY OVEREXPRESSED THREE DAYS POST-TRIGEMINAL INFLAMMATORY COMPRESSION RETURN TO CONSTITUTIVE LEVELS BY DAY 21, THESE THREE REGENERATION-ASSOCIATED GENES REMAIN SIGNIFICANTLY OVEREXPRESSED AT THE LATER TIME POINT. ON DAY 21, WHEN TISSUES ARE HEALED, OTHER DIFFERENTIALLY EXPRESSED GENES INCLUDE 39 OF THE TOP 50 UPREGULATED AND DOWNREGULATED GENES. REMARKABLY, PREEMPTIVE MANIPULATION OF GENE EXPRESSION WITH TWO HDAC INHIBITORS (HDACI'S), SUBERANILOHYDROXAMIC ACID (SAHA) AND MS-275, REDUCES THE MAGNITUDE AND DURATION OF WHISKER PAD MECHANICAL HYPERSENSITIVITY AND PREVENTS THE DEVELOPMENT OF A PERSISTENT PAIN STATE. THESE FINDINGS SUGGEST THAT TRIGEMINAL NERVE INJURY LEADS TO EPIGENETIC MODIFICATIONS FAVORING OVEREXPRESSION OF GENES INVOLVED IN NERVE REGENERATION AND THAT MAINTAINING TRANSCRIPTIONAL HOMEOSTASIS WITH EPIGENETIC MODIFYING DRUGS COULD HELP PREVENT THE DEVELOPMENT OF PERSISTENT PAIN. 2018 7 1167 35 CONTRIBUTION OF DORSAL ROOT GANGLION OCTAMER TRANSCRIPTION FACTOR 1 TO NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. NEUROPATHIC PAIN GENESIS IS RELATED TO GENE ALTERATIONS IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY. TRANSCRIPTION FACTORS CONTROL GENE EXPRESSION. IN THIS STUDY, WE INVESTIGATED WHETHER OCTAMER TRANSCRIPTION FACTOR 1 (OCT1), A TRANSCRIPTION FACTOR, CONTRIBUTED TO NEUROPATHIC PAIN CAUSED BY CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE. CHRONIC CONSTRICTION INJURY PRODUCED A TIME-DEPENDENT INCREASE IN THE LEVEL OF OCT1 PROTEIN IN THE IPSILATERAL L4/5 DRG, BUT NOT IN THE SPINAL CORD. BLOCKING THIS INCREASE THROUGH MICROINJECTION OF OCT1 SIRNA INTO THE IPSILATERAL L4/5 DRG ATTENUATED THE INITIATION AND MAINTENANCE OF CCI-INDUCED MECHANICAL ALLODYNIA, HEAT HYPERALGESIA, AND COLD ALLODYNIA AND IMPROVED MORPHINE ANALGESIA AFTER CCI, WITHOUT AFFECTING BASAL RESPONSES TO ACUTE MECHANICAL, HEAT, AND COLD STIMULI AS WELL AS LOCOMOTOR FUNCTIONS. MIMICKING THIS INCREASE THROUGH MICROINJECTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS 5 HARBORING FULL-LENGTH OCT1 INTO THE UNILATERAL L4/5 DRG LED TO MARKED MECHANICAL ALLODYNIA, HEAT HYPERALGESIA, AND COLD ALLODYNIA IN NAIVE RATS. MECHANISTICALLY, OCT1 PARTICIPATED IN CCI-INDUCED INCREASES IN DNMT3A MRNA AND ITS PROTEIN AND DNMT3A-MEDIATED DECREASES IN OPRM1 AND KCNA2 MRNAS AND THEIR PROTEINS IN THE INJURED DRG. THESE FINDINGS INDICATE THAT OCT1 MAY PARTICIPATE IN NEUROPATHIC PAIN AT LEAST IN PART BY TRANSCRIPTIONALLY ACTIVATING DNMT3A AND SUBSEQUENTLY EPIGENETIC SILENCING OF OPRM1 AND KCAN2 IN THE DRG. OCT1 MAY SERVE AS A POTENTIAL TARGET FOR THERAPEUTIC TREATMENTS AGAINST NEUROPATHIC PAIN. 2019 8 6472 36 TNFALPHA IN THE TRIGEMINAL NOCICEPTIVE SYSTEM IS CRITICAL FOR TEMPOROMANDIBULAR JOINT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) IS SIGNIFICANTLY INCREASED IN COMPLETE FREUND'S ADJUVANT (CFA)-TREATED TEMPOROMANDIBULAR JOINT (TMJ) TISSUES. HOWEVER, IT IS UNCLEAR WHETHER TNFALPHA IN THE TRIGEMINAL NOCICEPTIVE SYSTEM CONTRIBUTES TO THE DEVELOPMENT OF TMJ PAIN. IN THE PRESENT STUDY, WE INVESTIGATED THE ROLE OF TNFALPHA IN TRIGEMINAL GANGLIA (TG) AND SPINAL TRIGEMINAL NUCLEUS CAUDALIS (SP5C) IN CFA-INDUCED INFLAMMATORY TMJ PAIN. INTRA-TMJ INJECTION OF CFA (10 MUL, 5 MG/ML) INDUCED INFLAMMATORY PAIN IN THE TRIGEMINAL NERVE V2- AND V3-INNERVATED SKIN AREAS OF WT MICE, WHICH WAS PRESENT ON DAY 1 AFTER CFA AND PERSISTED FOR AT LEAST 10 DAYS. TNFALPHA IN BOTH TG AND SP5C OF WT MICE WAS UPREGULATED AFTER CFA INJECTION. THE CFA-INDUCED TMJ PAIN WAS SIGNIFICANTLY INHIBITED IN TNFALPHA KO MICE. THE IMMUNOFLUORESCENCE STAINING SHOWED THAT INTRA-TMJ CFA INJECTION NOT ONLY ENHANCED CO-LOCALIZATION OF TNFALPHA WITH IBA1 (A MARKER FOR MICROGLIA) IN BOTH TG AND SP5C BUT ALSO MARKEDLY INCREASED THE EXPRESSION OF TNFALPHA IN THE SP5C NEURONS. BY THE METHYLATED DNA IMMUNOPRECIPITATION ASSAY, WE ALSO FOUND THAT DNA METHYLATION AT THE TNF GENE PROMOTER REGION IN THE TG WAS DRAMATICALLY DIMINISHED AFTER CFA INJECTION, INDICATING THAT EPIGENETIC REGULATION MAY BE INVOLVED IN THE CFA-ENHANCED TNFALPHA EXPRESSION IN OUR MODEL. OUR RESULTS SUGGEST THAT TNFALPHA IN THE TRIGEMINAL NOCICEPTIVE SYSTEM PLAYS A CRITICAL ROLE IN CFA-INDUCED INFLAMMATORY TMJ PAIN. 2019 9 4176 43 MELATONIN RELIEVES NEUROPATHIC ALLODYNIA THROUGH SPINAL MT2-ENHANCED PP2AC AND DOWNSTREAM HDAC4 SHUTTLING-DEPENDENT EPIGENETIC MODIFICATION OF HMGB1 TRANSCRIPTION. MELATONIN (MLT; N-ACETYL-5-METHOXYTRYPTAMINE) EXHIBITS ANALGESIC PROPERTIES IN CHRONIC PAIN CONDITIONS. WHILE RESEARCHES LINKING MLT TO EPIGENETIC MECHANISMS HAVE GROWN EXPONENTIALLY OVER RECENT YEARS, VERY FEW STUDIES HAVE INVESTIGATED THE CONTRIBUTION OF MLT-ASSOCIATED EPIGENETIC MODIFICATION TO PAIN STATES. HERE, WE REPORT THAT TOGETHER WITH BEHAVIORAL ALLODYNIA, SPINAL NERVE LIGATION (SNL) INDUCED A DECREASE IN THE EXPRESSION OF CATALYTIC SUBUNIT OF PHOSPHATASE 2A (PP2AC) AND ENHANCED HISTONE DEACETYLASE 4 (HDAC4) PHOSPHORYLATION AND CYTOPLASMIC ACCUMULATION, WHICH EPIGENETICALLY ALLEVIATED HDAC4-SUPPRESSED HMGB1 GENE TRANSCRIPTION, RESULTING IN INCREASED HIGH-MOBILITY GROUP PROTEIN B1 (HMGB1) EXPRESSION SELECTIVELY IN THE IPSILATERAL DORSAL HORN OF RATS. FOCAL KNOCK-DOWN OF SPINAL PP2AC EXPRESSION ALSO RESULTED IN BEHAVIORAL ALLODYNIA IN ASSOCIATION WITH SIMILAR PROTEIN EXPRESSION AS OBSERVED WITH SNL. NOTABLY, INTRATHECAL ADMINISTRATION WITH MLT INCREASED PP2AC EXPRESSION, HDAC4 DEPHOSPHORYLATION AND NUCLEAR ACCUMULATION, RESTORED HDAC4-MEDIATED HMGB1 SUPPRESSION AND RELIEVED SNL-SENSITIZED BEHAVIORAL PAIN; THESE EFFECTS WERE ALL INHIBITED BY SPINAL INJECTION OF 4P-PDOT (A MT2 RECEPTOR ANTAGONIST, 30 MINUTES BEFORE MLT) AND OKADAIC ACID (OA, A PP2A INHIBITOR, 3 HR AFTER MLT). OUR FINDINGS DEMONSTRATE A NOVEL MECHANISM BY WHICH MLT AMELIORATES NEUROPATHIC ALLODYNIA VIA EPIGENETIC MODIFICATION. THIS MLT-EXHIBITED ANTI-ALLODYNIA IS MEDIATED BY MT2-ENHANCED PP2AC EXPRESSION THAT COUPLES PP2AC WITH HDAC4 TO INDUCE HDAC4 DEPHOSPHORYLATION AND NUCLEAR IMPORT, HEREIN INCREASES HDAC4 BINDING TO THE PROMOTER OF HMGB1 GENE AND UPREGULATES HMGB1 EXPRESSION IN DORSAL HORN NEURONS. 2016 10 1318 33 DEMETHYLATION OF G-PROTEIN-COUPLED RECEPTOR 151 PROMOTER FACILITATES THE BINDING OF KRUPPEL-LIKE FACTOR 5 AND ENHANCES NEUROPATHIC PAIN AFTER NERVE INJURY IN MICE. G-PROTEIN-COUPLED RECEPTORS ARE CONSIDERED TO BE CELL-SURFACE SENSORS OF EXTRACELLULAR SIGNALS, THEREBY HAVING A CRUCIAL ROLE IN SIGNAL TRANSDUCTION AND BEING THE MOST FRUITFUL TARGETS FOR DRUG DISCOVERY. G-PROTEIN-COUPLED RECEPTOR 151 (GPR151) WAS REPORTED TO BE EXPRESSED SPECIFICALLY IN THE HABENULAR AREA. HERE WE REPORT THE EXPRESSION AND THE EPIGENETIC REGULATION OF GRP151 IN THE SPINAL CORD AFTER SPINAL NERVE LIGATION (SNL) AND THE CONTRIBUTION OF GPR151 TO NEUROPATHIC PAIN IN MALE MICE. SNL DRAMATICALLY INCREASED GPR151 EXPRESSION IN SPINAL NEURONS. GPR151 MUTATION OR SPINAL INHIBITION BY SHRNA ALLEVIATED SNL-INDUCED MECHANICAL ALLODYNIA AND HEAT HYPERALGESIA. INTERESTINGLY, THE CPG ISLAND IN THE GPR151 GENE PROMOTER REGION WAS DEMETHYLATED, THE EXPRESSION OF DNA METHYLTRANSFERASE 3B (DNMT3B) WAS DECREASED, AND THE BINDING OF DNMT3B WITH GPR151 PROMOTER WAS REDUCED AFTER SNL. OVEREXPRESSION OF DNMT3B IN THE SPINAL CORD DECREASED GPR151 EXPRESSION AND ATTENUATED SNL-INDUCED NEUROPATHIC PAIN. FURTHERMORE, KRUPPEL-LIKE FACTOR 5 (KLF5), A TRANSCRIPTIONAL FACTOR OF THE KLF FAMILY, WAS UPREGULATED IN SPINAL NEURONS, AND THE BINDING AFFINITY OF KLF5 WITH GPR151 PROMOTER WAS INCREASED AFTER SNL. INHIBITION OF KLF5 REDUCED GPR151 EXPRESSION AND ATTENUATED SNL-INDUCED PAIN HYPERSENSITIVITY. FURTHER MRNA MICROARRAY ANALYSIS REVEALED THAT MUTATION OF GPR151 REDUCED THE EXPRESSION OF A VARIETY OF PAIN-RELATED GENES IN RESPONSE TO SNL, ESPECIALLY MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) SIGNALING PATHWAY-ASSOCIATED GENES. THIS STUDY REVEALS THAT GPR151, INCREASED BY DNA DEMETHYLATION AND THE ENHANCED INTERACTION WITH KLF5, CONTRIBUTES TO THE MAINTENANCE OF NEUROPATHIC PAIN VIA INCREASING MAPK PATHWAY-RELATED GENE EXPRESSION.SIGNIFICANCE STATEMENT G-PROTEIN-COUPLED RECEPTORS (GPCRS) ARE TARGETS OF VARIOUS CLINICALLY APPROVED DRUGS. HERE WE REPORT THAT SNL INCREASED GPR151 EXPRESSION IN THE SPINAL CORD, AND MUTATION OR INHIBITION OF GPR151 ALLEVIATED SNL-INDUCED NEUROPATHIC PAIN. IN ADDITION, SNL DOWNREGULATED THE EXPRESSION OF DNMT3B, WHICH CAUSED DEMETHYLATION OF GPR151 GENE PROMOTER, FACILITATED THE BINDING OF TRANSCRIPTIONAL FACTOR KLF5 WITH THE GPR151 PROMOTER, AND FURTHER INCREASED GPR151 EXPRESSION IN SPINAL NEURONS. THE INCREASED GPR151 MAY CONTRIBUTE TO THE PATHOGENESIS OF NEUROPATHIC PAIN VIA ACTIVATING MAPK SIGNALING AND INCREASING PAIN-RELATED GENE EXPRESSION. OUR STUDY REVEALS AN EPIGENETIC MECHANISM UNDERLYING GPR151 EXPRESSION AND SUGGESTS THAT TARGETING GPR151 MAY OFFER A NEW STRATEGY FOR THE TREATMENT OF NEUROPATHIC PAIN. 2018 11 4919 38 PANNEXIN-1 UP-REGULATION IN THE DORSAL ROOT GANGLION CONTRIBUTES TO NEUROPATHIC PAIN DEVELOPMENT. PANNEXIN-1 (PANX1) IS A LARGE-PORE MEMBRANE CHANNEL INVOLVED IN THE RELEASE OF ATP AND OTHER SIGNALING MEDIATORS. LITTLE IS KNOWN ABOUT THE EXPRESSION AND FUNCTIONAL ROLE OF PANX1 IN THE DORSAL ROOT GANGLION (DRG) IN THE DEVELOPMENT OF CHRONIC NEUROPATHIC PAIN. IN THIS STUDY, WE DETERMINED THE EPIGENETIC MECHANISM INVOLVED IN INCREASED PANX1 EXPRESSION IN THE DRG AFTER NERVE INJURY. SPINAL NERVE LIGATION IN RATS SIGNIFICANTLY INCREASED THE MRNA AND PROTEIN LEVELS OF PANX1 IN THE DRG BUT NOT IN THE SPINAL CORD. IMMUNOCYTOCHEMICAL LABELING SHOWED THAT PANX1 WAS PRIMARILY EXPRESSED IN A SUBSET OF MEDIUM AND LARGE DRG NEURONS IN CONTROL RATS AND THAT NERVE INJURY MARKEDLY INCREASED THE NUMBER OF PANX1-IMMUNOREACTIVE DRG NEURONS. NERVE INJURY SIGNIFICANTLY INCREASED THE ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME2 AND H3K9AC) AND DECREASED THE OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AROUND THE PROMOTER REGION OF PANX1 IN THE DRG. HOWEVER, NERVE INJURY HAD NO EFFECT ON THE DNA METHYLATION LEVEL AROUND THE PANX1 PROMOTER IN THE DRG. FURTHERMORE, INTRATHECAL INJECTION OF THE PANX1 BLOCKERS OR PANX1-SPECIFIC SIRNA SIGNIFICANTLY REDUCED PAIN HYPERSENSITIVITY INDUCED BY NERVE INJURY. IN ADDITION, SIRNA KNOCKDOWN OF PANX1 EXPRESSION IN A DRG CELL LINE SIGNIFICANTLY REDUCED CASPASE-1 RELEASE INDUCED BY NEURONAL DEPOLARIZATION. OUR FINDINGS SUGGEST THAT NERVE INJURY INCREASES PANX1 EXPRESSION LEVELS IN THE DRG THROUGH ALTERED HISTONE MODIFICATIONS. PANX1 UP-REGULATION CONTRIBUTES TO THE DEVELOPMENT OF NEUROPATHIC PAIN AND STIMULATION OF INFLAMMASOME SIGNALING. 2015 12 5625 33 SELECTIVE CLASS I HISTONE DEACETYLASE INHIBITORS SUPPRESS PERSISTENT SPONTANEOUS NOCICEPTION AND THERMAL HYPERSENSITIVITY IN A RAT MODEL OF BEE VENOM-INDUCED INFLAMMATORY PAIN. TO CONFIRM WHETHER CLASS I HISTONE DEACETYLASE INHIBITORS (HDACIS) ARE EFFECTIVE IN RELIEF OF PERIPHERAL INFLAMMATORY PAIN, THE EFFECTS OF TWO SELECTIVE INHIBITORS, MS-275 AND MGCD0103, WERE STUDIED IN RATS INFLAMED BY SUBCUTANEOUS (S.C.) INJECTION OF BEE VENOM (BV). THE BV TEST IS CHARACTERIZED BY DISPLAYING BOTH PERSISTENT SPONTANEOUS NOCICEPTION (PSN) AND PRIMARY HYPERSENSITIVITY. INTRATHECAL (I.T.) PRE-TREATMENT OF EITHER MS-275 OR MGCD0103 WITH A SINGLE DOSE OF 60 NMOL/20 MUL RESULTED IN PROFOUND SUPPRESSION OF BOTH PSN AND PRIMARY THERMAL HYPERSENSITIVITY BUT WITHOUT SIGNIFICANT INFLUENCE UPON THE PRIMARY MECHANICAL HYPERSENSITIVITY AND MIRROR-IMAGE THERMAL HYPERSENSITIVITY. MOREOVER, THE UP-REGULATION OF BOTH HDAC1 AND HDAC2 INDUCED BY S.C. BV INJECTION WAS COMPLETELY SUPPRESSED BY I.T. PRE-TREATMENT OF MS-275. THE PRESENT RESULTS PROVIDE WITH ANOTHER NEW LINE OF EVIDENCE SHOWING INVOLVEMENT OF EPIGENETIC REGULATION OF CHROMATIN STRUCTURE BY HDAC1/2-MEDIATED HISTONE HYPOACETYLATION IN THE BV-INDUCED PSN AND THERMAL HYPERSENSITIVITY AND DEMONSTRATE THE BENEFICIAL EFFECTS OF CLASS I HDACIS IN PREVENTION OF PERIPHERAL INFLAMMATORY PAIN FROM OCCURRING. 2015 13 3830 36 INVOLVEMENT OF HISTONE LYSINE CROTONYLATION IN THE REGULATION OF NERVE-INJURY-INDUCED NEUROPATHIC PAIN. HISTONE LYSINE CROTONYLATION (KCR), A NOVEL EPIGENETIC MODIFICATION, IS IMPORTANT IN REGULATING A BROAD SPECTRUM OF BIOLOGICAL PROCESSES AND VARIOUS DISEASES. HOWEVER, WHETHER KCR IS INVOLVED IN NEUROPATHIC PAIN REMAINS TO BE ELUCIDATED. WE FOUND KCR OCCURS IN MACROPHAGES, SENSORY NEURONS, AND SATELLITE GLIAL CELLS OF TRIGEMINAL GANGLIA (TG), NEURONS, ASTROCYTES, AND MICROGLIA OF THE MEDULLA OBLONGATA. KCR IN TG WAS DETECTED MAINLY IN SMALL AND MEDIUM SENSORY NEURONS, TO A LESSER EXTENT IN LARGE NEURONS. PERIPHERAL NERVE INJURY ELEVATED KCR LEVELS IN MACROPHAGES IN THE TRIGEMINAL AND DORSAL ROOT GANGLIA AND MICROGLIA IN THE MEDULLA OBLONGATA BUT REDUCED KCR LEVELS IN SENSORY NEURONS. INHIBITION OF HISTONE CROTONYLTRANSFERASES (P300) BY INTRA-TG OR INTRATHECAL ADMINISTRATION OF C646 SIGNIFICANTLY ALLEVIATED PARTIAL INFRAORBITAL NERVE TRANSECTION (PIONT)- OR SPINAL NERVE LIGATION (SNL)-INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA. INTRA-TG OR INTRATHECAL ADMINISTRATION OF CROTONYL COENZYME A TRILITHIUM SALT TO UPREGULATE KCR DOSE-DEPENDENTLY INDUCED MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA IN MICE. MECHANISMLY, INHIBITION OF P300 ALLEVIATED PIONT-INDUCED MACROPHAGE ACTIVATION AND REDUCED THE EXPRESSION OF PAIN-RELATED INFLAMMATORY CYTOKINES TNFALPHA, IL1BETA AND CHEMOKINES CCL2 AND CXCL10. CORRESPONDINGLY, EXOGENOUS CROTONYL-COA INDUCED MACROPHAGE ACTIVATION AND THE EXPRESSION OF TNFALPHA, IL1BETA, IL6, CCL2 AND CCL7 IN TG, WHICH C646 CAN REPRESS. THESE FINDINGS SUGGEST THAT HISTONE CROTONYLATION MIGHT BE FUNCTIONALLY INVOLVED IN NEUROPATHIC PAIN AND NEUROINFLAMMATION REGULATION. 2022 14 5354 41 RE1-SILENCING TRANSCRIPTION FACTOR CONTROLS THE ACUTE-TO-CHRONIC NEUROPATHIC PAIN TRANSITION AND CHRM2 RECEPTOR GENE EXPRESSION IN PRIMARY SENSORY NEURONS. NEUROPATHIC PAIN IS ASSOCIATED WITH PERSISTENT CHANGES IN GENE EXPRESSION IN PRIMARY SENSORY NEURONS, BUT THE UNDERLYING EPIGENETIC MECHANISMS THAT CAUSE THESE CHANGES REMAIN UNCLEAR. THE MUSCARINIC CHOLINERGIC RECEPTORS (MACHRS), PARTICULARLY THE M2 SUBTYPE (ENCODED BY THE CHOLINERGIC RECEPTOR MUSCARINIC 2 (CHRM2) GENE), ARE CRITICALLY INVOLVED IN THE REGULATION OF SPINAL NOCICEPTIVE TRANSMISSION. HOWEVER, LITTLE IS KNOWN ABOUT HOW CHRM2 EXPRESSION IS TRANSCRIPTIONALLY REGULATED. HERE WE SHOW THAT NERVE INJURY PERSISTENTLY INCREASED THE EXPRESSION OF RE1-SILENCING TRANSCRIPTION FACTOR (REST, ALSO KNOWN AS NEURON-RESTRICTIVE SILENCING FACTOR [NRSF]), A GENE-SILENCING TRANSCRIPTION FACTOR, IN THE DORSAL ROOT GANGLION (DRG). REMARKABLY, NERVE INJURY-INDUCED CHRONIC BUT NOT ACUTE PAIN HYPERSENSITIVITY WAS ATTENUATED IN MICE WITH REST KNOCKOUT IN DRG NEURONS. ALSO, SIRNA-MEDIATED REST KNOCKDOWN REVERSED NERVE INJURY-INDUCED CHRONIC PAIN HYPERSENSITIVITY IN RATS. NERVE INJURY PERSISTENTLY REDUCED CHRM2 EXPRESSION IN THE DRG AND DIMINISHED THE ANALGESIC EFFECT OF MUSCARINE. THE RE1 BINDING SITE ON THE CHRM2 PROMOTER IS REQUIRED FOR REST-MEDIATED CHRM2 REPRESSION, AND NERVE INJURY INCREASED THE ENRICHMENT OF REST IN THE CHRM2 PROMOTER IN THE DRG. FURTHERMORE, REST KNOCKDOWN OR GENETIC ABLATION IN DRG NEURONS NORMALIZED CHRM2 EXPRESSION AND AUGMENTED MUSCARINE'S ANALGESIC EFFECT ON NEUROPATHIC PAIN AND FULLY REVERSED THE NERVE INJURY-INDUCED REDUCTION IN THE INHIBITORY EFFECT OF MUSCARINE ON GLUTAMATERGIC INPUT TO SPINAL DORSAL HORN NEURONS. OUR FINDINGS INDICATE THAT NERVE INJURY-INDUCED REST UP-REGULATION IN DRG NEURONS PLAYS AN IMPORTANT ROLE IN THE ACUTE-TO-CHRONIC PAIN TRANSITION AND IS ESSENTIAL FOR THE TRANSCRIPTIONAL REPRESSION OF CHRM2 IN NEUROPATHIC PAIN. 2018 15 2751 34 EXPRESSION OF ACETYL-HISTONE H3 AND ACETYL-HISTONE H4 IN DORSAL ROOT GANGLION AND SPINAL DORSAL HORN IN RAT CHRONIC PAIN MODELS. AIMS: HISTONE ACETYLATION AND DEACETYLATION ARE TWO HISTONE POSTTRANSLATIONAL MODIFICATIONS THAT ARE USUALLY CONTROLLED BY HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS). ALTHOUGH HATS OR HDACS INHIBITORS COULD RELIEVE PAIN HYPERSENSITIVITIES IN CHRONIC PAIN ANIMAL MODELS, IT IS NOT CLEAR ON THE EXPRESSION OF GLOBAL HISTONE ACETYLATION IN THE DORSAL ROOT GANGLION (DRG) OR SPINAL DORSAL HORN IN CHRONIC PAIN CONDITIONS. MAIN METHODS: A SPINAL NERVE LIGATION (SNL)-INDUCED NEUROPATHIC PAIN MODEL AND A COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED INFLAMMATORY PAIN MODEL IN RATS WERE USED TO EXAMINE THE EXPRESSION OF TOTAL ACETYL-HISTONE H3 (ACH3) AND TOTAL ACETYL-HISTONE H4 (ACH4) BY IMMUNOFLUORESCENCE OR WESTERN BLOT. KEY FINDINGS: ACH3 AND ACH4 NOT ONLY LOCALIZED IN NEURONAL NUCLEI, BUT ALSO IN NUCLEI OF GLIAL CELLS IN THE DRG. UNILATERAL SNL INDUCED THE INCREASE OF ACH3 AND ACH4 EXPRESSION IN THE INJURED LUMBAR 5 (L5) DRG, BUT NOT IN THE UNINJURED L5 DRG OR THE SPINAL DORSAL HORN, WHILE UNILATERAL INTRAPLANTAR INJECTION OF CFA INCREASED ACH3 AND ACH4 EXPRESSION IN THE IPSILATERAL L4/5 SPINAL DORSAL HORN, BUT NOT IN THE L4/5 DRG. SIGNIFICANCE: THESE RESULTS PROVIDE MORPHOLOGICAL EVIDENCE FOR GLOBAL HISTONE ACETYLATION EXPRESSION IN THE DRG AND SPINAL CORD AND INDICATE THE DIFFERENTIAL EXPRESSION IN THE DRG AND SPINAL DORSAL HORN IN DIFFERENT CHRONIC PAIN MODELS. MORE PRECISE EPIGENETIC MECHANISMS OF HISTONE ACETYLATION ON THE TARGET GENES NEED TO BE REVEALED. 2018 16 2006 35 EPIGENETIC AUGMENTATION OF THE MACROPHAGE INFLAMMATORY PROTEIN 2/C-X-C CHEMOKINE RECEPTOR TYPE 2 AXIS THROUGH HISTONE H3 ACETYLATION IN INJURED PERIPHERAL NERVES ELICITS NEUROPATHIC PAIN. ALTHOUGH THERE IS GROWING EVIDENCE SHOWING THAT THE INVOLVEMENT OF CHEMOKINES IN THE PATHOGENESIS OF NEUROPATHIC PAIN IS ASSOCIATED WITH NEUROINFLAMMATION, THE DETAILS ARE UNCLEAR. WE INVESTIGATED THE C-X-C CHEMOKINE LIGAND TYPE 2 [MACROPHAGE INFLAMMATORY PROTEIN 2 (MIP-2)]/C-X-C CHEMOKINE RECEPTOR TYPE 2 (CXCR2) AXIS AND EPIGENETIC REGULATION OF THESE MOLECULES IN NEUROPATHIC PAIN AFTER PERIPHERAL NERVE INJURY. EXPRESSION OF MIP-2 AND CXCR2 WERE UP-REGULATED AND LOCALIZED ON ACCUMULATED NEUTROPHILS AND MACROPHAGES IN THE INJURED SCIATIC NERVE (SCN) AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). PERINEURAL INJECTION OF MIP-2-NEUTRALIZING ANTIBODY (ANTI-MIP-2) OR THE CXCR2 ANTAGONIST N-(2-BROMOPHENYL)-N'-(2-HYDROXY-4-NITROPHENYL)UREA (SB225002) PREVENTED PSL-INDUCED TACTILE ALLODYNIA AND THERMAL HYPERALGESIA. PERINEURAL INJECTION OF RECOMBINANT MIP-2 ELICITED NEUROPATHIC PAIN-LIKE BEHAVIORS. ANTI-MIP-2 SUPPRESSED NEUTROPHIL ACCUMULATION IN THE SCN AFTER PSL. NEUTROPHIL DEPLETION BY INTRAPERITONEAL INJECTION OF LY6G ANTIBODY ATTENUATED PSL-INDUCED NEUROPATHIC PAIN. BOTH ANTI-MIP-2 AND SB225002 SUPPRESSED UP-REGULATION OF INFLAMMATORY CYTOKINES AND CHEMOKINES IN THE INJURED SCN. IN ADDITION, ACETYLATION OF HISTONE H3 [LYSINE (LYS9)-ACETYLATED HISTONE H3 (ACK9-H3)] ON THE PROMOTER REGION OF MIP-2 AND CXCR2 WAS INCREASED IN THE INJURED SCN AFTER PSL. EXPRESSION OF ACK9-H3 WAS OBSERVED IN THE NUCLEI OF NEUTROPHILS AND MACROPHAGES SURROUNDING THE EPINEURIUM. ADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID SUPPRESSED THE UP-REGULATION OF MIP-2 AND CXCR2 IN THE SCN AFTER PSL AND RESULTED IN THE PREVENTION OF PSL-INDUCED NEUROPATHIC PAIN. TAKEN TOGETHER, THESE RESULTS SHOW THAT AUGMENTATION OF THE MIP-2/CXCR2 AXIS BY HYPERACETYLATION OF HISTONE H3 ON THE PROMOTER REGION OF MIP-2 AND CXCR2 LOCATED IN THE INJURED PERIPHERAL NERVE ELICITS CHRONIC NEUROINFLAMMATION THROUGH NEUTROPHIL ACCUMULATION, LEADING TO NEUROPATHIC PAIN. 2012 17 3368 34 HISTONE METHYLTRANSFERASE G9A DIMINISHES EXPRESSION OF CANNABINOID CB(1) RECEPTORS IN PRIMARY SENSORY NEURONS IN NEUROPATHIC PAIN. TYPE 1 CANNABINOID RECEPTORS (CB(1)RS) ARE EXPRESSED IN THE DORSAL ROOT GANGLION (DRG) AND CONTRIBUTE TO THE ANALGESIC EFFECT OF CANNABINOIDS. HOWEVER, THE EPIGENETIC MECHANISM REGULATING THE EXPRESSION OF CB(1)RS IN NEUROPATHIC PAIN IS UNKNOWN. G9A (ENCODED BY THE EHMT2 GENE), A HISTONE 3 AT LYSINE 9 METHYLTRANSFERASE, IS A KEY CHROMATIN REGULATOR RESPONSIBLE FOR GENE SILENCING. IN THIS STUDY, WE DETERMINED G9A'S ROLE IN REGULATING CB(1)R EXPRESSION IN THE DRG AND IN CB(1)R-MEDIATED ANALGESIC EFFECTS IN AN ANIMAL MODEL OF NEUROPATHIC PAIN. WE SHOW THAT NERVE INJURY PROFOUNDLY REDUCED MRNA LEVELS OF CB(1)RS BUT INCREASED THE EXPRESSION OF CB(2) RECEPTORS IN THE RAT DRG. CHIP RESULTS INDICATED INCREASED ENRICHMENT OF HISTONE 3 AT LYSINE 9 DIMETHYLATION, A G9A-CATALYZED REPRESSIVE HISTONE MARK, AT THE PROMOTER REGIONS OF THE CB(1)R GENES. G9A INHIBITION IN NERVE-INJURED RATS NOT ONLY UP-REGULATED THE CB(1)R EXPRESSION LEVEL IN THE DRG BUT ALSO POTENTIATED THE ANALGESIC EFFECT OF A CB(1)R AGONIST ON NERVE INJURY-INDUCED PAIN HYPERSENSITIVITY. FURTHERMORE, IN MICE LACKING EHMT2 IN DRG NEURONS, NERVE INJURY FAILED TO REDUCE CB(1)R EXPRESSION IN THE DRG AND TO DECREASE THE ANALGESIC EFFECT OF THE CB(1)R AGONIST. MOREOVER, NERVE INJURY DIMINISHED THE INHIBITORY EFFECT OF THE CB(1)R AGONIST ON SYNAPTIC GLUTAMATE RELEASE FROM PRIMARY AFFERENT NERVES TO SPINAL CORD DORSAL HORN NEURONS IN WT MICE BUT NOT IN MICE LACKING EHMT2 IN DRG NEURONS. OUR FINDINGS REVEAL THAT NERVE INJURY DIMINISHES THE ANALGESIC EFFECT OF CB(1)R AGONISTS THROUGH G9A-MEDIATED CB(1)R DOWN-REGULATION IN PRIMARY SENSORY NEURONS. 2020 18 532 33 ASTROCYTIC C-JUN N-TERMINAL KINASE-HISTONE DEACETYLASE-2 CASCADE CONTRIBUTES TO GLUTAMATE TRANSPORTER-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY IN RATS. DECREASE OF GLUTAMATE TRANSPORTER-1 (GLT-1) IN THE SPINAL DORSAL HORN AFTER NERVE INJURY INDUCES ENHANCED EXCITATORY TRANSMISSION AND CAUSES PERSISTENT PAIN. HISTONE DEACETYLASES (HDACS)-CATALYZED DEACETYLATION MIGHT CONTRIBUTE TO THE DECREASE OF GLT-1, WHILE THE DETAILED MECHANISMS HAVE YET TO BE FULLY ELABORATED. SPINAL NERVE LIGATION (SNL) INDUCED SIGNIFICANT INCREASES OF HDAC2 AND DECREASES OF GLT-1 IN SPINAL ASTROCYTES. INTRATHECAL INFUSION OF THE HDAC2 INHIBITORS ATTENUATED THE DECREASE OF GLT-1 AND ENHANCED PHOSPHORYLATION OF GLUTAMATE RECEPTORS. GLT-1 AND PHOSPHORYLATED C-JUN N-TERMINAL KINASE (JNK) WERE HIGHLY COLOCALIZED IN THE SPINAL CORD, AND A LARGE NUMBER OF PJNK POSITIVE CELLS WERE HDAC2 POSITIVE. INTRATHECALLY INFUSION OF THE JNK INHIBITOR SP600125 SIGNIFICANTLY INHIBITED SNL-INDUCED UPREGULATION OF HDAC2. SNL-INDUCED HDAC2 UP-REGULATION COULD BE INHIBITED BY THE NEUTRALIZING ANTI-TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) BINDING PROTEIN ETANERCEPT OR THE MICROGLIAL INHIBITOR MINOCYCLINE. IN CULTURED ASTROCYTES, TNF-ALPHA INDUCED ENHANCED PHOSPHORYLATION OF JNK AND A SIGNIFICANT INCREASE OF HDAC2, AS WELL AS A REMARKABLE DECREASE OF GLT-1, WHICH COULD BE PREVENTED BY SP600125 OR THE HDAC2 SPECIFIC INHIBITOR CAY10683. OUR DATA SUGGEST THAT ASTROCYTIC JNK-HDAC2 CASCADE CONTRIBUTES TO GLT-1 DECREASE AND MECHANICAL ALLODYNIA FOLLOWING PERIPHERAL NERVE INJURY. NEUROIMMUNE ACTIVATION AFTER PERIPHERAL NERVE INJURY COULD INDUCE EPIGENETIC MODIFICATION CHANGES IN ASTROCYTES AND CONTRIBUTE TO CHRONIC PAIN MAINTENANCE. 2021 19 6664 28 UPREGULATION OF LNCRNA71132 IN THE SPINAL CORD REGULATES HYPERSENSITIVITY IN A RAT MODEL OF BONE CANCER PAIN. BONE CANCER PAIN (BCP) IS A PERVASIVE CLINICAL SYMPTOM WHICH IMPAIRS THE QUALITY LIFE. LONG NONCODING RNAS (LNCRNAS) ARE ENRICHED IN THE CENTRAL NERVOUS SYSTEM AND PLAY INDISPENSABLE ROLES IN NUMEROUS BIOLOGICAL PROCESSES, WHILE ITS REGULATORY FUNCTION IN NOCICEPTIVE INFORMATION PROCESSING REMAINS ELUSIVE. HERE, WE REPORTED THAT FUNCTIONAL MODULATORY ROLE OF ENSRNOT00000071132 (LNCRNA71132) IN THE BCP PROCESS AND SPONGING WITH MIR-143 AND ITS DOWNSTREAM GPR85-DEPENDENT SIGNALING CASCADE. SPINAL LNCRNA71132 WAS REMARKABLY INCREASED IN THE RAT MODEL OF BONE CANCER PAIN. THE KNOCKDOWN OF SPINAL LNCRNA71132 REVERTED BCP BEHAVIORS AND SPINAL C-FOS NEURONAL SENSITIZATION. OVEREXPRESSION OF SPINAL LNCRNA71132 IN NAIVE RAT GENERATED PAIN BEHAVIORS, WHICH WERE ACCOMPANIED BY INCREASED SPINAL C-FOS NEURONAL SENSITIZATION. FURTHERMORE, IT WAS FOUND THAT LNCRNA71132 PARTICIPATES IN THE MODULATION OF BCP BY INVERSELY REGULATING THE PROCESSING OF MIR-143-5P. IN ADDITION, AN INCREASE IN EXPRESSION OF SPINAL LNCRNA71132 RESULTED IN THE DECREASE IN EXPRESSION OF MIR-143 UNDER THE BCP STATE. FINALLY, IT WAS FOUND THAT MIR-143-5P REGULATES PAIN BEHAVIORS BY TARGETING GPR85. OVEREXPRESSION OF MIR-143-5P IN THE SPINAL CORD REVERTED THE NOCICEPTIVE BEHAVIORS TRIGGERED BY BCP, ACCOMPANIED BY A DECREASE IN EXPRESSION OF SPINAL GPR85 PROTEIN, BUT NO INFLUENCE ON EXPRESSION OF GPR85 MRNA. THE FINDINGS OF THIS STUDY INDICATE THAT LNCRNA71132 WORKS AS A MIRNA SPONGE IN MIR-143-5P-MEDIATED POSTTRANSCRIPTIONAL MODULATION OF GPR85 EXPRESSION IN BCP. THEREFORE, EPIGENETIC INTERVENTIONS AGAINST LNCRNA71132 MAY POTENTIALLY WORK AS NOVEL TREATMENT AVENUES IN TREATING NOCICEPTIVE HYPERSENSITIVITY TRIGGERED BY BONE CANCER. 2023 20 5574 33 ROLE OF MICRORNA-143 IN NERVE INJURY-INDUCED UPREGULATION OF DNMT3A EXPRESSION IN PRIMARY SENSORY NEURONS. PERIPHERAL NERVE INJURY INCREASED THE EXPRESSION OF THE DNA METHYLTRANSFERASE 3A (DNMT3A) MRNA AND ITS ENCODING DNMT3A PROTEIN IN INJURED DORSAL ROOT GANGLIA (DRG). THIS INCREASE IS CONSIDERED AS AN ENDOGENOUS INSTIGATOR IN NEUROPATHIC PAIN GENESIS THROUGH EPIGENETIC SILENCING OF PAIN-ASSOCIATED GENES (SUCH AS OPRM1) IN INJURED DRG. HOWEVER, HOW DRG DNMT3A IS INCREASED FOLLOWING PERIPHERAL NERVE INJURY IS STILL ELUSIVE. WE REPORTED HERE THAT PERIPHERAL NERVE INJURY CAUSED BY THE FIFTH SPINAL NERVE LIGATION (SNL) DOWNREGULATED MICRORNA (MIR)-143 EXPRESSION IN INJURED DRG. THIS DOWNREGULATION WAS REQUIRED FOR SNL-INDUCED DRG DNMT3A INCREASE AS RESCUING MIR-143 DOWNREGULATION THROUGH MICROINJECTION OF MIR-143 MIMICS INTO INJURED DRG BLOCKED THE SNL-INDUCED INCREASE IN DNMT3A AND RESTORED THE SNL-INDUCED DECREASES IN OPRM1 MRNA AND ITS ENCODING MU OPIOID RECEPTOR (MOR) IN INJURED DRG, IMPAIRED SPINAL CORD CENTRAL SENSITIZATION AND NEUROPATHIC PAIN, AND IMPROVED MORPHINE ANALGESIC EFFECTS FOLLOWING SNL. MIMICKING SNL-INDUCED DRG MIR-143 DOWNREGULATION THROUGH DRG MICROINJECTION OF MIR143 INHIBITORS IN NAIVE RATS INCREASED THE EXPRESSION OF DNMT3A AND REDUCED THE EXPRESSION OF OPRM1 MRNA AND MOR IN INJECTED DRG AND PRODUCED NEUROPATHIC PAIN-LIKE SYMPTOMS. THESE FINDINGS SUGGEST THAT MIR-143 IS A NEGATIVE REGULATOR IN DNMT3A EXPRESSION IN THE DRG UNDER NEUROPATHIC PAIN CONDITIONS AND MAY BE A POTENTIAL TARGET FOR THERAPEUTIC MANAGEMENT OF NEUROPATHIC PAIN. 2017