1  532 107 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 2470  39 EPIGENETIC TRANSCRIPTIONAL ACTIVATION OF MONOCYTE CHEMOTACTIC PROTEIN 3 CONTRIBUTES TO LONG-LASTING NEUROPATHIC PAIN. A MULTIPLEX ANALYSIS FOR PROFILING THE EXPRESSION OF CANDIDATE GENES ALONG WITH EPIGENETIC MODIFICATION MAY LEAD TO A BETTER UNDERSTANDING OF THE COMPLEX MACHINERY OF NEUROPATHIC PAIN. IN THE PRESENT STUDY, WE FOUND THAT PARTIAL SCIATIC NERVE LIGATION MOST REMARKABLY INCREASED THE EXPRESSION OF MONOCYTE CHEMOTACTIC PROTEIN 3 (MCP-3, KNOWN AS CCL7) A TOTAL OF 33 541 GENES IN THE SPINAL CORD, WHICH LASTED FOR 4 WEEKS. THIS INCREASE IN MCP-3 GENE TRANSCRIPTION WAS ACCOMPANIED BY THE DECREASED TRIMETHYLATION OF HISTONE H3 AT LYS27 AT THE MCP-3 PROMOTER. THE INCREASED MCP-3 EXPRESSION ASSOCIATED WITH ITS EPIGENETIC MODIFICATION OBSERVED IN THE SPINAL CORD WAS ALMOST ABOLISHED IN INTERLEUKIN 6 KNOCKOUT MICE WITH PARTIAL SCIATIC NERVE LIGATION. CONSISTENT WITH THESE FINDINGS, A SINGLE INTRATHECAL INJECTION OF RECOMBINANT PROTEINS OF INTERLEUKIN 6 SIGNIFICANTLY INCREASED MCP-3 MESSENGER RNA WITH A DECREASE IN THE LEVEL OF LYS27 TRIMETHYLATION OF HISTONE H3 AT THE MCP-3 PROMOTER IN THE SPINAL CORD OF MICE. FURTHERMORE, DELETION OF THE C-C CHEMOKINE RECEPTOR TYPE 2 (CCR2) GENE, WHICH ENCODES A RECEPTOR FOR MCP-3, FAILED TO AFFECT THE ACCELERATION OF MCP-3 EXPRESSION IN THE SPINAL CORD AFTER PARTIAL SCIATIC NERVE LIGATION. A ROBUST INCREASE IN MCP-3 PROTEIN, WHICH LASTED FOR UP TO 2 WEEKS AFTER SURGERY, IN THE DORSAL HORN OF THE SPINAL CORD OF MICE WITH PARTIAL SCIATIC NERVE LIGATION WAS SEEN MOSTLY IN ASTROCYTES, BUT NOT MICROGLIA OR NEURONS. ON THE OTHER HAND, THE INCREASES IN BOTH MICROGLIA AND ASTROCYTES IN THE SPINAL CORD BY PARTIAL SCIATIC NERVE LIGATION WERE MOSTLY ABOLISHED IN INTERLEUKIN 6 KNOCKOUT MICE. MOREOVER, THIS INCREASE IN MICROGLIA WAS ALMOST ABOLISHED BY CCR2 GENE DELETION, WHEREAS THE INCREASE IN ASTROCYTES WAS NOT AFFECTED IN NERVE-LIGATED MICE THAT LACKED THE CCR2 GENE. WE ALSO FOUND THAT EITHER IN VIVO OR IN VITRO TREATMENT WITH MCP-3 CAUSED ROBUST MICROGLIA ACTIVATION. UNDER THESE CONDITIONS, INTRATHECAL ADMINISTRATION OF MCP-3 ANTIBODY SUPPRESSED THE INCREASE IN MICROGLIA WITHIN THE MOUSE SPINAL CORD AND NEUROPATHIC PAIN-LIKE BEHAVIOURS AFTER NERVE INJURY. WITH THE USE OF A FUNCTIONAL MAGNETIC RESONANCE IMAGING ANALYSIS, WE DEMONSTRATED THAT A SINGLE INTRATHECAL INJECTION OF MCP-3 INDUCED DRAMATIC INCREASES IN SIGNAL INTENSITY IN PAIN-RELATED BRAIN REGIONS. THESE FINDINGS SUGGEST THAT INCREASED MCP-3 EXPRESSION ASSOCIATED WITH INTERLEUKIN 6 DEPENDENT EPIGENETIC MODIFICATION AT THE MCP-3 PROMOTER AFTER NERVE INJURY, MOSTLY IN SPINAL ASTROCYTES, MAY SERVE TO FACILITATE ASTROCYTE-MICROGLIA INTERACTION IN THE SPINAL CORD AND COULD PLAY A CRITICAL ROLE IN THE NEUROPATHIC PAIN-LIKE STATE.	2013	

3 1318  37 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	
                        
4 5692  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5 5401  34 REDUCTION OF SIRT1 EPIGENETICALLY UPREGULATES NALP1 EXPRESSION AND CONTRIBUTES TO NEUROPATHIC PAIN INDUCED BY CHEMOTHERAPEUTIC DRUG BORTEZOMIB. BACKGROUND: BORTEZOMIB IS A FREQUENTLY USED CHEMOTHERAPEUTIC DRUG FOR THE TREATMENT OF MULTIPLE MYELOMA AND OTHER NONSOLID MALIGNANCIES. ACCUMULATING EVIDENCE HAS DEMONSTRATED THAT BORTEZOMIB-INDUCED PERSISTENT PAIN SERVES AS THE MOST FREQUENT REASON FOR TREATMENT DISCONTINUATION. METHODS: THE VON FREY TEST WAS PERFORMED TO EVALUATE NEUROPATHIC PAIN BEHAVIOR, AND REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION, CHROMATIN IMMUNOPRECIPITATION, WESTERN BLOT, IMMUNOHISTOCHEMISTRY, AND SMALL INTERFERING RNA WERE PERFORMED TO EXPLORE THE MOLECULAR MECHANISMS IN ADULT MALE SPRAGUE-DAWLEY RATS. RESULTS: WE FOUND THAT APPLICATION OF BORTEZOMIB SIGNIFICANTLY INCREASED THE EXPRESSION OF NALP1 PROTEIN AND MRNA LEVELS IN SPINAL DORSAL HORN NEURONS, AND INTRATHECAL APPLICATION OF NALP1 SIRNA ATTENUATED THE BORTEZOMIB-INDUCED MECHANICAL ALLODYNIA. IN ADDITION, BORTEZOMIB ALSO DECREASED THE SIRT1 EXPRESSION, AND TREATMENT WITH SIRT1 ACTIVATOR RESVERATROL AMELIORATED THE NALP1 UPREGULATION AND MECHANICAL ALLODYNIA INDUCED BY BORTEZOMIB. MEANWHILE, KNOCKDOWN OF SIRT1 USING THE SIRT1 SIRNA INDUCED THE NALP1 UPREGULATION IN DORSAL HORN AND MECHANICAL ALLODYNIA IN NORMAL ANIMAL. THESE RESULTS SUGGESTED THAT REDUCTION OF SIRT1 INDUCED THE NALP1 UPREGULATION IN DORSAL HORN NEURONS, AND PARTICIPATED IN BORTEZOMIB-INDUCED MECHANICAL ALLODYNIA. IMPORTANTLY, WE FOUND THAT THE BINDING OF SIRT1 AND NALP1 PROMOTER REGION DID NOT CHANGE BEFORE AND AFTER BORTEZOMIB TREATMENT, BUT SIRT1 DOWNREGULATION INCREASED P-STAT3 EXPRESSION. FURTHERMORE, THE ACTIVATION OF STAT3 ENHANCED THE RECRUITMENT OF P-STAT3 TO THE NALP1 GENE PROMOTER, WHICH INCREASED THE ACETYLATION OF HISTONE H3 AND H4 IN NALP1 PROMOTER REGIONS AND EPIGENETICALLY UPREGULATED NALP1 EXPRESSION IN THE RODENTS WITH BORTEZOMIB TREATMENT. CONCLUSION: THESE FINDINGS SUGGESTED A NEW EPIGENETIC MECHANISM FOR NALP1 UPREGULATION INVOLVING SIRT1 REDUCTION AND SUBSEQUENT STAT3-MEDIATED HISTONE HYPERACETYLATION IN NALP1 PROMOTER REGION IN DORSAL HORN NEURONS, WHICH CONTRIBUTED TO THE BORTEZOMIB-INDUCED MECHANICAL ALLODYNIA.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 1689  28 DUAL HDAC/BRD4 INHIBITORS RELIEVES NEUROPATHIC PAIN BY ATTENUATING INFLAMMATORY RESPONSE IN MICROGLIA AFTER SPARED NERVE INJURY. DESPITE THE EFFORT ON DEVELOPING NEW TREATMENTS, THERAPY FOR NEUROPATHIC PAIN IS STILL A CLINICAL CHALLENGE AND COMBINATION THERAPY REGIMES OF TWO OR MORE DRUGS ARE OFTEN NEEDED TO IMPROVE EFFICACY. ACCUMULATING EVIDENCE SHOWS AN ALTERED EXPRESSION AND ACTIVITY OF HISTONE ACETYLATION ENZYMES IN CHRONIC PAIN CONDITIONS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS PROMOTES PAIN-RELIEVING ACTIVITY. RECENT STUDIES SHOWED A SYNERGISTIC ACTIVITY IN NEUROPATHIC PAIN MODELS BY COMBINATION OF HISTONE DEACETYLASES (HDACS) AND BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) INHIBITORS. ON THESE PREMISES, THE PRESENT STUDY INVESTIGATED THE PHARMACOLOGICAL PROFILE OF NEW DUAL HDAC/BRD4 INHIBITORS, NAMED SUM52 AND SUM35, IN THE SPARED NERVE INJURY (SNI) MODEL IN MICE AS INNOVATIVE STRATEGY TO SIMULTANEOUSLY INHIBIT HDACS AND BETS. INTRANASAL ADMINISTRATION OF SUM52 AND SUM35 ATTENUATED THERMAL AND MECHANICAL HYPERSENSITIVITY IN THE ABSENCE OF LOCOMOTOR SIDE EFFECTS. BOTH DUAL INHIBITORS SHOWED A PREFERENTIAL INTERACTION WITH BRD4-BD2 DOMAIN, AND SUM52 RESULTED THE MOST ACTIVE COMPOUND. SUM52 REDUCED MICROGLIA-MEDIATED SPINAL NEUROINFLAMMATION IN SPINAL CORD SECTIONS OF SNI MICE AS SHOWED BY REDUCTION OF IBA1 IMMUNOSTAINING, INDUCIBLE NITRIC OXIDE SYNTHASE (INOS) EXPRESSION, P65 NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) AND P38 MAPK OVER-PHOSPHORYLATION. A ROBUST DECREASE OF THE SPINAL PROINFLAMMATORY CYTOKINES CONTENT (IL-6, IL-1SS) WAS ALSO OBSERVED AFTER SUM52 TREATMENT. PRESENT RESULTS, SHOWING THE PAIN-RELIEVING ACTIVITY OF HDAC/BRD4 DUAL INHIBITORS, INDICATE THAT THE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE ACTING AS MULTI-TARGET AGENT MIGHT REPRESENT A PROMISE FOR NEUROPATHIC PAIN RELIEF.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  804  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
8 4919  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 6148  38 THE EXPRESSION OF TRANSCRIPTION FACTORS MECP2 AND CREB IS MODULATED IN INFLAMMATORY PELVIC PAIN. EARLY ACTIVATION OF TRANSCRIPTION FACTORS IS ONE OF THE EPIGENETIC MECHANISMS CONTRIBUTING TO THE INDUCTION AND MAINTENANCE OF CHRONIC PAIN STATES. PREVIOUS STUDIES IDENTIFIED THE CHANGES IN A NUMBER OF NOCICEPTION-RELATED GENES, SUCH AS CALCITONIN GENE-RELATED PEPTIDE (CGRP), SUBSTANCE P (SP), AND BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IN THE PELVIC ORGANS AFTER TRANSIENT COLONIC INFLAMMATION. THE GENE AND PROTEIN EXPRESSION OF THESE NEUROPEPTIDES COULD BE MODULATED BY TRANSCRIPTION FACTORS METHYL-CPG-BINDING PROTEIN 2 (MECP2) AND CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB). IN THIS STUDY, WE AIMED TO EVALUATE TIME-DEPENDENT CHANGES IN THE EXPRESSION LEVELS OF MECP2 AND CREB IN THE LUMBOSACRAL (LS) SPINAL CORD AND SENSORY GANGLIA AFTER INFLAMMATION-INDUCED PELVIC PAIN IN RAT. ADULT SPRAGUE-DAWLEY RATS WERE TREATED WITH 2,4,6-TRINITROBENZENESULFONIC ACID (TNBS) TO INDUCE TRANSIENT COLONIC INFLAMMATION. LS (L6-S2) SPINAL CORD SEGMENTS AND RESPECTIVE DORSAL ROOT GANGLIAS (DRGS) WERE ISOLATED FROM CONTROL AND EXPERIMENTAL ANIMALS AT 1, 2, 6, 24 H AND 3 DAYS POST-TNBS TREATMENT. IMMUNOHISTOCHEMICAL (IHC) LABELING AND WESTERN BLOTTING EXPERIMENTS WERE PERFORMED TO ASSESS THE EXPRESSION OF MECP2, CREB AND THEIR PHOSPHORYLATED FORMS. TOTAL MECP2 EXPRESSION, BUT NOT PHOSPHORYLATED P-MECP2 (PS421MECP2) EXPRESSION WAS DETECTED IN THE CELLS OF THE SPINAL DORSAL HORN UNDER CONTROL CONDITIONS. COLONIC INFLAMMATION TRIGGERED A SIGNIFICANT DECREASE IN THE NUMBER OF MECP2-EXPRESSING NEURONS IN PARALLEL WITH ELEVATED NUMBERS OF PS421MECP2-EXPRESSING CELLS AT 2 H AND 6 H POST-TNBS. THE MAJORITY OF MECP2-POSITIVE CELLS (80 +/- 6%) CO-EXPRESSED CREB. TNBS TREATMENT CAUSED A TRANSIENT UP-REGULATION OF CREB-EXPRESSING CELLS AT 1 H POST-TNBS ONLY. THE NUMBER OF CELLS EXPRESSING PHOSPHORYLATED CREB (PS133CREB) DID NOT CHANGE AT 1 H AND 2 H POST-TNBS, BUT WAS DOWN-REGULATED BY THREE FOLDS AT 6 H POST-TNBS. ANALYSIS OF DRG SECTIONS REVEALED THAT THE NUMBER OF MECP2-POSITIVE NEURONS WAS UP-REGULATED BY TNBS TREATMENT, REACHING THREE-FOLD INCREASE AT 2 H POST-TNBS, AND EIGHT-FOLD INCREASE AT 6 H POST-TNBS (P </= 0.05 TO CONTROL). THESE DATA SHOWED EARLY CHANGES IN MECP2 AND CREB EXPRESSION IN THE DORSAL HORN OF THE SPINAL CORD AND SENSORY GANGLIA AFTER COLONIC INFLAMMATION, SUGGESTING A POSSIBLE CONTRIBUTION MECP2 AND CREB SIGNALING IN THE DEVELOPMENT OF VISCERAL HYPERALGESIA AND PELVIC PAIN FOLLOWING PERIPHERAL INFLAMMATION.	2018	
                                                                                                                                                                                                                             
10 2203  26 EPIGENETIC MODIFICATION OF SPINAL MIR-219 EXPRESSION REGULATES CHRONIC INFLAMMATION PAIN BY TARGETING CAMKIIGAMMA. EMERGING EVIDENCE HAS SHOWN THAT MIRNA-MEDIATED GENE EXPRESSION MODULATION CONTRIBUTES TO CHRONIC PAIN, BUT ITS FUNCTIONAL REGULATORY MECHANISM REMAINS UNKNOWN. HERE, WE FOUND THAT COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED CHRONIC INFLAMMATION PAIN SIGNIFICANTLY REDUCED MIRNA-219 (MIR-219) EXPRESSION IN MICE SPINAL NEURONS. FURTHERMORE, THE EXPRESSION OF SPINAL CAMKIIGAMMA, AN EXPERIMENTALLY VALIDATED TARGET OF MIR-219, WAS INCREASED IN CFA MICE. OVEREXPRESSION OF SPINAL MIR-219 PREVENTED AND REVERSED THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AND SPINAL NEURONAL SENSITIZATION INDUCED BY CFA. CONCURRENTLY, INCREASED EXPRESSION OF SPINAL CAMKIIGAMMA WAS REVERSED BY MIR-219 OVEREXPRESSION. DOWNREGULATION OF SPINAL MIR-219 IN NAIVE MICE INDUCED PAIN-RESPONSIVE BEHAVIORS AND INCREASED P-NMDAR1 EXPRESSION, WHICH COULD BE INHIBITED BY KNOCKDOWN OF CAMKIIGAMMA. BISULFITE SEQUENCING SHOWED THAT CFA INDUCED THE HYPERMETHYLATION OF CPG ISLANDS IN THE MIR-219 PROMOTER. TREATMENT WITH DEMETHYLATION AGENT 5'-AZA-2'-DEOXYCYTIDINE MARKEDLY ATTENUATED PAIN BEHAVIOR AND SPINAL NEURONAL SENSITIZATION, WHICH WAS ACCOMPANIED WITH THE INCREASE OF SPINAL MIR-219 AND DECREASE OF CAMKIIGAMMA EXPRESSION. TOGETHER, WE CONCLUDE THAT METHYLATION-MEDIATED EPIGENETIC MODIFICATION OF SPINAL MIR-219 EXPRESSION REGULATES CHRONIC INFLAMMATORY PAIN BY TARGETING CAMKIIGAMMA.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11 3368  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12 1167  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13 5063  32 PHOSPHORYLATED HISTONE 3 AT SERINE 10 IDENTIFIES ACTIVATED SPINAL NEURONS AND CONTRIBUTES TO THE DEVELOPMENT OF TISSUE INJURY-ASSOCIATED PAIN. TRANSCRIPTIONAL CHANGES IN SUPERFICIAL SPINAL DORSAL HORN NEURONS (SSDHN) ARE ESSENTIAL IN THE DEVELOPMENT AND MAINTENANCE OF PROLONGED PAIN. EPIGENETIC MECHANISMS INCLUDING POST-TRANSLATIONAL MODIFICATIONS IN HISTONES ARE PIVOTAL IN REGULATING TRANSCRIPTION. HERE, WE REPORT THAT PHOSPHORYLATION OF SERINE 10 (S10) IN HISTONE 3 (H3) SPECIFICALLY OCCURS IN A GROUP OF RAT SSDHN FOLLOWING THE ACTIVATION OF NOCICEPTIVE PRIMARY SENSORY NEURONS BY BURN INJURY, CAPSAICIN APPLICATION OR SUSTAINED ELECTRICAL ACTIVATION OF NOCICEPTIVE PRIMARY SENSORY NERVE FIBRES. IN CONTRAST, BRIEF THERMAL OR MECHANICAL NOCICEPTIVE STIMULI, WHICH FAIL TO INDUCE TISSUE INJURY OR INFLAMMATION, DO NOT PRODUCE THE SAME EFFECT. BLOCKING N-METHYL-D-ASPARTATE RECEPTORS OR ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2, OR BLOCKING OR DELETING THE MITOGEN- AND STRESS-ACTIVATED KINASES 1 AND 2 (MSK1/2), WHICH PHOSPHORYLATE S10 IN H3, INHIBIT UP-REGULATION IN PHOSPHORYLATED S10 IN H3 (P-S10H3) AS WELL AS FOS TRANSCRIPTION, A DOWN-STREAM EFFECT OF P-S10H3. DELETING MSK1/2 ALSO INHIBITS THE DEVELOPMENT OF CARRAGEENAN-INDUCED INFLAMMATORY HEAT HYPERALGESIA IN MICE. WE PROPOSE THAT P-S10H3 IS A NOVEL MARKER FOR NOCICEPTIVE PROCESSING IN SSDHN WITH HIGH RELEVANCE TO TRANSCRIPTIONAL CHANGES AND THE DEVELOPMENT OF PROLONGED PAIN.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14 6429  26 THE UPREGULATION OF NLRP3 INFLAMMASOME IN DORSAL ROOT GANGLION BY TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 2 (TET2) CONTRIBUTED TO DIABETIC NEUROPATHIC PAIN IN MICE. BACKGROUND: THE NUCLEOTIDE OLIGOMERIZATION DOMAIN (NOD)-LIKE RECEPTOR FAMILY PYRIN DOMAIN CONTAINING 3 (NLRP3) IN DORSAL ROOT GANGLION (DRG) CONTRIBUTES TO PAIN HYPERSENSITIVITY IN MULTIPLE NEUROPATHIC PAIN MODELS, BUT THE FUNCTION OF THE NLRP3 IN DIABETIC NEUROPATHIC PAIN (DNP) AND THE REGULATION MECHANISM ARE STILL LARGELY UNKNOWN. EPIGENETIC REGULATION PLAYS A VITAL ROLE IN THE CONTROLLING OF GENE EXPRESSION. TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 2 (TET2) IS A DNA DEMETHYLASE THAT CONTRIBUTES TO TRANSCRIPTIONAL ACTIVATION. TET2 IS ALSO INVOLVED IN HIGH GLUCOSE (HG)-INDUCED PATHOLOGY. METHODS: DNP WAS INDUCED IN MICE VIA THE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN (STZ) FOR FIVE CONSECUTIVE DAYS AND THE MECHANICAL THRESHOLD WAS EVALUATED IN STZ-DIABETIC MICE BY USING VON FREY HAIRS. THE EXPRESSION LEVEL OF THE NLRP3 PATHWAY AND TET2 IN DRG WERE DETERMINED THROUGH MOLECULAR BIOLOGY EXPERIMENTS. THE REGULATION OF THE NLRP3 PATHWAY BY TET2 WAS EXAMINED IN IN VITRO AND IN VIVO CONDITIONS. RESULTS: IN THE PRESENT RESEARCH, WE FIRST ESTABLISHED THE DNP MODEL AND FOUND THAT NLRP3 PATHWAY WAS ACTIVATED IN DRG. THE TREATMENT OF NLRP3 INHIBITOR MCC950 ALLEVIATED THE MECHANICAL ALLODYNIA OF DNP MICE. THEN WE REVEALED THAT IN STZ-DIABETIC MICE DRG, THE GENOMIC DNA WAS DEMETHYLATED, AND THE EXPRESSION OF DNA DEMETHYLASE TET2 WAS INCREASED EVIDENTLY. USING RNA-SEQUENCING ANALYSIS, WE FOUND THAT THE EXPRESSION OF TXNIP, A GENE THAT ENCODES A THIOREDOXIN-INTERACTING PROTEIN (TXNIP) WHICH MEDIATES NLRP3 ACTIVATION, WAS ELEVATED IN THE DRG AFTER STZ TREATMENT. IN ADDITION, KNOCKING DOWN OF TET2 EXPRESSION IN DRG USING TET2-SIRNA SUPPRESSED THE MRNA EXPRESSION OF TXNIP AND SUBSEQUENTLY INHIBITED THE EXPRESSION/ACTIVATION OF NLRP3 INFLAMMASOME IN VITRO AND IN VIVO AS WELL AS RELIEVED THE PAIN SENSITIVITY OF DNP ANIMALS. CONCLUSION: THE RESULTS SUGGESTED THAT THE UPREGULATION OF THE TXNIP/NLRP3 PATHWAY BY TET2 IN DRG WAS INVOLVED IN THE PAIN HYPERSENSITIVITY OF THE DNP MODEL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  657  28 BLOCKING THE SPINAL FBXO3/CARM1/K(+) CHANNEL EPIGENETIC SILENCING PATHWAY AS A STRATEGY FOR NEUROPATHIC PAIN RELIEF. MANY EPIGENETIC REGULATORS ARE INVOLVED IN PAIN-ASSOCIATED SPINAL PLASTICITY. COACTIVATOR-ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1), AN EPIGENETIC REGULATOR OF HISTONE ARGININE METHYLATION, IS A HIGHLY INTERESTING TARGET IN NEUROPLASTICITY. HOWEVER, ITS POTENTIAL CONTRIBUTION TO SPINAL PLASTICITY-ASSOCIATED NEUROPATHIC PAIN DEVELOPMENT REMAINS POORLY EXPLORED. HERE, WE REPORT THAT NERVE INJURY DECREASED THE EXPRESSION OF SPINAL CARM1 AND INDUCED ALLODYNIA. MOREOVER, DECREASING SPINAL CARM1 EXPRESSION BY FBXO3-MEDIATED CARM1 UBIQUITINATION PROMOTED H3R17ME2 DECREMENT AT THE K(+) CHANNEL PROMOTER, THEREBY CAUSING K(+) CHANNEL EPIGENETIC SILENCING AND THE DEVELOPMENT OF NEUROPATHIC PAIN. REMARKABLY, IN NAIVE RATS, DECREASING SPINAL CARM1 USING CARM1 SIRNA OR A CARM1 INHIBITOR RESULTED IN SIMILAR EPIGENETIC SIGNALING AND ALLODYNIA. FURTHERMORE, INTRATHECAL ADMINISTRATION OF BC-1215 (A NOVEL FBXO3 INHIBITOR) PREVENTED CARM1 UBIQUITINATION TO BLOCK K(+) CHANNEL GENE SILENCING AND AMELIORATE ALLODYNIA AFTER NERVE INJURY. COLLECTIVELY, THE RESULTS REVEAL THAT THIS NEWLY IDENTIFIED SPINAL FBXO3-CARM1-K(+) CHANNEL GENE FUNCTIONAL AXIS PROMOTES NEUROPATHIC PAIN. THESE FINDINGS PROVIDE ESSENTIAL INSIGHTS THAT WILL AID IN THE DEVELOPMENT OF MORE EFFICIENT AND SPECIFIC THERAPIES AGAINST NEUROPATHIC PAIN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  743  36 CANNABINOID TYPE 2 RECEPTOR SYSTEM MODULATES PACLITAXEL-INDUCED MICROGLIAL DYSREGULATION AND CENTRAL SENSITIZATION IN RATS. PACLITAXEL INDUCES MICROGLIAL ACTIVATION AND PRODUCTION OF PROINFLAMMATORY MEDIATORS IN THE DORSAL HORN, WHICH CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF CENTRAL SENSITIZATION AND PAIN BEHAVIOR. MDA7, 1-([3-BENZYL-3-METHYL-2,3-DIHYDRO-1-BENZOFURAN-6-YL]CARBONYL) PIPERIDINE, IS A NOVEL HIGHLY SELECTIVE CANNABINOID TYPE 2 (CB2) AGONIST. WE TESTED THE HYPOTHESIS THAT ACTIVATION OF CB2 RECEPTOR BY MDA7 MODULATES MICROGLIAL DYSREGULATION, SUPPRESSES THE OVEREXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN MICROGLIA IN THE DORSAL HORN, AND ATTENUATES THE CENTRAL SENSITIZATION AND PAIN BEHAVIOR INDUCED BY PACLITAXEL. FOR 4 CONSECUTICE DAYS, GROUPS OF RATS RANDOMLY RECEIVED SALINE OR 1.0 MG/KG OF PACLITAXEL DAILY INTRAPERITONEALLY FOR A TOTAL CUMULATIVE DOSE OF 4 MG/KG. MDA7 15 MG/KG INTRAPERITONEALLY OR VEHICLE WERE ADMINISTERED 15 MIN BEFORE ADMINISTERING PACLITAXEL FOR 4 DAYS AND THEN CONTINUED FOR ANOTHER 10 DAYS. BEHAVIORAL AND MOLECULAR STUDIES WERE PERFORMED. PACLITAXEL INDUCED THE EXPRESSION OF CB2 RECEPTORS AND PRODUCTION OF INTERLEUKIN (IL)-6 IN MICROGLIA IN THE DORSAL HORN. MDA7 ATTENUATED THE EXPRESSION OF IL-6 AND PROMOTED THE EXPRESSION OF IL-10. PACLITAXEL INDUCED EPIGENETIC UPREGULATION OF IRF8 AND P2X PURINOCEPTOR 4 (P2X4) IN MICROGLIA AND SUBSEQUENTLY INCREASED THE EXPRESSION OF ALPHA ISOFORM OF CALCIUM/CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKIIALPHA), TRANSCRIPTIONAL FACTORS P-CREB AND DELTAFOSB, LEADING TO THE OVERPRODUCTION OF BDNF IN MICROGLIA. PACLITAXEL ALSO UPREGULATED THE EXPRESSION OF GLUTAMATE RECEPTOR SUBUNITS GLUR1 AND NR2B, DECREASED THE EXPRESSION OF K(+)-CL(-) COTRANSPORTER, AND INDUCED MECHANICAL ALLODYNIA IN RATS. ALL OF THE AFOREMENTIONED MOLECULAR CHANGES WERE ATTENUATED BY MDA7. OUR DATA SHOW THAT MDA7 ATTENUATED PACLITAXEL-INDUCED MOLECULAR AND BEHAVIORAL CHANGES IN RATS. PERSPECTIVE: THIS STUDY PROVIDES EVIDENCE THAT PACLITAXEL INDUCED MICROGLIA DYSREGULATION AND EPIGENETICALLY UPREGULATED THE MICROGLIAL EXPRESSION OF BDNF, WHICH LED TO SENSITIZATION OF DORSAL HORN NEURONS AND MECHANICAL ALLODYNIA IN RATS. THE CB2 AGONIST MDA7 ALLEVIATED THESE PATHOLOGICAL PROCESSES. MDA7 REPRESENTS AN INNOVATIVE THERAPEUTIC APPROACH FOR TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                             
17 4637  22 NEURON-RESTRICTIVE SILENCER FACTOR CAUSES EPIGENETIC SILENCING OF KV4.3 GENE AFTER PERIPHERAL NERVE INJURY. PERIPHERAL NERVE INJURY CAUSES A VARIETY OF ALTERATIONS IN PAIN-RELATED GENE EXPRESSION IN PRIMARY AFFERENT, WHICH UNDERLIE THE NEURONAL PLASTICITY IN NEUROPATHIC PAIN. ONE OF THE CHARACTERISTIC ALTERATIONS IS A LONG-LASTING DOWNREGULATION OF VOLTAGE-GATED POTASSIUM (K(V)) CHANNEL, INCLUDING K(V)4.3, IN THE DORSAL ROOT GANGLION (DRG). THE PRESENT STUDY SHOWED THAT NERVE INJURY REDUCES THE MESSENGER RNA (MRNA) EXPRESSION LEVEL OF K(V)4.3 GENE, WHICH CONTAINS A CONSERVED NEURON-RESTRICTIVE SILENCER ELEMENT (NRSE), A BINDING SITE FOR NEURON-RESTRICTIVE SILENCER FACTOR (NRSF). MOREOVER, WE FOUND THAT INJURY CAUSES AN INCREASE IN DIRECT NRSF BINDING TO K(V)4.3-NRSE IN THE DRG, USING CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY. CHIP ASSAY FURTHER REVEALED THAT ACETYLATION OF HISTONE H4, BUT NOT H3, AT K(V)4.3-NRSE IS MARKEDLY REDUCED AT DAY 7 POST-INJURY. FINALLY, THE INJURY-INDUCED K(V)4.3 DOWNREGULATION WAS SIGNIFICANTLY BLOCKED BY ANTISENSE-KNOCKDOWN OF NRSF. TAKEN TOGETHER, THESE DATA SUGGEST THAT NERVE INJURY CAUSES AN EPIGENETIC SILENCING OF K(V)4.3 GENE MEDIATED THROUGH TRANSCRIPTIONAL SUPPRESSOR NRSF IN THE DRG.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 2006  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19 4861  23 ORGANIC ANION TRANSPORTER 1 IS AN HDAC4-REGULATED MEDIATOR OF NOCICEPTIVE HYPERSENSITIVITY IN MICE. PERSISTENT PAIN IS SUSTAINED BY MALADAPTIVE CHANGES IN GENE TRANSCRIPTION RESULTING IN ALTERED FUNCTION OF THE RELEVANT CIRCUITS; THERAPIES ARE STILL UNSATISFACTORY. THE EPIGENETIC MECHANISMS AND AFFECTED GENES LINKING NOCICEPTIVE ACTIVITY TO TRANSCRIPTIONAL CHANGES AND PATHOLOGICAL SENSITIVITY ARE UNCLEAR. HERE, WE FOUND THAT, AMONG SEVERAL HISTONE DEACETYLASES (HDACS), SYNAPTIC ACTIVITY SPECIFICALLY AFFECTS HDAC4 IN MURINE SPINAL CORD DORSAL HORN NEURONS. NOXIOUS STIMULI THAT INDUCE LONG-LASTING INFLAMMATORY HYPERSENSITIVITY CAUSE NUCLEAR EXPORT AND INACTIVATION OF HDAC4. THE DEVELOPMENT OF INFLAMMATION-ASSOCIATED MECHANICAL HYPERSENSITIVITY, BUT NEITHER ACUTE NOR BASAL SENSITIVITY, IS IMPAIRED BY THE EXPRESSION OF A CONSTITUTIVELY NUCLEAR LOCALIZED HDAC4 MUTANT. NEXT GENERATION RNA-SEQUENCING REVEALED AN HDAC4-REGULATED GENE PROGRAM COMPRISING MEDIATORS OF SENSITIZATION INCLUDING THE ORGANIC ANION TRANSPORTER OAT1, KNOWN FOR ITS RENAL TRANSPORT FUNCTION. USING PHARMACOLOGICAL AND MOLECULAR TOOLS TO MODULATE OAT1 ACTIVITY OR EXPRESSION, WE CAUSALLY LINK OAT1 TO PERSISTENT INFLAMMATORY HYPERSENSITIVITY IN MICE. THUS, HDAC4 IS A KEY EPIGENETIC REGULATOR THAT TRANSLATES NOCICEPTIVE ACTIVITY INTO SENSITIZATION BY REGULATING OAT1, WHICH IS A POTENTIAL TARGET FOR PAIN-RELIEVING THERAPIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
20 5354  33 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