1  1147 152 CONDYLE MODELING STABILITY, CRANIOFACIAL ASYMMETRY AND ACTN3 GENOTYPES: CONTRIBUTION TO TMD PREVALENCE IN A COHORT OF DENTOFACIAL DEFORMITIES. CRANIOFACIAL ASYMMETRY, MANDIBULAR CONDYLAR MODELING AND TEMPOROMANDIBULAR JOINT DISORDERS ARE COMMON COMORBIDITIES OF SKELETALLY DISPROPORTIONATE MALOCCLUSIONS, BUT ETIOLOGY OF OCCURRENCE TOGETHER IS POORLY UNDERSTOOD. WE COMPARED ASYMMETRY, CONDYLE MODELING STABILITY AND TEMPOROMANDIBULAR HEALTH IN A COHORT OF 128 PATIENTS HAVING ORTHODONTICS AND ORTHOGNATHIC SURGERY TO CORRECT DENTOFACIAL DEFORMITY MALOCCLUSIONS. WE ALSO COMPARED ACTN3 AND ENPP1 GENOTYPES FOR ASSOCIATION TO CLINICAL CONDITIONS. PRE-SURGICAL POSTERIOR-ANTERIOR CEPHALOMETRIC AND PANOMETRIC RADIOGRAPHIC ANALYSES; JAW PAIN AND FUNCTION QUESTIONNAIRE AND CLINICAL EXAMINATION OF TMD; AND SNP-GENOTYPE ANALYSIS FROM SALIVA SAMPLES WERE COMPARED TO ASSESS INTERRELATIONSHIPS. ALMOST HALF HAD ASYMMETRIES IN NEED OF SURGICAL CORRECTION, WHICH COULD BE SUBDIVIDED INTO FOUR DISTINCT MORPHOLOGICAL PATTERNS. ASYMMETRIC CONDYLE MODELING BETWEEN SIDES WAS SIGNIFICANTLY GREATER IN CRANIOFACIAL ASYMMETRY, BUT MOST COMMONLY HAD AN UNANTICIPATED PATTERN. OFTEN, LONGER OR LARGER CONDYLES OCCURRED ON THE SHORTER MANDIBULAR RAMUS SIDE. SUBJECTS WITH LONGER RAMUS BUT DIMENSIONALLY SMALLER CONDYLES WERE MORE LIKELY TO HAVE SELF-REPORTED TMD SYMPTOMS (P = 0.023) AND SIGNIFICANTLY GREATER CLINICAL DIAGNOSIS OF TMD (P = 0 .000001), WITH MASTICATORY MYALGIA MOST PROMINENT. GENOTYPING FOUND TWO SIGNIFICANT GENOTYPE ASSOCIATIONS FOR ACTN3 RS1671064 (Q523R MISSENSE) P = 0.02; RS678397 (INTRONIC SNP) P = 0.04 AND ONE SIGNIFICANT ALLELE ASSOCIATION RS1815739 (R577X NONSENSE) P = 0.00. SKELETAL ASYMMETRY, UNUSUAL CONDYLE MODELING AND TMD ARE COMMON AND INTERRELATED COMPONENTS OF MANY DENTOFACIAL DEFORMITIES. IMBALANCED MUSCULOSKELETAL FUNCTIONAL ADAPTATIONS AND GENETIC OR EPIGENETIC INFLUENCES CONTRIBUTE TO THE ETIOLOGY, AND REQUIRE FURTHER INVESTIGATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  5328  27 PULSED RADIOFREQUENCY ATTENUATES COMPLETE FREUND'S ADJUVANT-INDUCED EPIGENETIC SUPPRESSION OF POTASSIUM CHLORIDE COTRANSPORTER 2 EXPRESSION. BACKGROUND: PULSED RADIOFREQUENCY (PRF) TREATMENT OFFERS PAIN RELIEF FOR PATIENTS SUFFERING FROM CHRONIC PAIN WHO DO NOT RESPOND WELL TO CONVENTIONAL TREATMENTS. WE TESTED WHETHER PRF TREATMENT ATTENUATED COMPLETE FREUND'S ADJUVANT (CFA)-INDUCED INFLAMMATORY PAIN. EPIGENETIC MODIFICATION OF POTASSIUM-CHLORIDE COTRANSPORTER 2 (KCC2) GENE EXPRESSION WAS EXAMINED TO ELUCIDATE THE POTENTIAL CONTRIBUTING MECHANISM. METHODS: MALE SPRAGUE-DAWLEY RATS WERE INJECTED WITH CFA INTO THE PLANTAR SURFACE OF THE LEFT HIND PAW TO INDUCE INFLAMMATION. PRF (20 MINUTES OF 500-KHZ RF PULSES, DELIVERED AT A RATE OF 2 HZ, MAXIMUM TEMPERATURE 42 MASCULINEC) WAS DELIVERED TO THE L5 AND L6 ANTERIOR PRIMARY RAMUS JUST DISTAL TO THE INTERVERTEBRAL FORAMEN OF ADULT CFA OR SALINE RATS. THE HIND PAW WITHDRAWAL THRESHOLD TO VON FREY FILAMENT STIMULI AND WITHDRAWAL LATENCY TO RADIANT HEAT WERE DETERMINED BEFORE AND AFTER CFA. ACETYL-HISTONE H3 AND H4 WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN SPINAL DORSAL HORN. KCC2 EXPRESSION WAS DETERMINED BY WESTERN BLOT. INHIBITORY SYNAPTIC FUNCTION WAS EVALUATED BY PATCH CLAMP IN LAMINA II NEURONS. RESULTS: KCC2 GENE EXPRESSION WAS SUPPRESSED THROUGH HISTONE HYPOACETYLATION, RESULTING IN DECREASED EFFICACY OF GABAERGIC SIGNALING IN CFA RATS. PRF INCREASED HISTONE ACETYLATION AND KCC2 EXPRESSION, PARTIALLY RESTORED THE GABA SYNAPTIC FUNCTION, AND RELIEVED SENSITIZED PAIN BEHAVIOR. CONCLUSION: THESE FINDINGS SUGGEST THAT PRF MIGHT BE AN ALTERNATIVE THERAPY FOR INFLAMMATORY PAIN. ONE OF THE UNDERLYING MECHANISMS IS THROUGH MODIFICATION OF KCC2, WHICH IS AN IMPORTANT DETERMINANT FOR THE EFFICACY OF INHIBITORY NEUROTRANSMISSION IN THE SPINAL CORD, AND ITS EXPRESSION LEVELS ARE REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING INFLAMMATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  2452  22 EPIGENETIC SUPPRESSION OF POTASSIUM-CHLORIDE CO-TRANSPORTER 2 EXPRESSION IN INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). BACKGROUND: MULTIPLE MECHANISMS CONTRIBUTE TO THE STIMULUS-EVOKED PAIN HYPERSENSITIVITY THAT MAY BE EXPERIENCED AFTER PERIPHERAL INFLAMMATION. PERSISTENT PATHOLOGICAL STIMULI IN MANY PAIN CONDITIONS AFFECT THE EXPRESSION OF CERTAIN GENES THROUGH EPIGENETIC ALTERNATIONS. THE MAIN PURPOSE OF OUR STUDY WAS TO INVESTIGATE THE ROLE OF EPIGENETIC MODIFICATION ON POTASSIUM-CHLORIDE CO-TRANSPORTER 2 (KCC2) GENE EXPRESSION IN THE PERSISTENCE OF INFLAMMATORY PAIN. METHODS: PERSISTENT INFLAMMATORY PAIN WAS INDUCED THROUGH THE INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN THE LEFT HIND PAW OF RATS. ACETYL-HISTONE H3 AND H4 LEVEL WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN THE SPINAL DORSAL HORN. PAIN BEHAVIOUR AND INHIBITORY SYNAPTIC FUNCTION OF SPINAL CORD WERE DETERMINED BEFORE AND AFTER CFA INJECTION. KCC2 EXPRESSION WAS DETERMINED BY REAL TIME RT-PCR AND WESTERN BLOT. INTRATHECAL KCC2 SIRNA (2 MUG PER 10 MUL PER RAT) OR HDAC INHIBITOR (10 MUG PER 10 MUL PER RAT) WAS INJECTED ONCE DAILY FOR 3 DAYS BEFORE CFA INJECTION. RESULTS: PERSISTENT INFLAMMATORY PAIN EPIGENETICALLY SUPPRESSED KCC2 EXPRESSION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN DECREASED INHIBITORY SIGNALLING EFFICACY. KCC2 KNOCK-DOWN CAUSED BY INTRATHECAL ADMINISTRATION OF KCC2 SIRNA IN NAIVE RATS REDUCED KCC2 EXPRESSION IN THE SPINAL CORD, LEADING TO SENSITIZED PAIN BEHAVIOURS AND IMPAIRED INHIBITORY SYNAPTIC TRANSMISSION IN THEIR SPINAL CORDS. MOREOVER, INTRATHECAL HDAC INHIBITOR INJECTION IN CFA RATS INCREASED KCC2 EXPRESSION, PARTIALLY RESTORING THE SPINAL INHIBITORY SYNAPTIC TRANSMISSION AND RELIEVING THE SENSITIZED PAIN BEHAVIOUR. CONCLUSION: THESE FINDINGS SUGGEST THAT THE TRANSCRIPTION OF SPINAL KCC2 IS REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING CFA. SIGNIFICANCE: PERSISTENT PAIN SUPPRESSES KCC2 EXPRESSION THROUGH HDAC-MEDIATED HISTONE HYPOACETYLATION AND CONSEQUENTLY IMPAIRS THE INHIBITORY FUNCTION OF INHIBITORY INTERNEURONS. DRUGS SUCH AS HDAC INHIBITORS THAT SUPPRESS THE INFLUENCES OF PERSISTENT PAIN ON THE EXPRESSION OF KCC2 MAY SERVE AS A NOVEL ANALGESIC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  6612  22 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  3955  19 LONG MARCH TOWARD SAFE AND EFFECTIVE ANALGESIA BY ENHANCING GENE EXPRESSION OF KCC2: FIRST STEPS TAKEN. LOW INTRANEURONAL CHLORIDE IN SPINAL CORD DORSAL HORN PAIN RELAY NEURONS IS CRITICAL FOR PHYSIOLOGIC TRANSMISSION OF PRIMARY PAIN AFFERENTS BECAUSE LOW INTRANEURONAL CHLORIDE DICTATES WHETHER GABA-ERGIC AND GLYCIN-ERGIC NEUROTRANSMISSION IS INHIBITORY. IF THE NEURONAL CHLORIDE ELEVATES TO PATHOLOGIC LEVELS, THEN SPINAL CORD PRIMARY PAIN RELAY BECOMES LEAKY AND EXHIBITS THE BEHAVIORAL HALLMARKS OF PATHOLOGIC PAIN, NAMELY HYPERSENSITIVITY AND ALLODYNIA. LOW CHLORIDE IN SPINAL CORD DORSAL HORN NEURONS IS MAINTAINED BY PROPER GENE EXPRESSION OF KCC2 AND SUSTAINED PHYSIOLOGIC FUNCTION OF THE KCC2 CHLORIDE EXTRUDING ELECTRONEUTRAL TRANSPORTER. PERIPHERAL NERVE INJURY AND OTHER FORMS OF NEURAL INJURY EVOKE GREATLY DIMINISHED KCC2 GENE EXPRESSION AND SUBSEQUENT CORRUPTION OF INHIBITORY NEUROTRANSMISSION IN THE SPINAL CORD DORSAL HORN, THUS CAUSING DERAILMENT OF THE GATE FUNCTION FOR PAIN. HERE I REVIEW KEY DISCOVERIES THAT HAVE HELPED US UNDERSTAND THESE FUNDAMENTALS, AND FOCUS ON RECENT INSIGHTS RELATING TO THE DISCOVERY OF KCC2 GENE EXPRESSION ENHANCING COMPOUNDS VIA COMPOUND SCREENS IN NEURONS. ONE SUCH STUDY CHARACTERIZED THE KINASE INHIBITOR, KENPAULLONE, MORE IN-DEPTH, REVEALING ITS FUNCTION AS A ROBUST AND LONG-LASTING ANALGESIC IN PRECLINICAL MODELS OF NERVE INJURY AND CANCER BONE PAIN, ALSO ELUCIDATING ITS MECHANISM OF ACTION VIA GSK3BETA INHIBITION, DIMINISHING DELTA-CATENIN PHOSPHORYLATION, AND FACILITATING ITS NUCLEAR TRANSFER AND SUBSEQUENT ENHANCEMENT OF KCC2 GENE EXPRESSION BY DE-REPRESSING KAISO EPIGENETIC TRANSCRIPTIONAL REGULATOR. FUTURE DIRECTIONS RE KCC2 GENE EXPRESSION ENHANCEMENT ARE DISCUSSED, NAMELY COMBINATION WITH OTHER ANALGESICS AND ANALGESIC METHODS, SUCH AS SPINAL CORD STIMULATION AND ELECTROACUPUNCTURE, GENE THERAPY, AND LEVERAGING KCC2 GENE EXPRESSION-ENHANCING NANOMATERIALS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  2365  23 EPIGENETIC REGULATION OF SPINAL CXCR2 SIGNALING IN INCISIONAL HYPERSENSITIVITY IN MICE. BACKGROUND: THE REGULATION OF GENE EXPRESSION IN NOCICEPTIVE PATHWAYS CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF PAIN SENSITIZATION. HISTONE ACETYLATION IS A KEY EPIGENETIC MECHANISM CONTROLLING CHROMATIN STRUCTURE AND GENE EXPRESSION. CHEMOKINE CC MOTIF RECEPTOR 2 (CXCR2) IS A PROINFLAMMATORY RECEPTOR IMPLICATED IN NEUROPATHIC AND INFLAMMATORY PAIN AND IS KNOWN TO BE REGULATED BY HISTONE ACETYLATION IN SOME SETTINGS. THE AUTHORS SOUGHT TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION ON SPINAL CXCR2 SIGNALING AFTER INCISION. METHODS: GROUPS OF 5-8 MICE UNDERWENT HIND PAW INCISION. SUBEROYLANILIDE HYDROXAMIC ACID AND ANACARDIC ACID WERE USED TO INHIBIT HISTONE DEACETYLASE AND HISTONE ACETYLTRANSFERASE, RESPECTIVELY. BEHAVIORAL MEASURES OF THERMAL AND MECHANICAL SENSITIZATION AS WELL AS HYPERALGESIC PRIMING WERE USED. BOTH MESSAGE RNA QUANTIFICATION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS WERE USED TO STUDY THE REGULATION OF CXCR2 AND LIGAND EXPRESSION. FINALLY, THE SELECTIVE CXCR2 ANTAGONIST SB225002 WAS ADMINISTERED INTRATHECALLY TO REVEAL THE FUNCTION OF SPINAL CXCR2 RECEPTORS AFTER HIND PAW INCISION. RESULTS: SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY EXACERBATED MECHANICAL SENSITIZATION AFTER INCISION. CONVERSELY, ANACARDIC ACID REDUCED INCISIONAL SENSITIZATION AND ALSO ATTENUATED INCISION-INDUCED HYPERALGESIC PRIMING. OVERALL, ACETYLATED HISTONE H3 AT LYSINE 9 WAS INCREASED IN SPINAL CORD TISSUES AFTER INCISION, AND ENHANCED ASSOCIATION OF ACETYLATED HISTONE H3 AT LYSINE 9 WITH THE PROMOTER REGIONS OF CXCR2 AND KERATINOCYTE-DERIVED CHEMOKINE (CXCL1) WAS OBSERVED AS WELL. BLOCKING CXCR2 REVERSED MECHANICAL HYPERSENSITIVITY AFTER HIND PAW INCISION. CONCLUSIONS: HISTONE MODIFICATION IS AN IMPORTANT EPIGENETIC MECHANISM REGULATING INCISION-INDUCED NOCICEPTIVE SENSITIZATION. THE SPINAL CXCR2 SIGNALING PATHWAY IS ONE EPIGENETICALLY REGULATED PATHWAY CONTROLLING EARLY AND LATENT SENSITIZATION AFTER INCISION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  2751  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  5480  26 RESVERATROL REVERSES MORPHINE-INDUCED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS BY REVERSAL HDAC1 EXPRESSION. BACKGROUND/PURPOSE: WE PREVIOUSLY SHOWED THAT SUBSEQUENT INTRATHECAL (I.T.) INJECTION OF RESVERATROL (30 MUG) SIGNIFICANTLY REVERSES MORPHINE-EVOKED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS. THE PRESENT STUDY EXAMINED THE UNDERLYING MECHANISM. METHODS: MALE WISTAR RATS WERE IMPLANTED WITH TWO I.T. CATHETERS, ONE OF WHICH WAS CONNECTED TO A MINIOSMOTIC PUMP AND USED FOR MORPHINE (15 MUG/H) OR SALINE INFUSION FOR 120 HOURS. TO EXAMINE THE EFFECTS ON SPINAL CORD EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1), THE INFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), AND TNF RECEPTOR (TNFR) 1 AND TNFR2 DURING TOLERANCE INDUCTION, A TAIL-FLICK TEST WAS PERFORMED PRIOR TO INFUSION AND AFTER 24 HOURS, 48 HOURS, 72 HOURS, 96 HOURS, AND 120 HOURS OF INFUSION. RESULTS: RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE RESTORED THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN MORPHINE-TOLERANT RATS AND REVERSED THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1, TNF-ALPHA, AND TNFR1 EXPRESSION. MOREOVER, CHRONIC MORPHINE INFUSION INCREASED TNFR1-SPECIFIC EXPRESSION IN NEURON IN MORPHINE-TOLERANT RAT SPINAL CORDS, AND THIS EFFECT WAS ALMOST COMPLETELY INHIBITED BY RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE. CONCLUSION: RESVERATROL RESTORES THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY REVERSING MORPHINE INFUSION-INDUCED SPINAL CORD NEUROINFLAMMATION AND INCREASE IN TNFR1 EXPRESSION. THE REVERSAL OF THE MORPHINE-INDUCED INCREASE IN TNFR1 EXPRESSION BY RESVERATROL IS PARTIALLY DUE TO REVERSAL OF THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1 EXPRESSION. RESVERATROL PRETREATMENT CAN BE USED AS AN ADJUVANT IN CLINICAL PAIN MANAGEMENT FOR PATIENTS WHO NEED LONG-TERM MORPHINE TREATMENT OR WITH NEUROPATHIC PAIN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  4699  26 NFATC2-DEPENDENT EPIGENETIC UPREGULATION OF CXCL14 IS INVOLVED IN THE DEVELOPMENT OF NEUROPATHIC PAIN INDUCED BY PACLITAXEL. BACKGROUND: THE MAJOR DOSE-LIMITING TOXICITY OF PACLITAXEL, ONE OF THE MOST COMMONLY USED DRUGS TO TREAT SOLID TUMOR, IS PAINFUL NEUROPATHY. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING PACLITAXEL-INDUCED PAINFUL NEUROPATHY ARE LARGELY UNCLARIFIED. METHODS: PAW WITHDRAWAL THRESHOLD WAS MEASURED IN THE RATS FOLLOWING INTRAPERITONEAL INJECTION OF PACLITAXEL. THE QPCR, WESTERN BLOTTING, PROTEIN OR CHROMATIN IMMUNOPRECIPITATION, CHIP-SEQ IDENTIFICATION OF NFATC2 BINDING SITES, AND MICROARRAY ANALYSIS WERE PERFORMED TO EXPLORE THE MOLECULAR MECHANISM. RESULTS: WE FOUND THAT PACLITAXEL TREATMENT INCREASED THE NUCLEAR EXPRESSION OF NFATC2 IN THE SPINAL DORSAL HORN, AND KNOCKDOWN OF NFATC2 WITH NFATC2 SIRNA SIGNIFICANTLY ATTENUATED THE MECHANICAL ALLODYNIA INDUCED BY PACLITAXEL. FURTHER BINDING SITE ANALYSIS UTILIZING CHIP-SEQ ASSAY COMBINING WITH GENE EXPRESSION PROFILE REVEALED A SHIFT OF NFATC2 BINDING SITE CLOSER TO TTS OF TARGET GENES IN DORSAL HORN AFTER PACLITAXEL TREATMENT. WE FURTHER FOUND THAT NFATC2 OCCUPANCY MAY DIRECTLY UPREGULATE THE CHEMOKINE CXCL14 EXPRESSION IN DORSAL HORN, WHICH WAS MEDIATED BY ENHANCED INTERACTION BETWEEN NFATC2 AND P300 AND CONSEQUENTLY INCREASED ACETYLATION OF HISTONE H4 IN CXCL14 PROMOTER REGION. ALSO, KNOCKDOWN OF CXCL14 IN DORSAL HORN SIGNIFICANTLY ATTENUATED MECHANICAL ALLODYNIA INDUCED BY PACLITAXEL. CONCLUSION: THESE RESULTS SUGGESTED THAT ENHANCED INTERACTION BETWEEN P300 AND NFATC2 MEDIATED THE EPIGENETIC UPREGULATION OF CXCL14 IN THE SPINAL DORSAL HORN, WHICH CONTRIBUTED TO THE CHEMOTHERAPEUTIC PACLITAXEL-INDUCED CHRONIC PAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10  1800  19 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11  4579  19 N(6)-METHYLADENOSINE METHYLASE METTL3 CONTRIBUTES TO NEUROPATHIC PAIN BY EPIGENETIC SILENCING OF MU OPIOID RECEPTOR. WE AIMED AT EXPLORING THE ROLE AND MECHANISM OF METTL3-MEDIATED M(6)A MODIFICATION IN NEUROPATHIC PAIN. MALE SPRAGUE-DAWLEY RATS WERE RANDOMLY DIVIDED INTO FOUR GROUPS: SHAM OPERATION GROUP (SHAM GROUP), CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE MODEL GROUP (NPP GROUP), INTRATHECAL INJECTION OF VIRUS DOWN-REGULATED METTL3 + CCI MODEL GROUP (M3 + NPP GROUP) AND INTRATHECAL INJECTION OF NEGATIVE CONTROL VIRUS + CCI MODEL GROUP (SCR + NPP GROUP). THE M3 + NPP GROUP AND THE SCR + NPP GROUP WERE INTRATHECALLY INJECTED WITH VIRUS NINETEEN DAYS BEFORE OPERATION. THE PAW WITHDRAWAL MECHANICAL THRESHOLDS AND PAW WITHDRAWAL LATENCY WERE RESPECTIVELY RECORDED ONE DAY BEFORE OPERATION, THREE DAYS, FIVE DAYS AND SEVEN DAYS AFTER OPERATION. THE RATS WERE SACRIFICED ON THE SEVENTH DAY AFTER OPERATION, AND THEIR SPINAL CORD TISSUES WERE TAKEN. THE FROZEN SECTIONS OF RATS WERE PERFORMED TO OBSERVE THE EXPRESSION OF GREEN FLUORESCENT PROTEIN OF THE VIRUS. THE METHYLATION LEVEL OF RNA, THE PROTEIN EXPRESSION OF M(6)A-RELATED ENZYME (METTL3) AND MU OPIOID RECEPTOR (MOR) IN SPINAL CORD TISSUES OF THE FOUR GROUPS WERE MEASURED. DOWNREGULATION OF METTL3 HAD NO EFFECT ON THE OVERALL METHYLATION LEVEL OF THE SPINAL CORD, BUT IT COULD REGULATE THE METHYLATION LEVEL OF THE OPRM1 GENE RNA ENCODING MOR, PARTIALLY RESTORE THE EXPRESSION OF MOR, AND RELIEVE PAIN IN RATS. IN THE PROCESS OF NPP, METTL3 MAY INHIBIT THE EXPRESSION OF MOR BY REGULATING THE METHYLATION LEVEL OF OPRM1 GENE RNA ENCODING MOR, AND ULTIMATELY PROMOTE THE OCCURRENCE AND DEVELOPMENT OF NPP.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  6660  27 UPREGULATION OF CXCR4 THROUGH PROMOTER DEMETHYLATION CONTRIBUTES TO INFLAMMATORY HYPERALGESIA IN RATS. AIM AND METHODS: CHRONIC PAIN ASSOCIATED WITH INFLAMMATION IS A COMMON CLINICAL PROBLEM, AND THE UNDERLYING MECHANISMS YET ARE INCOMPLETELY DEFINED. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF CHRONIC PAIN. HOWEVER, THE SPECIFIC GENES REGULATED BY DNA METHYLATION UNDER INFLAMMATORY PAIN CONDITION REMAIN LARGELY UNKNOWN. HERE, WE INVESTIGATED HOW CHEMOKINE RECEPTOR CXCR4 EXPRESSION IS REGULATED BY DNA METHYLATION AND HOW IT CONTRIBUTES TO INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA) IN RATS. RESULTS: INTRAPLANTAR INJECTION OF CFA COULD NOT ONLY INDUCE SIGNIFICANT HYPERALGESIA IN RATS, BUT ALSO SIGNIFICANTLY INCREASE THE EXPRESSION OF CXCR4 MRNA AND PROTEIN IN THE DORSAL ROOT GANGLION (DRG). INTRATHECAL INJECTION OF CXCR4 ANTAGONIST AMD3100 SIGNIFICANTLY RELIEVED HYPERALGESIA IN INFLAMMATORY RATS IN A TIME- AND DOSE-DEPENDENT MANNER. BISULFITE SEQUENCING AND METHYLATION-SPECIFIC PCR DEMONSTRATE THAT CFA INJECTION LED TO A SIGNIFICANT DEMETHYLATION OF CPG ISLAND AT CXCR4 GENE PROMOTER. CONSISTENTLY, THE EXPRESSION OF DNMT3B WAS SIGNIFICANTLY DOWNREGULATED AFTER CFA INJECTION. ONLINE SOFTWARE PREDICTION REVEALS THREE BINDING SITES OF P65 IN THE CPG ISLAND OF CXCR4 GENE PROMOTER, WHICH HAS CONFIRMED BY THE CHROMATIN IMMUNOPRECIPITATION ASSAY, CFA TREATMENT SIGNIFICANTLY INCREASES THE RECRUITMENT OF P65 TO CXCR4 GENE PROMOTER. INHIBITION OF NF-KB SIGNALING USING P65 INHIBITOR PYRROLIDINE DITHIOCARBAMATE SIGNIFICANTLY PREVENTED THE INCREASES OF THE CXCR4 EXPRESSION. CONCLUSION: UPREGULATION OF CXCR4 EXPRESSION DUE TO PROMOTER DEMETHYLATION FOLLOWED BY INCREASED RECRUITMENT OF P65 TO PROMOTER OF CXCR4 GENE CONTRIBUTES TO INFLAMMATORY HYPERALGESIA. THESE FINDINGS PROVIDE A THEORETICAL BASIS FOR THE TREATMENT OF CHRONIC PAIN FROM AN EPIGENETIC PERSPECTIVE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  2363  29 EPIGENETIC REGULATION OF SPINAL CORD GENE EXPRESSION CONTRIBUTES TO ENHANCED POSTOPERATIVE PAIN AND ANALGESIC TOLERANCE SUBSEQUENT TO CONTINUOUS OPIOID EXPOSURE. BACKGROUND: OPIOIDS HAVE BECOME THE MAINSTAY FOR TREATMENT OF MODERATE TO SEVERE PAIN AND ARE COMMONLY USED TO TREAT SURGICAL PAIN. WHILE OPIOID ADMINISTRATION HAS BEEN SHOWN TO CAUSE OPIOID-INDUCED HYPERALGESIA AND TOLERANCE, INTERACTIONS BETWEEN OPIOID ADMINISTRATION AND SURGERY WITH RESPECT TO THESE PROBLEMATIC ADAPTATIONS HAVE SCARCELY BEEN ADDRESSED. ACCUMULATING EVIDENCE SUGGESTS OPIOIDS AND NOCICEPTIVE SIGNALING MAY CONVERGE ON EPIGENETIC MECHANISMS IN SPINAL CORD TO ENHANCE OR PROLONG NEUROPLASTIC CHANGES. EPIGENETIC REGULATION OF BDNF (BRAIN-DERIVED NEUROTROPHIC FACTOR) AND PDYN (PRODYNORPHIN) GENES MAY BE INVOLVED. RESULTS: FOUR DAYS OF ASCENDING DOSES OF MORPHINE TREATMENT CAUSED OPIOID-INDUCED HYPERALGESIA AND REDUCED OPIOID ANALGESIC EFFICACY IN MICE. BOTH OPIOID-INDUCED HYPERALGESIA AND THE REDUCED OPIOID ANALGESIC EFFICACY WERE ENHANCED IN MICE THAT RECEIVED HINDPAW INCISIONS. THE EXPRESSION OF BDNF AND PDYN (QPCR) WAS INCREASED AFTER MORPHINE TREATMENT AND INCISION. CHROMATIN IMMUNOPRECIPITATION ASSAYS DEMONSTRATED THAT THE PDYN AND BDNF PROMOTERS WERE MORE STRONGLY ASSOCIATED WITH ACETYLATED H3K9 AFTER MORPHINE PLUS INCISION THAN IN THE MORPHINE OR INCISION ALONE GROUPS. SELECTIVE TROPOMYOSIN-RELATED KINASE B (ANA-12) AND KAPPA-OPIOID RECEPTOR (NOR-BINALTORPHIMINE) ANTAGONISTS WERE ADMINISTERED INTRATHECALLY, BOTH REDUCED HYPERALGESIA ONE OR THREE DAYS AFTER SURGERY. ADMINISTRATION OF ANA-12 OR NOR-BINALTORPHIMINE ATTENUATED THE DECREASED MORPHINE ANALGESIC EFFICACY ON DAY 1, BUT ONLY NOR-BINALTORPHIMINE WAS EFFECTIVE ON DAY 3 AFTER INCISION IN OPIOID-EXPOSED GROUP. COADMINISTRATION OF HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID DAILY WITH MORPHINE BLOCKED THE DEVELOPMENT OF OPIOID-INDUCED HYPERALGESIA AND ATTENUATED INCISION-ENHANCED HYPERALGESIA IN MORPHINE-TREATED MICE. ANACARDIC ACID HAD SIMILAR EFFECTS ON ANALGESIC TOLERANCE, SHOWING THE INVOLVEMENT OF HISTONE ACETYLATION IN THE INTERACTIONS DETECTED. CONCLUSIONS: SPINAL EPIGENETIC CHANGES INVOLVING BDNF AND PDYN MAY CONTRIBUTE TO THE ENHANCED POSTOPERATIVE NOCICEPTIVE SENSITIZATION AND ANALGESIC TOLERANCE OBSERVED AFTER CONTINUOUS OPIOID EXPOSURE. TREATMENTS BLOCKING THE EPIGENETICALLY MEDIATED UP-REGULATION OF THESE GENES OR ADMINISTRATION OF TRKB OR KAPPA-OPIOID RECEPTOR ANTAGONISTS MAY IMPROVE THE CLINICAL UTILITY OF OPIOIDS, PARTICULARLY AFTER SURGERY.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14  3331  23 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15   742  23 CANNABINOID CB2 RECEPTORS ARE UPREGULATED VIA BIVALENT HISTONE MODIFICATIONS AND CONTROL PRIMARY AFFERENT INPUT TO THE SPINAL CORD IN NEUROPATHIC PAIN. TYPE-2 CANNABINOID RECEPTORS (CB2, ENCODED BY THE CNR2 GENE) ARE MAINLY EXPRESSED IN IMMUNE CELLS, AND CB2 AGONISTS NORMALLY HAVE NO ANALGESIC EFFECT. HOWEVER, NERVE INJURY UPREGULATES CB2 IN THE DORSAL ROOT GANGLION (DRG), FOLLOWING WHICH CB2 STIMULATION REDUCES NEUROPATHIC PAIN. IT IS UNCLEAR HOW NERVE INJURY INCREASES CB2 EXPRESSION OR HOW CB2 ACTIVITY IS TRANSFORMED IN NEUROPATHIC PAIN. IN THIS STUDY, IMMUNOBLOTTING SHOWED THAT SPINAL NERVE LIGATION (SNL) INDUCED A DELAYED AND SUSTAINED INCREASE IN CB2 EXPRESSION IN THE DRG AND DORSAL SPINAL CORD SYNAPTOSOMES. RNASCOPE IN SITU HYBRIDIZATION ALSO SHOWED THAT SNL SUBSTANTIALLY INCREASED CB2 MRNA LEVELS, MOSTLY IN MEDIUM AND LARGE DRG NEURONS. FURTHERMORE, WE FOUND THAT THE SPECIFIC CB2 AGONIST JWH-133 SIGNIFICANTLY INHIBITS THE AMPLITUDE OF DORSAL ROOT-EVOKED GLUTAMATERGIC EXCITATORY POSTSYNAPTIC CURRENTS IN SPINAL DORSAL HORN NEURONS IN SNL RATS, BUT NOT IN SHAM CONTROL RATS; INTRATHECAL INJECTION OF JWH-133 REVERSED PAIN HYPERSENSITIVITY IN SNL RATS, BUT HAD NO EFFECT IN SHAM CONTROL RATS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION-QPCR ANALYSIS SHOWED THAT SNL INCREASED ENRICHMENT OF TWO ACTIVATING HISTONE MARKS (H3K4ME3 AND H3K9AC) AND DIMINISHED OCCUPANCY OF TWO REPRESSIVE HISTONE MARKS (H3K9ME2 AND H3K27ME3) AT THE CNR2 PROMOTER IN THE DRG. IN CONTRAST, SNL HAD NO EFFECT ON DNA METHYLATION LEVELS AROUND THE CNR2 PROMOTER. OUR FINDINGS SUGGEST THAT PERIPHERAL NERVE INJURY PROMOTES CB2 EXPRESSION IN PRIMARY SENSORY NEURONS VIA EPIGENETIC BIVALENT HISTONE MODIFICATIONS AND THAT CB2 ACTIVATION REDUCES NEUROPATHIC PAIN BY ATTENUATING NOCICEPTIVE TRANSMISSION FROM PRIMARY AFFERENT NERVES TO THE SPINAL CORD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  5865  27 SUPPRESSION OF HDAC2 IN SPINAL CORD ALLEVIATES MECHANICAL HYPERALGESIA AND RESTORES KCC2 EXPRESSION IN A RAT MODEL OF BONE CANCER PAIN. EPIGENETIC MODULATION PARTICIPATES IN THE MECHANISM OF MULTIPLE TYPES OF PATHOLOGICAL PAIN, SO TARGETING THE INVOLVED REGULATORS MAY BE A PROMISING STRATEGY FOR PAIN TREATMENT. OUR PREVIOUS RESEARCH IDENTIFIED THE ANALGESIC EFFECT OF THE HISTONE DEACETYLASE (HDAC) INHIBITOR TRICHOSTATIN A (TSA) ON MECHANICAL HYPERALGESIA IN A RAT MODEL OF BONE CANCER PAIN (BCP) VIA RESTORATION OF MU-OPIOID RECEPTOR (MOR) EXPRESSION. HOWEVER, THE SPECIFIC TYPES OF HDACS CONTRIBUTING TO BCP HAVE NOT BEEN EXPLORED. THE PRESENT STUDY INVESTIGATED THE EXPRESSION PATTERN OF SOME COMMON HDACS AND FOUND THAT HDAC2 WAS UP-REGULATED IN A TIME-DEPENDENT MANNER IN THE LUMBAR SPINAL CORD OF BCP RATS. TSA APPLICATION SUPPRESSED HDAC2 EXPRESSION IN CULTURED PC12 CELLS AND REVERSED THE AUGMENTED HDAC2 IN BCP RATS. AN RNA-INTERFERING STRATEGY CONFIRMED THE ESSENTIAL ROLE OF HDAC2 IN THE MODULATION OF MECHANICAL HYPERALGESIA FOLLOWING TUMOR CELL INOCULATION, AND WE FURTHER EXAMINED ITS POSSIBLE DOWNSTREAM TARGETS. NOTABLY, HDAC2 KNOCK-DOWN DID NOT RESTORE MOR EXPRESSION, BUT IT ROBUSTLY REVERSED THE DOWN-REGULATION OF POTASSIUM-CHLORIDE COTRANSPORTER 2 (KCC2). THE IMPAIRED KCC2 EXPRESSION IS A VITAL MECHANISM OF MANY TYPES OF PATHOLOGICAL PAIN. THEREFORE, OUR RESULTS DEMONSTRATED THAT HDAC2 IN SPINAL CORD CONTRIBUTED TO THE MECHANICAL HYPERALGESIA IN BCP RATS, AND THIS EFFECT MAY BE ASSOCIATED WITH KCC2 MODULATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  5297  22 PROTEIN ARGININE METHYLTRANSFERASE 5 CONTRIBUTES TO PACLITAXEL-INDUCED NEUROPATHIC PAIN BY ACTIVATING TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 EPIGENETIC MODIFICATION IN DORSAL ROOT GANGLION. BACKGROUND: PACLITAXEL (PTX), WHICH IS A FIRST-LINE CHEMOTHERAPY DRUG USED TO TREAT VARIOUS TYPES OF CANCERS, EXHIBITS PERIPHERAL NEUROPATHY AS A COMMON SIDE EFFECT THAT IS DIFFICULT TO TREAT. PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT 5) IS A KEY REGULATOR OF THE CHEMOTHERAPY RESPONSE, AS CHEMOTHERAPY DRUGS INDUCE PRMT5 EXPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PRMT5-MEDIATED EPIGENETIC MECHANISMS INVOLVED IN PTX-INDUCED NEUROPATHIC ALLODYNIA. METHODS: SPRAGUE-DAWLEY RATS WERE INTRAPERITONEALLY GIVEN PTX TO INDUCE NEUROPATHIC PAIN. BIOCHEMICAL ANALYSES WERE CONDUCTED TO MEASURE THE PROTEIN EXPRESSION LEVELS IN THE DORSAL ROOT GANGLION (DRG) OF THE ANIMALS. THE VON FREY TEST AND HOT PLATE TEST WERE USED TO EVALUATE NOCICEPTIVE BEHAVIORS. RESULTS: PTX INCREASED THE PRMT5 (MEAN DIFFERENCE [MD]: 0.68, 95% CONFIDENCE INTERVAL [CI], 0.88-0.48; P < .001 FOR VEHICLE)-MEDIATED DEPOSITION OF HISTONE H3R2 DIMETHYL SYMMETRIC (H3R2ME2S) AT THE TRANSIENT RECEPTOR POTENTIAL VANILLOID 1 (TRPV1) PROMOTER IN THE DRG. PRMT5-INDUCED H3R2ME2S RECRUITED WD REPEAT DOMAIN 5 (WDR5) TO INCREASE TRIMETHYLATION OF LYSINE 4 ON HISTONE H3 (H3K4ME3) AT TRPV1 PROMOTERS, THUS RESULTING IN TRPV1 TRANSCRIPTIONAL ACTIVATION (MD: 0.65, 95% CI, 0.82-0.49; P < .001 FOR VEHICLE) IN DRG IN PTX-INDUCED NEUROPATHIC PAIN. MOREOVER, PTX INCREASED THE ACTIVITY OF NADPH OXIDASE 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 FOR VEHICLE), PRMT5-INDUCED H3R2ME2S, AND WDR5-MEDIATED H3K4ME3 IN THE DRG IN PTX-INDUCED NEUROPATHIC PAIN. PHARMACOLOGICAL ANTAGONISM AND THE SELECTIVE KNOCKDOWN OF PRMT5 IN DRG NEURONS COMPLETELY BLOCKED PRMT5-MEDIATED H3R2ME2S, WDR5-MEDIATED H3K4ME3, OR TRPV1 EXPRESSION AND NEUROPATHIC PAIN DEVELOPMENT AFTER PTX INJECTION. REMARKABLY, NOX4 INHIBITION NOT ONLY ATTENUATED ALLODYNIA BEHAVIOR AND REVERSED THE ABOVE-MENTIONED SIGNALING BUT ALSO REVERSED NOX4 UPREGULATION VIA PTX. CONCLUSIONS: THUS, THE NOX4/PRMT5-ASSOCIATED EPIGENETIC MECHANISM IN DRG HAS A DOMINANT FUNCTION IN THE TRANSCRIPTIONAL ACTIVATION OF TRPV1 IN PTX-INDUCED NEUROPATHIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  5176  26 PREFACE TO COAST 2016 INNOVATORS' WORKSHOP ON PERSONALIZED AND PRECISION ORTHODONTIC THERAPY. OBJECTIVE: A SECOND FOCUSED WORKSHOP EXPLORED HOW TO TRANSFER NOVEL FINDINGS INTO CLINICAL ORTHODONTIC PRACTICE. SETTING AND SAMPLE POPULATION: PARTICIPANTS MET IN WEST PALM BEACH (FLORIDA, USA), ON 9-11 SEPTEMBER 2016 FOR THE CONSORTIUM FOR ORTHODONTIC ADVANCES IN SCIENCE AND TECHNOLOGY 2016 INNOVATORS' WORKSHOP (COAST). APPROXIMATELY 65 REGISTERED ATTENDEES CONSIDERED AND DISCUSSED INFORMATION FROM 27 TO 34 SPEAKERS, 8 TO 15 POSTER PRESENTERS AND FOUR LUNCH-HOUR FOCUS GROUP LEADERS. MATERIAL AND METHODS: THE INNOVATORS' WORKSHOPS WERE ORGANIZED ACCORDING TO FIVE THEMED SESSIONS. THE AIMS OF THE DISCUSSION SESSIONS WERE TO IDENTIFY THE FOLLOWING: I) THE STRENGTH AND IMPACT OF THE EVIDENCED-BASED DISCOVERIES, II) REQUIRED STEPS TO ENABLE FURTHER DEVELOPMENT AND III) REQUIRED STEPS TO TRANSLATE THESE NEW DISCOVERIES INTO ORTHODONTIC PRACTICE. RESULTS: THE ROLE OF GENE-ENVIRONMENT INTERACTIONS THAT UNDERLIE COMPLEX CRANIOFACIAL TRAITS WAS THE FOCUS OF SEVERAL SESSIONS. IT WAS AGREED THAT DIVERSE APPROACHES ARE CALLED FOR, SUCH AS (I) LARGE-SCALE COLLABORATIVE EFFORTS FOR FUTURE GENETIC STUDIES OF COMPLEX TRAITS; (II) DEEP GENOME SEQUENCING TO ADDRESS THE ISSUES OF ISOLATED MUTATIONS; (III) QUANTIFYING EPIGENETIC-ENVIRONMENTAL VARIABLES IN DIVERSE AREAS MYOFASCIAL PAIN, ALVEOLAR REMODELLING AND MANDIBULAR GROWTH. COMMON NEEDS IDENTIFIED FROM THE THEMED SESSIONS WERE MULTISCALE/MULTISPECIES MODELLING AND EXPERIMENTATION USING CONTROLLED AND QUANTIFIED MECHANICS AND TRANSLATION OF THE FINDINGS IN BONE BIOLOGY BETWEEN SPECIES. PANEL DISCUSSIONS LED TO THE CONSENSUS THAT A CONSORTIUM APPROACH TO ESTABLISH STANDARDS FOR INTRA-ORAL SCANNING AND 3D IMAGING SHOULD BE INITIATED. CONCLUSIONS: CURRENT AND EMERGING TECHNOLOGIES STILL REQUIRE SUPPORTED RESEARCH TO TRANSLATE NEW FINDINGS FROM THE LABORATORY TO ORTHODONTIC PRACTICE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
19  2321  23 EPIGENETIC REGULATION OF GENES THAT MODULATE CHRONIC STRESS-INDUCED VISCERAL PAIN IN THE PERIPHERAL NERVOUS SYSTEM. BACKGROUND & AIMS: CHRONIC STRESS ALTERS THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, INCREASES GUT MOTILITY, AND INCREASES THE PERCEPTION OF VISCERAL PAIN. WE INVESTIGATED WHETHER EPIGENETIC MECHANISMS REGULATE CHRONIC STRESS-INDUCED VISCERAL PAIN IN THE PERIPHERAL NERVOUS SYSTEMS OF RATS. METHODS: MALE RATS WERE SUBJECTED TO 1 HOUR OF WATER AVOIDANCE STRESS EACH DAY, OR GIVEN DAILY SUBCUTANEOUS INJECTIONS OF CORTICOSTERONE, FOR 10 CONSECUTIVE DAYS. L4-L5 AND L6-S2 DORSAL ROOT GANGLIA (DRG) WERE COLLECTED AND COMPARED BETWEEN STRESSED AND CONTROL RATS (PLACED FOR 1 HOUR EACH DAY IN A TANK WITHOUT WATER). LEVELS OF CANNABINOID RECEPTOR 1 (CNR1), DNA (CYTOSINE-5-)-METHYLTRANSFERASE 1 (DNMT1), TRANSIENT RECEPTOR POTENTIAL VANILLOID TYPE 1 (TRPV1), AND EP300 WERE KNOCKED DOWN IN DRG NEURONS IN SITU WITH SMALL INTERFERING RNAS. WE MEASURED DNA METHYLATION AND HISTONE ACETYLATION AT GENES ENCODING THE GLUCOCORTICOID RECEPTOR (NR3C1), CNR1, AND TRPV1. VISCERAL PAIN WAS MEASURED IN RESPONSE TO COLORECTAL DISTENTION. RESULTS: CHRONIC STRESS WAS ASSOCIATED WITH INCREASED METHYLATION OF THE NR3C1 PROMOTER AND REDUCED EXPRESSION OF THIS GENE IN L6-S2, BUT NOT L4-L5, DRGS. STRESS ALSO WAS ASSOCIATED WITH UP-REGULATION IN DNMT1-ASSOCIATED METHYLATION OF THE CNR1 PROMOTER AND DOWN-REGULATION OF GLUCOCORTICOID-RECEPTOR-MEDIATED EXPRESSION OF CNR1 IN L6-S2, BUT NOT L4-L5, DRGS. CONCURRENTLY, CHRONIC STRESS INCREASED EXPRESSION OF THE HISTONE ACETYLTRANSFERASE EP300 AND INCREASED HISTONE ACETYLATION AT THE TRPV1 PROMOTER AND EXPRESSION OF THE TRPV1 RECEPTOR IN L6-S2 DRG NEURONS. KNOCKDOWN OF DNMT1 AND EP300 IN L6-S2 DRG NEURONS OF RATS REDUCED DNA METHYLATION AND HISTONE ACETYLATION, RESPECTIVELY, AND PREVENTED CHRONIC STRESS-INDUCED INCREASES IN VISCERAL PAIN. CONCLUSIONS: CHRONIC STRESS INCREASES DNA METHYLATION AND HISTONE ACETYLATION OF GENES THAT REGULATE VISCERAL PAIN SENSATION IN THE PERIPHERAL NERVOUS SYSTEM OF RATS. BLOCKING EPIGENETIC REGULATORY PATHWAYS IN SPECIFIC REGIONS OF THE SPINAL CORD MIGHT BE DEVELOPED TO TREAT PATIENTS WITH CHRONIC ABDOMINAL PAIN.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  1920  30 ENVIRONMENTAL ENRICHMENT PREVENTS STRESS-INDUCED EPIGENETIC CHANGES IN THE EXPRESSION OF GLUCOCORTICOID RECEPTOR AND CORTICOTROPHIN RELEASING HORMONE IN THE CENTRAL NUCLEUS OF THE AMYGDALA TO INHIBIT VISCERAL HYPERSENSITIVITY. INTRODUCTION: STRESS IS A KNOWN TRIGGER FOR THE SYMPTOMS OF IRRITABLE BOWEL SYNDROME (IBS), A GASTROINTESTINAL (GI) DISORDER THAT PRESENTS WITH ABNORMAL BOWEL HABITS AND ABDOMINAL PAIN DUE TO VISCERAL HYPERSENSITIVITY. WHILE BEHAVIORAL THERAPIES HAVE BEEN USED TO ATTENUATE IBS SYMPTOMS, THE UNDERLYING MECHANISMS BY WHICH THESE THERAPIES INTERACT WITH STRESS-INDUCED PATHOLOGY REMAINS TO BE DELINEATED. HERE WE USE A RAT MODEL TO TEST THE HYPOTHESIS THAT EXPOSURE TO ENVIRONMENTAL ENRICHMENT (EE) INHIBITS STRESS-INDUCED CHANGES WITHIN THE BRAIN-GUT AXIS TO PREVENT VISCERAL AND SOMATIC HYPERSENSITIVITY AND COLONIC HYPERPERMEABILITY. METHODS: FEMALE RATS (N = 8/GROUP) WERE HOUSED IN EE ONE WEEK BEFORE AND ONE WEEK DURING EXPOSURE TO WATER AVOIDANCE STRESS (WAS) WHILE CONTROLS WERE HOUSED IN STANDARD CAGES (SH). ONE DAY AFTER THE FINAL WAS EXPOSURE, COLONIC AND SOMATIC SENSITIVITY WERE ASSESSED BY THE VISCEROMOTOR RESPONSE (VMR) TO COLORECTAL DISTENSION (CRD) AND WITHDRAWAL THRESHOLD ELICITED BY AN ELECTRONIC VON FREY ON THE HIND PAW OF THE RATS RESPECTIVELY. ALL RATS WERE RETURNED TO SH FOR 3 WEEKS BEFORE COLONIC AND SOMATIC SENSITIVITY WERE REASSESSED ON DAY 28. THE RATS WERE THEN IMMEDIATELY EUTHANIZED AND THE SPINAL CORD WAS COLLECTED TO ASSESS CHANGES IN NEURONAL ACTIVATION (ASSESSED VIA ERK PHOSPHORYLATION) IN RESPONSE TO NOXIOUS CRD. A SEPARATE COHORT OF ANIMALS (N = 8/GROUP) THAT DID NOT UNDERGO BEHAVIORAL ASSESSMENTS WAS EUTHANIZED THE DAY AFTER THE FINAL WAS EXPOSURE AND THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) WAS COLLECTED TO INVESTIGATE WAS AND EE INDUCED EPIGENETIC CHANGES AT THE GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN RELEASING HORMONE (CRH) PROMOTER. THE COLON FROM THESE RATS WAS ALSO COLLECTED TO ASSESS COLONIC PERMEABILITY VIA CHANGES IN TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) IN VITRO. RESULTS: EXPOSURE TO STRESS PERSISTENTLY INCREASED VMR TO CRD (P < 0.01) AND DECREASED THE HIND PAW WITHDRAWAL THRESHOLD (P < 0.001) IN FEMALE RATS. WAS ALSO DECREASED TEER IN THE COLON TISSUE OF FEMALE RATS (P = 0.05). IN THE CEA, WAS INDUCED A DECREASE IN HISTONE ACETYLATION AT THE GR PROMOTER BUT INCREASED HISTONE ACETYLATION AT THE CRH PROMOTER AND REDUCED GR-CRH INTERACTIONS IN THE CEA. ANALYSIS OF THE SPINAL CORD SHOWED THAT WAS INCREASED CRD-EVOKED ERK PHOSPHORYLATION IN THE DORSAL HORN. EXPOSURE TO EE PREVENTED WAS-INDUCED CHANGES IN THE CEA, DORSAL HORN AND COLON RESPECTIVELY TO PREVENT VISCERAL AND SOMATIC HYPERSENSITIVITY. CONCLUSION: OUR DATA REVEALS THAT BEHAVIORAL THERAPIES CAN PRODUCE LONG LASTING MOLECULAR AND EPIGENETIC CHANGES THAT CAN PREVENT STRESS-INDUCED PATHOLOGIES EVEN AFTER COMPLETION OF THE THERAPY. THESE RESULTS HIGHLIGHT THE POTENTIAL MECHANISMS BY WHICH BEHAVIORAL THERAPIES MAY AMELIORATE VISCERAL PAIN ASSOCIATED STRESS-RELATED PATHOLOGIES SUCH AS THE IRRITABLE BOWEL SYNDROME.	2021