1 821 117 CHARACTERIZATION OF ACETYLATION OF HISTONE H3 AT LYSINE 9 IN THE TRIGEMINAL GANGLION OF A RAT TRIGEMINAL NEURALGIA MODEL. TRIGEMINAL NEURALGIA (TN) IS A CHRONIC NEUROPATHIC PAIN DISORDER CHARACTERIZED BY SPONTANEOUS AND ELICITED PAROXYSMS OF ELECTRIC-SHOCK-LIKE OR STABBING PAIN IN A REGION OF THE FACE. THE EPIGENETIC REGULATION OF TN IS STILL OBSCURE. IN CURRENT STUDY, A RAT TN MODEL SUBJECT TO CARBAMAZEPINE (CBZ) TREATMENT WAS ESTABLISHED, AND TRANSCRIPTOME- AND GENOME-SCALE PROFILING OF H3K9AC AND HDAC3 WAS PERFORMED BY RNA-SEQ AND CHIP-SEQ. WE OBSERVED THAT H3K9AC LEVELS IN THE TRIGEMINAL GANGLION WERE LOWER IN THE TN RATS COMPARED WITH THOSE IN THE CONTROL, AND CBZ TREATMENT LED TO RECOVERY OF H3K9AC LEVELS. FURTHER, WE FOUND THAT HDAC3 WAS OVERACTIVATED, WHICH INTERFERED WITH H3K9 ACETYLATION DUE TO HIGHER PHOSPHORYLATION IN TN COMPARED WITH THAT IN THE CONTROL. FINALLY, THE PHOSPHOKINASE LEUCINE-RICH REPEAT KINASE 2 (LRRK2) WAS DEMONSTRATED TO CONTRIBUTE TO HDAC3 ACTIVITY VIA THE MAPK SIGNALING PATHWAY. TAKEN TOGETHER, WE IDENTIFIED A REGULATORY MECHANISM IN WHICH THE PHOSPHATE GROUPS TRANSFERRED FROM ACTIVATED ERK AND LRRK2 TO HDAC3 CAUSED GENOME-SCALE DEACETYLATION AT H3K9 AND RESULTED IN THE SILENCING OF A LARGE NUMBER OF GENES IN TN. THE KINASES OR IMPORTANT ENZYMES WITHIN THIS REGULATORY AXIS MAY REPRESENT IMPORTANT TARGETS FOR TN THERAPY AND PREVENTION. 2022 2 656 28 BLOCKADE OF THE IL-1R1/TLR4 PATHWAY MEDIATES DISEASE-MODIFICATION THERAPEUTIC EFFECTS IN A MODEL OF ACQUIRED EPILEPSY. WE RECENTLY DISCOVERED THAT FOREBRAIN ACTIVATION OF THE IL-1 RECEPTOR/TOLL-LIKE RECEPTOR (IL-1R1/TLR4) INNATE IMMUNITY SIGNAL PLAYS A PIVOTAL ROLE IN NEURONAL HYPEREXCITABILITY UNDERLYING SEIZURES IN RODENTS. SINCE THIS PATHWAY IS ACTIVATED IN NEURONS AND GLIA IN HUMAN EPILEPTOGENIC FOCI, IT REPRESENTS A POTENTIAL TARGET FOR DEVELOPING DRUGS INTERFERING WITH THE MECHANISMS OF EPILEPTOGENESIS THAT LEAD TO SPONTANEOUS SEIZURES. THE LACK OF SUCH DRUGS REPRESENTS A MAJOR UNMET CLINICAL NEED. WE TESTED THEREFORE NOVEL THERAPIES INHIBITING THE IL-1R1/TLR4 SIGNALING IN AN ESTABLISHED MURINE MODEL OF ACQUIRED EPILEPSY. WE USED AN EPIGENETIC APPROACH BY INJECTING A SYNTHETIC MIMIC OF MICRO(MI)RNA-146A THAT IMPAIRS IL1R1/TLR4 SIGNAL TRANSDUCTION, OR WE BLOCKED RECEPTOR ACTIVATION WITH ANTIINFLAMMATORY DRUGS. BOTH INTERVENTIONS WHEN TRANSIENTLY APPLIED TO MICE AFTER EPILEPSY ONSET, PREVENTED DISEASE PROGRESSION AND DRAMATICALLY REDUCED CHRONIC SEIZURE RECURRENCE, WHILE THE ANTICONVULSANT DRUG CARBAMAZEPINE WAS INEFFECTIVE. WE CONCLUDE THAT IL-1R1/TLR4 IS A NOVEL POTENTIAL THERAPEUTIC TARGET FOR ATTAINING DISEASE-MODIFICATIONS IN PATIENTS WITH DIAGNOSED EPILEPSY. 2017 3 3542 37 IMMUNOHISTOCHEMICAL ANALYSIS OF HISTONE H3 ACETYLATION IN THE TRIGEMINAL ROOT ENTRY ZONE IN AN ANIMAL MODEL OF TRIGEMINAL NEURALGIA. OBJECTIVE: THE TRIGEMINAL ROOT ENTRY ZONE (TREZ) IS A TRANSITIONAL ZONE BETWEEN THE CENTRAL NERVOUS SYSTEM (CNS) AND PERIPHERAL NERVOUS SYSTEM (PNS), ADJACENT TO THE BRAINSTEM. MICROVASCULAR COMPRESSION OF THE TREZ HAS BEEN CONSIDERED TO BE THE PRIMARY ETIOLOGY IN MOST CASES OF TRIGEMINAL NEURALGIA (TN), BUT WHETHER EPIGENETIC REGULATION IS INVOLVED IN THE PATHOGENESIS OF TN IS STILL UNCLEAR. THEREFORE, THIS STUDY WAS DESIGNED TO INVESTIGATE THE EPIGENETIC REGULATION OF HISTONE H3 ACETYLATION IN THE TREZ IN AN ANIMAL MODEL OF TN. METHODS: AN ANIMAL MODEL OF TN WAS ESTABLISHED, AND ADULT MALE SPRAGUE-DAWLEY RATS WERE RANDOMLY ASSIGNED TO A TN GROUP WITH TRIGEMINAL NERVE ROOT COMPRESSION, SHAM OPERATION GROUP, TN+HDACI GROUP (TN PLUS SELECTIVE HISTONE DEACETYLASE INHIBITOR INJECTION INTO THE TREZ), OR TN+VEH GROUP (TN PLUS VEHICLE INJECTION INTO THE TREZ). TO MEASURE THE LENGTH OF THE CENTRAL PORTION OF THE TREZ FROM THE JUNCTION OF THE TRIGEMINAL NERVE ROOT ENTERING THE PONS TO THE INTERFACE OF THE DOME-SHAPED CNS-PNS TRANSITIONAL ZONE, IMMUNOFLUORESCENT STAINING OF GLIA AND GLIAL NUCLEI WAS PERFORMED USING GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP) ANTIBODY AND DAPI, RESPECTIVELY. TO INVESTIGATE THE ACETYLATION OF HISTONE H3 WITHIN THE TREZ IN A TN ANIMAL MODEL GROUP AND A SHAM OPERATION GROUP, LOCALIZATION OF HISTONE H3K9, H3K18, AND H3K27 ACETYLATION WAS EXAMINED VIA IMMUNOHISTOCHEMICAL STAINING METHODS. RESULTS: MEASUREMENTS OF THE CNS-PNS TRANSITIONAL ZONE IN THE TREZ REVEALED THAT THE AVERAGE LENGTH FROM THE JUNCTION OF THE TRIGEMINAL NERVE ROOT CONNECTING THE PONS TO THE GLIAL FRINGE OF THE TREZ IN THE TN GROUP WAS LONGER THAN THAT IN THE SHAM OPERATION GROUP (P < 0.05) AND THAT THE INTERFACE GRADUALLY MIGRATED DISTALLY. CELLS THAT STAINED POSITIVE FOR ACETYLATED HISTONE H3K9, H3K18, AND H3K27 WERE DISTRIBUTED AROUND BOTH SIDES OF THE BORDER OF THE CNS-PNS JUNCTION IN THE TREZ. THE RATIO OF IMMUNOREACTIVE H3K9-, H3K18- AND H3K27-POSITIVE CELLS IN THE TN GROUP WAS OBVIOUSLY HIGHER THAN THAT IN THE SHAM OPERATION GROUP ON POSTOPERATIVE DAYS 7, 14, 21, AND 28 (P < 0.05). CONCLUSIONS: THESE RESULTS SUGGESTED THAT CHRONIC COMPRESSION OF THE TRIGEMINAL NERVE ROOT MAY BE INVOLVED IN THE PATHOGENESIS OF TN IN AN ANIMAL MODEL BY INFLUENCING THE PLASTICITY OF THE CNS-PNS TRANSITIONAL ZONE AND THE LEVEL OF HISTONE ACETYLATION IN THE TREZ. 2018 4 6256 32 THE MITOGEN AND STRESS-ACTIVATED PROTEIN KINASE 1 REGULATES THE RAPID EPIGENETIC TAGGING OF DORSAL HORN NEURONS AND NOCIFENSIVE BEHAVIOUR. PHOSPHORYLATION OF HISTONE H3 AT SERINE 10 (P-H3S10) IS A MARKER OF ACTIVE GENE TRANSCRIPTION. USING COGNITIVE MODELS OF NEURAL PLASTICITY, P-H3S10 WAS SHOWN TO BE DOWNSTREAM OF EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALLING IN THE HIPPOCAMPUS. IN THIS STUDY, WE SHOW THAT NOCICEPTIVE SIGNALLING AFTER PERIPHERAL FORMALIN INJECTION INCREASED P-H3S10 EXPRESSION IN THE IPSILATERAL DORSAL HORN. THIS INCREASE WAS MAXIMAL 30 MINUTES AFTER FORMALIN INJECTION AND OCCURRED MAINLY WITHIN P-ERK-POSITIVE NEURONS. SPINAL P-H3S10-ENHANCED EXPRESSION WAS ALSO OBSERVED IN NEUROKININ 1 RECEPTOR (NK1R), C-FOS, AND ZIF268 POSITIVE NEURONS AND WAS INHIBITED BY ABLATION OF SEROTONERGIC DESCENDING CONTROLS. THE MITOGEN AND STRESS-ACTIVATED PROTEIN KINASE 1 (MSK1) IS DOWNSTREAM OF ERK AND CAN INDUCE P-H3S10. WE FOUND THAT, AFTER FORMALIN INJECTION, MOST PHOSPHO-MSK1 (P-MSK1)-POSITIVE CELLS (87% +/- 3%) EXPRESSED P-ERK AND THE MAJORITY OF P-H3S10-POSITIVE CELLS (85% +/- 5%) EXPRESSED P-MSK1. INHIBITION OF ERK ACTIVITY WITH THE MEK INHIBITOR SL327 REDUCED FORMALIN-INDUCED P-ERK, P-MSK1, AND P-H3S10, DEMONSTRATING THAT SPINAL P-MSK1 AND P-H3S10 WERE AT LEAST PARTLY DOWNSTREAM OF ERK SIGNALLING. CRUCIALLY, PHARMACOLOGICAL BLOCKADE OF SPINAL MSK1 ACTIVITY WITH THE NOVEL MSK1 INHIBITOR SB727651A INHIBITED FORMALIN-INDUCED SPINAL P-H3S10 AND NOCIFENSIVE BEHAVIOUR. THESE FINDINGS ARE THE FIRST TO ESTABLISH THE INVOLVEMENT OF P-H3S10 AND ITS MAIN KINASE, MSK1, IN ERK REGULATION OF NOCICEPTION. GIVEN THE GENERAL IMPORTANCE OF ERK SIGNALLING IN PAIN PROCESSING, OUR RESULTS SUGGEST THAT P-H3S10 COULD PLAY A ROLE IN THE RESPONSE TO INJURY. 2016 5 5062 34 PHOSPHATE NIMA-RELATED KINASE 2-DEPENDENT EPIGENETIC PATHWAYS IN DORSAL ROOT GANGLION NEURONS MEDIATES PACLITAXEL-INDUCED NEUROPATHIC PAIN. BACKGROUND: THE MICROTUBULE-STABILIZING DRUG PACLITAXEL (PTX) IS AN IMPORTANT CHEMOTHERAPEUTIC AGENT FOR CANCER TREATMENT AND CAUSES PERIPHERAL NEUROPATHY AS A COMMON SIDE EFFECT THAT SUBSTANTIALLY IMPACTS THE FUNCTIONAL STATUS AND QUALITY OF LIFE OF PATIENTS. THE MECHANISTIC ROLE FOR NIMA-RELATED KINASE 2 (NEK2) IN THE PROGRESSION OF PTX-INDUCED NEUROPATHIC PAIN HAS NOT BEEN ESTABLISHED. METHODS: ADULT MALE SPRAGUE-DAWLEY RATS INTRAPERITONEALLY RECEIVED PTX TO INDUCE NEUROPATHIC PAIN. THE PROTEIN EXPRESSION LEVELS IN THE DORSAL ROOT GANGLION (DRG) OF ANIMALS WERE MEASURED BY BIOCHEMICAL ANALYSES. NOCICEPTIVE BEHAVIORS WERE EVALUATED BY VON FREY TESTS AND HOT PLATE TESTS. RESULTS: PTX INCREASED PHOSPHORYLATION OF THE IMPORTANT MICROTUBULE DYNAMICS REGULATOR NEK2 IN DRG NEURONS AND INDUCED PROFOUND NEUROPATHIC ALLODYNIA. PTX-ACTIVATED PHOSPHORYLATED NEK2 (PNEK2) INCREASED JUMONJI DOMAIN-CONTAINING 3 (JMJD3) PROTEIN, A HISTONE DEMETHYLASE PROTEIN, TO SPECIFICALLY CATALYZE THE DEMETHYLATION OF THE REPRESSIVE HISTONE MARK H3 LYSINE 27 TRIMETHYLATION (H3K27ME3) AT THE TRPV1 GENE, THEREBY ENHANCING TRANSIENT RECEPTOR POTENTIAL VANILLOID SUBTYPE-1 (TRPV1) EXPRESSION IN DRG NEURONS. MOREOVER, THE PNEK2-DEPENDENT PTX RESPONSE PROGRAM IS REGULATED BY ENHANCING P90 RIBOSOMAL S6 KINASE 2 (RSK2) PHOSPHORYLATION. CONVERSELY, INTRATHECAL INJECTIONS OF KAEMPFEROL (A SELECTIVE RSK2 ACTIVATION ANTAGONIST), NCL 00017509 (A SELECTIVE NEK2 INHIBITOR), NEK2-TARGETED SIRNA, GSK-J4 (A SELECTIVE JMJD3 INHIBITOR), OR CAPSAZEPINE (AN ANTAGONIST OF TRPV1 RECEPTOR) INTO PTX-TREATED RATS REVERSED NEUROPATHIC ALLODYNIA AND RESTORED SILENCING OF THE TRPV1 GENE, SUGGESTING THE HIERARCHY AND INTERACTION AMONG PHOSPHORYLATED RSK2 (PRSK2), PNEK2, JMJD3, H3K27ME3, AND TRPV1 IN THE DRG NEURONS IN PTX-INDUCED NEUROPATHIC PAIN. CONCLUSIONS: PRSK2/JMJD3/H3K27ME3/TRPV1 SIGNALING IN THE DRG NEURONS PLAYS AS A KEY REGULATOR FOR PTX THERAPEUTIC APPROACHES. 2023 6 4176 31 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 7 3368 31 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 8 532 26 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 9 3332 32 HISTONE DEACETYLASE INHIBITOR-INDUCED EMERGENCE OF SYNAPTIC DELTA-OPIOID RECEPTORS AND BEHAVIORAL ANTINOCICEPTION IN PERSISTENT NEUROPATHIC PAIN. THE EFFICACY OF OPIOIDS IN PATIENTS WITH CHRONIC NEUROPATHIC PAIN REMAINS CONTROVERSIAL. ALTHOUGH ACTIVATION OF DELTA-OPIOID RECEPTORS (DORS) IN THE BRAINSTEM REDUCES INFLAMMATION-INDUCED PERSISTENT HYPERALGESIA, IT IS NOT EFFECTIVE UNDER PERSISTENT NEUROPATHIC PAIN CONDITIONS AND THESE CLINICAL PROBLEMS REMAIN LARGELY UNKNOWN. IN THIS STUDY, BY USING A CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN RATS, WE FOUND THAT IN THE BRAINSTEM NUCLEUS RAPHE MAGNUS (NRM), DORS EMERGED ON THE SURFACE MEMBRANE OF CENTRAL SYNAPTIC TERMINALS ON DAY 3 AFTER CCI SURGERY AND DISAPPEARED ON DAY 14. HISTONE DEACETYLASE (HDAC) INHIBITORS MICROINJECTED INTO THE NRM IN VIVO INCREASED THE LEVEL OF SYNAPTOSOMAL DOR PROTEIN AND NRM INFUSION OF DOR AGONISTS PRODUCING AN ANTINOCICEPTIVE EFFECT IN A NERVE GROWTH FACTOR (NGF) SIGNALING-DEPENDENT MANNER. IN VITRO, IN CCI RAT SLICES INCUBATED WITH HDAC INHIBITORS, DOR AGONISTS SIGNIFICANTLY INHIBITED EPSCS. THIS EFFECT WAS BLOCKED BY TYROSINE RECEPTOR KINASE A ANTAGONISTS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT NRM INFUSION OF HDAC INHIBITORS IN CCI RATS INCREASED THE LEVEL OF HISTONE H4 ACETYLATION AT NGF GENE PROMOTER REGIONS. NGF WAS INFUSED INTO THE NRM OR INCUBATED CCI RAT SLICES DROVE DORS TO THE SURFACE MEMBRANE OF SYNAPTIC TERMINALS. TAKEN TOGETHER, EPIGENETIC UPREGULATION OF NGF ACTIVITY BY HDAC INHIBITORS IN THE NRM PROMOTES THE TRAFFICKING OF DORS TO PAIN-MODULATING NEURONAL SYNAPSES UNDER NEUROPATHIC PAIN CONDITIONS, LEADING TO DELTA-OPIOID ANALGESIA. THESE FINDINGS INDICATE THAT THERAPEUTIC USE OF DOR AGONISTS COMBINED WITH HDAC INHIBITORS MIGHT BE EFFECTIVE IN CHRONIC NEUROPATHIC PAIN MANAGEMENTS. 2016 10 2751 26 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 11 3334 30 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 12 4919 31 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 13 2006 31 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 14 3154 30 GLUN2B/CAMKII MEDIATES CFA-INDUCED HYPERALGESIA VIA HDAC4-MODIFIED SPINAL COX2 TRANSCRIPTION. HISTONE DEACETYLASE 4 (HDAC4), WHICH ACTIVELY SHUTTLES BETWEEN THE NUCLEUS AND CYTOPLASM, IS AN ATTRACTIVE CANDIDATE FOR A REPRESSOR MECHANISM IN EPIGENETIC MODIFICATION. HOWEVER, THE POTENTIAL ROLE OF HDAC4-DEPENDENT EPIGENETICS IN THE NEURAL PLASTICITY UNDERLYING THE DEVELOPMENT OF INFLAMMATORY PAIN HAS NOT BEEN WELL ESTABLISHED. BY INJECTING COMPLETE FREUND'S ADJUVANT (CFA) INTO THE HIND-PAW OF SPRAGUE-DAWLEY RATS (200-250 G), WE FOUND ANIMALS DISPLAYED BEHAVIORAL HYPERALGESIA WAS ACCOMPANIED WITH HDAC4 PHOSPHORYLATION AND CYTOPLASMIC REDISTRIBUTION IN THE DORSAL HORN NEURONS. CYTOPLASMIC HDAC4 RETENTION LED TO ITS UNCOUPLING WITH THE COX2 PROMOTER, HENCE PROMPTING SPINAL COX2 TRANSCRIPTION AND EXPRESSION IN THE DORSAL HORN. MOREOVER, THE GLUN2B-BEARING N-METHYL-D-ASPARTATE RECEPTOR (GLUN2B-NMDAR)/CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKII) ACTED AS AN UPSTREAM CASCADE TO FACILITATE HDAC4 PHOSPHORYLATION/REDISTRIBUTION-ASSOCIATED SPINAL COX2 EXPRESSION AFTER INFLAMMATORY INSULTS. THE RESULTS OF THIS PILOT STUDY DEMONSTRATED THAT THE DEVELOPMENT AND/OR MAINTENANCE OF INFLAMMATORY PAIN INVOLVED THE SPINAL HDAC4-DEPENDENT EPIGENETIC MECHANISMS. OUR FINDINGS OPEN UP A NEW AVENUE FOR THE DEVELOPMENT OF A NOVEL MEDICAL STRATEGY FOR THE RELIEF OF INFLAMMATORY PAIN. 2018 15 804 33 CENTRAL ENDOTHELIN-1 CONFERS ANALGESIA BY TRIGGERING SPINAL NEURONAL HISTONE DEACETYLASE 5 (HDAC5) NUCLEAR EXCLUSION IN PERIPHERAL NEUROPATHIC PAIN IN MICE. THE RATIONALE OF SPINAL ADMINISTRATION OF ENDOTHELIN-1(ET-1) MEDIATED ANTI-NOCICEPTIVE EFFECT HAS NOT BEEN ELUCIDATED. ET-1 IS REPORTED TO PROMOTE NUCLEAR EFFLUXION OF HISTONE DEACETYLASE 5 (HDAC5) IN MYOCYTES, AND SPINAL HDAC5 IS IMPLICATED IN MODULATION OF PAIN PROCESSING. IN THIS STUDY, WE AIMED TO INVESTIGATE WHETHER CENTRAL ET-1 PLAYS AN ANTI-NOCICEPTIVE ROLE BY FACILITATING SPINAL HDAC5 NUCLEAR SHUTTLING UNDER NEUROPATHIC PAIN. HERE, WE DEMONSTRATE THAT UPREGULATING SPINAL ET-1 ATTENUATED THE NOCICEPTION INDUCED BY PARTIAL SCIATIC NERVE LIGATION SURGERY AND THIS ANALGESIC EFFECT MEDIATED BY ET-1 WAS ATTENUATED BY INTRATHECAL INJECTION OF ENDOTHELIN A RECEPTOR SELECTIVE INHIBITOR (BQ123) OR BY BLOCKING THE EXPORTATION OF NUCLEAR HDAC5 BY ADENO-ASSOCIATED VIRUSES TARGETING NEURONAL HDAC5 (AVV-HDAC5 S259/498A MUTANT). NOTABLY, ET-1 ADMINISTRATION INCREASED SPINAL GLUTAMATE ACID DECARBOXYLASES (GAD65/67) EXPRESSION VIA INITIATING HDAC5 NUCLEAR EXPORTATION AND INCREASED THE ACETYLATION OF HISTONE 3 AT LYSINE 9 (ACETYL-H3K9) IN THE PROMOTOR REGIONS OF SPINAL GAD1 AND GAD2 GENES. THIS WAS REVERSED BY BLOCKING ENDOTHELIN A RECEPTOR FUNCTION OR BY INHIBITING THE SPINAL NEURONAL NUCLEAR EXPORTATION OF HDAC5. THEREFORE, INDUCING SPINAL GABAERGIC NEURONAL HDAC5 NUCLEAR EXPORTATION MAY BE A NOVEL THERAPEUTIC APPROACH FOR MANAGING NEUROPATHIC PAIN. PERSPECTIVE: NEUROPATHIC PAIN IS INTRACTABLE IN A CLINICAL SETTING, AND EPIGENETIC REGULATION IS CONSIDERED TO CONTRIBUTE TO THIS PROCESSING. CHARACTERIZING THE ANTI-NOCICEPTIVE EFFECT OF ET-1 AND INVESTIGATING THE ASSOCIATED EPIGENETIC MECHANISMS IN ANIMAL MODELS MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC STRATEGIES AND TARGETS FOR TREATING NEUROPATHIC PAIN. 2021 16 5354 26 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 17 1018 26 CIRCFHIT MODULATES GABAERGIC SYNAPTIC TRANSMISSION VIA REGULATING THE PARENTAL GENE FHIT EXPRESSION IN THE SPINAL DORSAL HORN IN A RAT MODEL OF NEUROPATHIC PAIN. EFFECTIVE TREATMENTS FOR NEUROPATHIC PAIN ARE LACKING DUE TO OUR LIMITED UNDERSTANDING OF THE MECHANISMS. THE CIRCRNAS ARE MAINLY ENRICHED IN THE CENTRAL NERVOUS SYSTEM. HOWEVER, THEIR FUNCTION IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS HAVE YET TO BE DETERMINED. HERE, WE IDENTIFIED CIRCFHIT, AN EXON-INTRON CIRCRNA EXPRESSED IN GABAERGIC NEURONS, WHICH REDUCED THE INHIBITORY SYNAPTIC TRANSMISSION IN THE SPINAL DORSAL HORN TO MEDIATE SPARED NERVE INJURY-INDUCED NEUROPATHIC PAIN. MOREOVER, WE FOUND THAT CIRCFHIT DECREASED THE EXPRESSION OF GAD65 AND INDUCED HYPEREXCITATION IN NK1R(+) NEURONS BY PROMOTING THE EXPRESSION OF ITS PARENTAL GENE FHIT IN CIS. MECHANISTICALLY, CIRCFHIT WAS DIRECTLY BOUND TO THE INTRONIC REGION OF FHIT, AND FORMED A CIRCFHIT/HNRNPK COMPLEX TO PROMOTE POL II PHOSPHORYLATION AND H2B MONOUBIQUITINATION BY RECRUITING CDK9 AND RNF40 TO THE FHIT INTRON. IN SUMMARY, WE REVEALED THAT THE EXON-INTRON CIRCFHIT CONTRIBUTES TO GABAERGIC NEURON-MEDIATED NK1R(+) NEURONAL HYPEREXCITATION AND NEUROPATHIC PAIN VIA REGULATING FHIT IN CIS. 2023 18 5780 24 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 19 2476 32 EPIGENETIC UPREGULATION OF CCL2 AND CCL3 VIA HISTONE MODIFICATIONS IN INFILTRATING MACROPHAGES AFTER PERIPHERAL NERVE INJURY. TO GAIN INSIGHT INTO THE EPIGENETIC REGULATION OF CC-CHEMOKINE LIGAND (CCL) 2 AND CCL3, KEY PLAYERS IN THE PERIPHERAL SENSITIZATION LEADING TO NEUROPATHIC PAIN, WE EXAMINED THE RELATIONSHIP BETWEEN HISTONE H3 MODIFICATION AND THE UPREGULATION OF THESE MOLECULES USING A MOUSE MODEL OF NEUROPATHIC PAIN AFTER PARTIAL SCIATIC NERVE LIGATION (PSL). WE FOUND THAT CIRCUITING BONE MARROW (BM)-DERIVED MACROPHAGES INFILTRATED INTO THE INJURED SCIATIC NERVE (SCN) USING ENHANCED GREEN FLUORESCENT PROTEIN CHIMERIC MICE. THE MRNA LEVELS OF CCL2, CCL3 AND THEIR RECEPTORS (CCR2 AND CCR1/CCR5, RESPECTIVELY) WERE INCREASED IN THE INJURED SCN. CHROMATIN IMMUNOPRECIPITATION ASSAY REVEALED THAT LEVELS OF LYSINE 9-ACETYLATED HISTONE H3 (H3K9AC) AND LYSINE 4-TRIMETHYLATED H3 (H3K4ME(3)) IN THE PROMOTER REGIONS OF THE CCL2 AND CCL3 GENES WERE INCREASED IN THE INJURED SCN AFTER PSL, INDICATING THE ENHANCEMENT OF GENE EXPRESSION. IMMUNOREACTIVITY FOR H3K9AC AND H3K4ME(3) WAS LOCALIZED IN THE NUCLEI OF INFILTRATING BM-DERIVED CELLS AND CCL-EXPRESSING CELLS IN THE INJURED SCN. WE OBSERVED H3K9AC AND H3K4ME(3) MAINLY IN THE NUCLEI OF RECRUITED MACROPHAGES ON DAY 7 AFTER PSL. FURTHERMORE, UPREGULATION OF CCLS AND CCRS WERE SUPPRESSED BY HISTONE ACETYLTRANSFERASE INHIBITOR, ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS DEMONSTRATE THAT CCL2 AND CCL3 ARE UPREGULATED IN THE INJURED PERIPHERAL NERVE THROUGH EPIGENETIC HISTONE MODIFICATION IN INFILTRATING IMMUNE CELLS SUCH AS MACROPHAGES. THESE CHEMOKINE CASCADES MAY SUBSEQUENTLY ELICIT CHRONIC NEUROINFLAMMATION FOLLOWING NERVE INJURY. 2013 20 1167 30 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