1 3280 125 HERPES ZOSTER OPHTHALMICUS FOLLOWING ONABOTULINUMTOXINA ADMINISTRATION FOR CHRONIC MIGRAINE: A CASE REPORT AND LITERATURE REVIEW. BACKGROUND: THERE IS A GROWING BODY OF LITERATURE DOCUMENTING LOCAL HERPES ZOSTER OUTBREAK FOLLOWING PROCEDURES. THE MECHANISM UNDERLYING THESE OUTBREAKS REMAINS ELUSIVE. WE PRESENT A CASE OF ZOSTER FOLLOWING ONABOTULINUMTOXINA (BTX) FOR MIGRAINE AND A LITERATURE REVIEW. METHODS: CHART AND LITERATURE REVIEW. CASE: A 72-YEAR-OLD WOMAN WITH CHRONIC MIGRAINE RECEIVED BTX INJECTIONS FOR 3 YEARS WITHOUT INCIDENT. SHE HAD A HISTORY OF THORACIC ZOSTER WITH SUBSEQUENT POST-HERPETIC NEURALGIA. IN AUGUST 2013, 48 HOURS AFTER RECEIVING BTX INJECTIONS, SHE DEVELOPED A PAINFUL RASH IN THE RIGHT V1 DISTRIBUTION CONSISTENT WITH HERPES ZOSTER OPHTHALMICUS. ONE WEEK LATER THE RASH HAD RESOLVED WITHOUT TREATMENT. LITERATURE REVIEW: WE IDENTIFIED 65 (INCLUDING 2 FROM JUEL-JENSON) CASES OF ZOSTER REACTIVATION FOLLOWING MINOR PROCEDURES. THESE CASES TEND TO BE IN YOUNG PATIENTS WITHOUT SPECIFIC RISK FACTORS. OUTBREAKS CHARACTERISTICALLY OCCUR AT THE LEVEL OF EXPOSURE TO LOCAL TRAUMA. DISCUSSION: OUR REVIEW SUGGESTS THAT LOCAL TRAUMA, REGARDLESS OF THE NATURE OF STIMULI, MAY BE SUFFICIENT FOR ZOSTER REACTIVATION. WE HYPOTHESIZE THAT THE STRESSORS IN THESE REPORTED CASES EXERT A LOCAL EPIGENETIC INFLUENCE ON VIRAL TRANSCRIPTION, ALLOWING FOR VIRAL REACTIVATION. CONCLUSION: ZOSTER IS A POTENTIAL COMPLICATION OF BTX ADMINISTRATION FOR CHRONIC MIGRAINE IN ADULTS. PHYSICIAN AWARENESS CAN REDUCE THE SIGNIFICANT MORBIDITY ASSOCIATED WITH THIS DISEASE. 2015 2 2571 25 EPIGENETICS OF CHRONIC PAIN AFTER THORACIC SURGERY. PURPOSE OF REVIEW: CHRONIC PAIN AFTER SURGERY IS A MAJOR PUBLIC HEALTH PROBLEM AND A MAJOR CONCERN FOR PERIOPERATIVE PHYSICIANS. THORACIC SURGERY PRESENTS A UNIQUE CHALLENGE, AS THORACOTOMY IS AMONG THE HIGHEST RISK SURGERIES TO DEVELOP PERSISTENT POSTSURGICAL PAIN. THE PURPOSE OF THIS REVIEW IS TO DISCUSS THE RELEVANCE OF RESEARCH IN PAIN EPIGENETICS TO PATIENTS WITH PERSISTENT PAIN AFTER THORACIC SURGERY. RECENT FINDINGS: RECENT ADVANCES HAVE LINKED CHRONIC PAIN STATES TO GENETIC AND EPIGENETIC CHANGES. PROGRESS IN OUR UNDERSTANDING OF CHRONIC PAIN HAS HIGHLIGHTED THE IMPORTANCE OF IMMUNE MODULATION OF PAIN. IT IS POSSIBLE THAT EPIGENETIC CHANGES DRIVING CHRONIC PAIN OCCUR IN THE PERIOPERATIVE SETTING VIA HISTONE MODIFICATION AND DNA METHYLATION. SUMMARY: THE TRANSITION FROM ACUTE TO CHRONIC PAIN AFTER THORACIC SURGERY MAY BE MEDIATED BY EPIGENETICS. HERE, WE DISCUSS EPIGENETIC MODIFICATIONS THAT HAVE BEEN DISCOVERED IN ANIMAL MODELS OF CHRONIC PAIN THAT MAY PREDISPOSE PATIENTS TO PERSISTENT NEUROPATHIC PAIN AFTER THORACIC SURGERY. 2014 3 33 27 A CASE STUDY OF CHIROPRACTIC MANAGEMENT OF PREGNANCY-RELATED HEARTBURN WITH POSTULATED FETAL EPIGENOME IMPLICATIONS. OBJECTIVE: THIS CASE STUDY REPORTS ON CHIROPRACTIC CARE FOR PREGNANCY-RELATED HEARTBURN. THE PURPOSE OF THIS ARTICLE IS TO RELATE THE BENEFIT OF CHIROPRACTIC TREATMENT FOR ONE INDIVIDUAL, TO CONTRAST CHIROPRACTIC MANAGEMENT WITH THE BIOMEDICAL STANDARD OF CARE FOR PREGNANCY-RELATED HEARTBURN, AND TO POINT TO POTENTIAL EPIGENETIC IMPLICATIONS OF THE STANDARD OF CARE. CLINICAL FEATURES: A 32-YEAR-OLD WOMAN WHO WAS 24 WEEKS PREGNANT PRESENTED WITH PERSISTENT HEARTBURN THAT SHE WAS TREATING WITH RANITIDINE (ZANTAC(R)) AND CALCIUM CARBONATE (TUMS(R)) DAILY AT THE INITIATION OF CHIROPRACTIC CARE. INTERVENTION AND OUTCOME: FINDINGS OF THE INITIAL EXAMINATION WERE THORACIC INTERSEGMENTAL DYSFUNCTION AND PAIN UPON PALPATION OF THE DIAPHRAGM, WITH HYPERTONICITY NOTED. THERAPY LOCALIZATION WAS POSITIVE FOR REFLEXES ASSOCIATED WITH THE ESOPHAGUS AND LOWER ESOPHAGEAL SPHINCTER, SUGGESTING SPASMS. EMOTIONAL COMPONENTS ALSO WERE IDENTIFIED IN ASSOCIATION WITH THE SYMPTOMS BY THE USE OF A MIND-BODY THERAPY CALLED NEUROEMOTIONAL TECHNIQUE. THE PATIENT WAS TREATED BY ADJUSTING THE THORACIC SPINE, MANUALLY RELEASING THE DIAPHRAGM SPASMS, AND RELEASING THE ESOPHAGEAL SPASM WITH AN ACTIVATOR (A SMALL HAND-HELD INSTRUMENT THAT CREATES A PERCUSSIVE FORCE). THE PATIENT WAS SYMPTOM-FREE AND DID NOT USE MEDICATION AFTER THE FIFTH TREATMENT. SHE WAS FOLLOWED THROUGHOUT THE REMAINDER OF HER PREGNANCY AND WAS ASYMPTOMATIC AND REQUIRED NO FURTHER TREATMENT. CONCLUSIONS: A LARGER STUDY SHOULD INVESTIGATE THE EFFECTIVENESS OF CHIROPRACTIC CARE FOR THE TREATMENT OF PREGNANCY-RELATED HEARTBURN. 2012 4 3324 30 HISTONE DEACETYLASE 2 IS INVOLVED IN MICRO?OPIOID RECEPTOR SUPPRESSION IN THE SPINAL DORSAL HORN IN A RAT MODEL OF CHRONIC PANCREATITIS PAIN. CHRONIC PAIN OCCURS IN ~85-90% OF CHRONIC PANCREATITIS (CP) PATIENTS. HOWEVER, AS THE PATHOGENESIS OF CP PAIN REMAINS TO BE FULLY UNDERSTOOD, THE CURRENT THERAPIES FOR CP PAIN REMAIN INADEQUATE. EMERGING EVIDENCE HAS SUGGESTED THAT THE EPIGENETIC MODULATIONS OF GENES ARE INVOLVED IN CHRONIC PAIN. IN THE PRESENT STUDY, INTRAPANCREATIC TRINITROBENZENE SULFONIC ACID INFUSIONS WERE USED TO ESTABLISH A CP MODEL IN RATS. MECHANICAL ALLODYNIA WAS MEASURED WITH VON FREY FILAMENTS. IMMUNOFLUORESCENT STAINING ANALYSIS WAS USED TO OBSERVE THE EXPRESSION CHANGES OF HISTONE DEACETYLASE 2 (HDAC2) AND MICRO?OPIOID RECEPTOR (MOR), AND INTRATHECAL ADMINISTRATION OF THE SELECTIVE HDAC2 INHIBITOR AR?42 WAS USED TO ASSESS THE UNDERLYING MECHANISMS. THE EXPRESSION LEVELS OF C?JUN N?TERMINAL KINASE (JNK) IN THE THORACIC SPINAL CORD WERE DETECTED BY WESTERN BLOTTING, AND THE MRNA EXPRESSION LEVELS OF INTERLEUKIN (IL)1?BETA, IL?6 AND TUMOR NECROSIS FACTOR (TNF)?ALPHA WERE DETECTED BY REVERSE TRANSCRIPTION?QUANTITATIVE POLYMERASE CHAIN REACTION. THE RESULTS DEMONSTRATED THAT HDAC2 EXPRESSION WAS UPREGULATED DURING THE COURSE OF CP INDUCTION, WHILE MOR ACTIVITY IN THE THORACIC SPINAL DORSAL HORN WAS SIGNIFICANTLY SUPPRESSED. INTRATHECAL INFUSION OF AR?42 SIGNIFICANTLY ATTENUATED CP?INDUCED MECHANICAL ALLODYNIA, WITH RESCUED MOR ACTIVITY. ADDITIONALLY, HDAC2 FACILITATED THE RELEASE OF INFLAMMATORY CYTOKINES, INCLUDING IL?1BETA, IL?6 AND TNF?ALPHA. THESE RESULTS SUGGESTED THAT THE UNDERLYING MECHANISMS OF HDAC2 REGULATING MOR ACTIVITY UNDER CP INDUCTION MAY OCCUR VIA PROMOTING THE RELEASE OF INFLAMMATORY CYTOKINES, THUS ACTIVATING THE JNK SIGNALING PATHWAY. THE PRESENT STUDY SUGGESTED THAT THE EPIGENETIC?REGULATED DISTURBANCE OF MOR IS DEPENDENT ON THE ENDOGENOUS ANALGESIA SYSTEM IN CP, WHICH MAY A PROVIDE NOVEL THERAPEUTIC STRATEGY FOR TREATING PAIN IN CP. 2018 5 500 21 ASSOCIATION BETWEEN NEUROPATHIC PAIN CHARACTERISTICS AND DNA METHYLATION OF TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 IN HUMAN PERIPHERAL BLOOD. ELUCIDATION OF EPIGENETIC MECHANISMS CORRELATING WITH NEUROPATHIC PAIN IN HUMANS IS CRUCIAL FOR THE PREVENTION AND TREATMENT OF THIS TREATMENT-RESISTANT PAIN STATE. IN THE PRESENT STUDY, ASSOCIATIONS BETWEEN NEUROPATHIC PAIN CHARACTERISTICS AND DNA METHYLATION OF THE TRANSIENT RECEPTOR POTENTIAL ANKYRIN 1 (TRPA1) GENE WERE EVALUATED IN CHRONIC PAIN PATIENTS AND PREOPERATIVE PATIENTS. PAIN AND PSYCHOLOGICAL STATES WERE PROSPECTIVELY ASSESSED IN PATIENTS WHO SUFFERED CHRONIC PAIN OR WERE SCHEDULED FOR THORACIC SURGERY. NEUROPATHIC CHARACTERISTICS WERE ASSESSED USING THE DOULEUR NEUROPATHIQUE 4 (DN4) QUESTIONNAIRE. DNA METHYLATION LEVELS OF THE CPG ISLANDS IN THE TRPA1 GENE WERE EXAMINED USING WHOLE BLOOD. FORTY-EIGHT ADULT PATIENTS WERE ENROLLED IN THIS STUDY. INCREASES IN DNA METHYLATION RATES AT CPG -51 SHOWED POSITIVE CORRELATIONS WITH INCREASES IN THE DN4 SCORE BOTH IN PREOPERATIVE AND CHRONIC PAIN PATIENTS. COMBINED METHYLATION RATES AT CPG -51 IN THESE PATIENTS ALSO SIGNIFICANTLY INCREASED TOGETHER WITH INCREASE IN DN4 SCORES. NEUROPATHIC PAIN CHARACTERISTICS ARE LIKELY ASSOCIATED WITH METHYLATION RATES AT THE PROMOTER REGION OF THE TRPA1 GENE IN HUMAN PERIPHERAL BLOOD. 2020 6 2751 18 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 7 5708 20 SIRT1 ATTENUATES NEUROPATHIC PAIN BY EPIGENETIC REGULATION OF MGLUR1/5 EXPRESSIONS IN TYPE 2 DIABETIC RATS. ACCUMULATING EVIDENCE HAS DEMONSTRATED THAT EPIGENETIC MODIFICATION-MEDIATED CHANGES IN PAIN-RELATED GENE EXPRESSIONS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN. SIRTUIN 1 (SIRT1), A NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD)-DEPENDENT DEACETYLASE, IS INVOLVED IN THE DEVELOPMENT OF CHRONIC PAIN. MOREOVER, SIRT1 MAY BE A NOVEL THERAPEUTIC TARGET FOR THE PREVENTION OF TYPE 2 DIABETES MELLITUS (T2DM). BUT THE ROLE OF SIRT1 IN T2DM-INDUCED NEUROPATHIC PAIN REMAINS UNKNOWN. IN THIS STUDY, WE FOUND THAT SPINAL SIRT1 EXPRESSION AND ACTIVITY WERE DOWNREGULATED SIGNIFICANTLY IN HIGH-FAT-FED/LOW-DOSE STREPTOZOTOCIN-INDUCED NEUROPATHIC PAIN RATS. SIRT1 LOCALIZED IN SPINAL NEURONS BUT NOT IN ASTROCYTES OR MICROGLIA. FURTHERMORE, THE EXPRESSIONS OF METABOTROPIC GLUTAMATE RECEPTOR (MGLUR1) AND MGLUR5, WHICH PLAY A KEY ROLE IN CENTRAL SENSITIZATION AND NEUROPATHIC PAIN, AND H3 ACETYLATION LEVELS AT GRM1/5 (ENCODING MGLUR1/5) PROMOTER REGIONS WERE INCREASED IN DIABETIC NEUROPATHIC PAIN RATS. SIRT1 ACTIVATOR SRT1720 REVERSED THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AND SPINAL NEURONAL ACTIVATION IN DIABETIC NEUROPATHIC PAIN RATS. CONCURRENTLY, INCREASED EXPRESSIONS OF MGLUR1/5 AND H3 ACETYLATION LEVELS AT GRM1/5 PROMOTER REGIONS WERE REVERSED BY SIRT1 ACTIVATION. IN ADDITION, KNOCKDOWN OF SIRT1 BY AD-SIRT1-SHRNA INDUCED PAIN BEHAVIORS AND SPINAL NEURONAL ACTIVATION IN NORMAL RATS, WHICH WAS ACCOMPANIED BY THE INCREASED EXPRESSIONS OF MGLUR1/5 AND H3 ACETYLATION LEVELS AT GRM1/5 PROMOTER REGIONS. THEREFORE, WE CONCLUDED THAT SIRT1-MEDIATED EPIGENETIC REGULATION OF MGLUR1/5 EXPRESSIONS WAS INVOLVED IN THE DEVELOPMENT OF NEUROPATHIC PAIN IN TYPE 2 DIABETIC RATS. 2017 8 1631 27 DNMT3A METHYLATION IN NEUROPATHIC PAIN. BACKGROUND: MU OPIOID RECEPTOR (MOR) PLAYS A CRUCIAL ROLE IN MEDIATING ANALGESIC EFFECTS OF OPIOIDS AND IS CLOSELY ASSOCIATED WITH THE PATHOLOGIES OF NEUROPATHIC PAIN. PREVIOUS STUDIES HAVE REPORTED THAT PERIPHERAL NERVE INJURY DOWNREGULATES MOR EXPRESSION, BUT THE EPIGENETIC MECHANISMS REMAIN UNKNOWN. OBJECTIVE: THEREFORE, WE INVESTIGATED DNA METHYLTRANSFERASE3A (DNMT3A) EXPRESSION OR METHYLATION CHANGES WITHIN MOR PROMOTER IN THE SPINAL CORD IN A NEUROPATHIC PAIN INDUCED BY A CHRONIC CONSTRICTION INJURY (CCI) MOUSE MODEL AND FURTHER DETERMINED WHETHER THESE INJURY-ASSOCIATED CHANGES ARE REVERSIBLE BY PHARMACOLOGICAL INTERVENTIONS. METHODS: A CCI MOUSE MODEL WAS ESTABLISHED AND TISSUE SPECIMENS OF LUMBAR SPINAL CORDS WERE COLLECTED. THE NOCICEPTION THRESHOLD WAS EVALUATED BY A MODEL HEATED 400 BASE. DNMT3A AND MOR MRNA AND PROTEIN LEVEL WERE DETECTED BY REAL-TIME-POLYMERASE CHAIN REACTION AND WESTERN BLOT, RESPECTIVELY. METHYLATION OF DNMT3A GENE WAS MEASURED BY METHYLATION-SPECIFIC PCR. RESULTS: OUR DATA SHOWED THAT CHRONIC NERVE INJURY LED TO A SIGNIFICANT UPREGULATION OF DNMT3A EXPRESSION THAT WAS ASSOCIATED WITH INCREASED METHYLATION OF MOR GENE PROMOTER AND DECREASED MOR PROTEIN EXPRESSION IN THE SPINAL CORD. INHIBITION OF DNMT3A CATALYTIC ACTIVITY WITH DNMT INHIBITOR RG108 SIGNIFICANTLY BLOCKED THE INCREASE IN METHYLATION OF THE MOR PROMOTER, AND THEN UPREGULATED MOR EXPRESSION AND ATTENUATED THERMAL HYPERALGESIA IN NEUROPATHIC PAIN MICE. CONCLUSION: THIS STUDY DEMONSTRATES THAT AN INCREASE OF DNMT3A EXPRESSION AND MOR METHYLATION EPIGENETICALLY PLAY AN IMPORTANT ROLE IN NEUROPATHIC PAIN. TARGETING DNMT3A TO THE PROMOTER OF MOR GENE BY DNMT INHIBITOR MAY BE A PROMISING APPROACH TO THE DEVELOPMENT OF NEW NEUROPATHIC PAIN THERAPY. 2017 9 3832 20 INVOLVEMENT OF SPINAL SIRT1 IN DEVELOPMENT OF CHRONIC CONSTRICTION INJURY INDUCED NEUROPATHIC PAIN IN RATS. IT IS KNOWN THAT THE EPIGENETIC PROCESS OF HISTONE ACETYLATION IS INVOLVED IN THE NEUROPATHIC PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER SIRTUIN TYPE 1 (SIRT1), AN NAD(+) DEPENDENT DEACETYLASE, AFFECTED ALLODYNIA AND HYPERALGESIA IN NEUROPATHIC PAIN. THE NEUROPATHIC PAIN MODEL WAS ESTABLISHED BY LIGATURE OF THE RIGHT SCIATIC NERVE TO INDUCE CHRONIC CONSTRICTION INJURY (CCI) IN RATS. HISTONE ACETYLTRANSFERASE (HAT) ACTIVITY WAS INCREASED AND, AND HISTONE DEACETYLASE (HDAC) ACTIVITY WAS DECLINED IN TISSUE OF THE SPINAL DORSA HORN IN CCI RATES BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). THE PERSISTENT HYPERALGESIA AND ALLODYNIA CAUSED BY CCI WERE ASSOCIATED WITH DOWNREGULATION OF SIRT1 AND UPREGULATION OF ACETYLATED-H3 (AC-H3) IN TISSUE OF THE SPINAL CORD BY WESTERN BLOT ASSAY, WHICH WAS REVERSED AFTER INTRATHECAL INJECTION OF SIRT1 AGONIST SRT1720. SRT1720 TREATMENT ACHIEVED ANALGESIC THROUGH INHIBITING THE ACETYLATION OF NUCLEAR FACTOR KAPPA B (NF-KAPPAB) AND BLOCKING THE RELEASES OF THE INFLAMMATORY FACTORS INCLUDING TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) AND INTERLEUKIN (IL)-6 BY MEANS OF WESTERN BLOT AND REAL-TIME QUANTITATIVE PCR (RT-PCR), RESPECTIVELY. TAKEN TOGETHER, THESE DATA SUGGEST THAT SIRT1 IN THE SPINAL CORD PLAYS AN IMPORTANT ROLE IN THE NEUROPATHIC PAIN IN THE RAT MODEL. 2018 10 1822 24 EFFECTS OF DIETARY OLEACEIN TREATMENT ON ENDOTHELIAL DYSFUNCTION AND LUPUS NEPHRITIS IN BALB/C PRISTANE-INDUCED MICE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC IMMUNE-INFLAMMATORY DISEASE CHARACTERIZED BY MULTIORGAN AFFECTATION AND LOWERED SELF-TOLERANCE. ADDITIONALLY, EPIGENETIC CHANGES HAVE BEEN DESCRIBED AS PLAYING A PIVOTAL ROLE IN SLE. THIS WORK AIMS TO ASSESS THE EFFECTS OF OLEACEIN (OLA), ONE OF THE MAIN EXTRA VIRGIN OLIVE OIL SECOIRIDOIDS, WHEN USED TO SUPPLEMENT THE DIET OF A MURINE PRISTANE-INDUCED SLE MODEL. IN THE STUDY, 12-WEEK-OLD FEMALE BALB/C MICE WERE INJECTED WITH PRISTANE AND FED WITH AN OLA-ENRICHED DIET (0.01 % (W/W)) FOR 24 WEEKS. THE PRESENCE OF IMMUNE COMPLEXES WAS EVALUATED BY IMMUNOHISTOCHEMISTRY AND IMMUNOFLUORESCENCE. ENDOTHELIAL DYSFUNCTION WAS STUDIED IN THORACIC AORTAS. SIGNALING PATHWAYS AND OXIDATIVE-INFLAMMATORY-RELATED MEDIATORS WERE EVALUATED BY WESTERN BLOTTING. MOREOVER, WE STUDIED EPIGENETIC CHANGES SUCH AS DNA METHYLTRANSFERASE (DNMT-1) AND MICRO(MI)RNAS EXPRESSION IN RENAL TISSUE. NUTRITIONAL TREATMENT WITH OLA REDUCED THE DEPOSITION OF IMMUNE COMPLEXES, AMELIORATING KIDNEY DAMAGE. THESE PROTECTIVE EFFECTS COULD BE RELATED TO THE MODULATION OF MITOGEN-ACTIVATED PROTEIN KINASES, THE JANUS KINASE/SIGNAL TRANSDUCER AND TRANSCRIPTION ACTIVATOR OF TRANSCRIPTION, NUCLEAR FACTOR KAPPA, NUCLEAR-FACTOR-ERYTHROID-2-RELATED FACTOR 2, INFLAMMASOME SIGNALING PATHWAYS, AND THE REGULATION OF MIRNAS (MIRNA-126, MIRNA-146A, MIRNA-24-3P, AND MIRNA-123) AND DNMT-1 EXPRESSION. MOREOVER, THE OLA-ENRICHED DIET NORMALIZED ENDOTHELIAL NITRIC OXIDE SYNTHASE AND NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (NADPH) OXIDASE-1 OVEREXPRESSION. THESE PRELIMINARY RESULTS SUGGEST THAT AN OLA-SUPPLEMENTED DIET COULD CONSTITUTE A NEW ALTERNATIVE NUTRACEUTICAL THERAPY IN THE MANAGEMENT OF SLE, SUPPORTING THIS COMPOUND AS A NOVEL EPIGENETIC MODULATOR OF THE IMMUNOINFLAMMATORY RESPONSE. 2023 11 2680 18 EVALUATION OF EPIGENETIC (HDAC, DNMT) AND PAIN (GAD65, TGF) FACTORS FOLLOWING PHOTOBIOMODULATION THERAPY IN A NEUROPATHIC PAIN MODEL. PHOTOBIOMODULATION THERAPY (PBMT) IS CONVERTED TO THE MOST COMMON ANALGESIC TREATMENT BEFORE THE WHOLE MECHANISM IS YET TO BE DISCOVERED. THIS STUDY FOR THE FIRST TIME WAS DESIGNED TO INVESTIGATE ALTERNATIONS OF EPIGENETIC FACTORS AFTER PAIN AND PBMT. THE CCI MODEL WAS CHOSEN TO INDUCE PAIN. PAIN EVALUATION TESTS INCLUDING PLANTAR, ACETONE, VON FREY, AND PINCH WERE DONE WEEKLY. THEN SPINAL CORD TISSUE WAS ISOLATED FOR EVALUATING MRNA EXPRESSION OF DNMT3A, HDAC1, AND NRSF USING RT-QPCR METHOD, AND PROTEIN EXPRESSION FACTORS OF HDAC2 AND DNMT3A USING WESTERN BLOTTING. GAD65 AND TGF-BETA PROTEINS WERE ASSESSED BY THE IHC METHOD. PBMT INCREASED THE PAIN THRESHOLD UP TO THE POINT WHERE IT ROUGHLY MET THE PAIN THRESHOLD OF THE CONTROL GROUP. AFTER THREE WEEKS OF TREATMENT, BOTH PBMT PROTOCOLS DEMONSTRATED A REDUCTION IN ALLODYNIA AND HYPERALGESIA. WHILE SOME MOLECULES, SUCH AS TGF-BETA AND GAD65, INCREASED FOLLOWING PBMT, WE OBSERVED NO INHIBITION OF NRSF, HDAC1, AND DNMT3A EXPRESSION DESPITE IMPLEMENTING TWO DIFFERENT PROTOCOLS. 2023 12 5927 25 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC VISCERAL PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. BACKGROUND: CHRONIC VISCERAL PAIN IS PERSISTENT PAIN EMANATING FROM THORACIC, PELVIC, OR ABDOMINAL ORIGIN THAT IS POORLY LOCALIZED WITH REGARD TO THE SPECIFIC ORGAN AFFECTED. THE PREVALENCE CAN RANGE UP TO 25% IN THE ADULT POPULATION AS CHRONIC VISCERAL PAIN IS A COMMON FEATURE OF MANY VISCERAL DISORDERS, WHICH MAY OR MAY NOT BE ACCOMPANIED BY DISTINCT STRUCTURAL OR HISTOLOGICAL ABNORMALITIES WITHIN THE VISCERAL ORGANS. MOUNTING EVIDENCE SUGGESTS THAT CHANGES IN EPIGENETIC MECHANISMS ARE INVOLVED IN THE TOP-DOWN OR BOTTOM-UP SENSITIZATION OF PAIN PATHWAYS AND THE DEVELOPMENT OF CHRONIC PAIN. EPIGENETIC CHANGES CAN LEAD TO LONG-TERM ALTERATIONS IN GENE EXPRESSION PROFILES OF NEURONS AND CONSEQUENTLY ALTER FUNCTIONALITY OF PERIPHERAL NEURONS, DORSAL ROOT GANGLIA, SPINAL CORD, AND BRAIN NEURONS. HOWEVER, EPIGENETIC MODIFICATIONS ARE DYNAMIC, AND THUS, DETRIMENTAL CHANGES MAY BE REVERSIBLE. HENCE, EXTERNAL FACTORS/THERAPEUTIC INTERVENTIONS MAY BE CAPABLE OF MODULATING THE EPIGENOME AND RESTORE NORMAL GENE EXPRESSION FOR EXTENDED PERIODS OF TIME. PURPOSE: THE GOAL OF THIS REVIEW IS TO HIGHLIGHT THE LATEST DISCOVERIES MADE TOWARD UNDERSTANDING THE EPIGENETIC MECHANISMS THAT ARE INVOLVED IN THE DEVELOPMENT OR MAINTENANCE OF CHRONIC VISCERAL PAIN. FURTHERMORE, THIS REVIEW WILL PROVIDE EVIDENCE SUPPORTING THAT TARGETING THESE EPIGENETIC MECHANISMS MAY REPRESENT A NOVEL APPROACH TO TREAT CHRONIC VISCERAL PAIN. 2019 13 1126 25 COMPLEX REGULATION OF THE REGULATOR OF SYNAPTIC PLASTICITY HISTONE DEACETYLASE 2 IN THE RODENT DORSAL HORN AFTER PERIPHERAL INJURY. HISTONE DEACETYLASES (HDACS), HDAC2 IN PARTICULAR, HAVE BEEN SHOWN TO REGULATE VARIOUS FORMS OF LEARNING AND MEMORY. SINCE COGNITIVE PROCESSES SHARE MECHANISMS WITH SPINAL NOCICEPTIVE SIGNALLING, WE DECIDED TO INVESTIGATE THE HDAC2 EXPRESSION IN THE DORSAL HORN AFTER PERIPHERAL INJURY. USING IMMUNOHISTOCHEMISTRY, WE FOUND THAT SPINAL HDAC2 WAS MAINLY SEEN IN NEURONS AND ASTROCYTES, WITH NEURONAL EXPRESSION IN NAIVE TISSUE 2.6 TIMES GREATER THAN THAT IN ASTROCYTES. CYSTEINE (S)-NITROSYLATION OF HDAC2 RELEASES HDAC2 GENE SILENCING AND IS CONTROLLED BY NITRIC OXIDE (NO). A DURATION OF 48 H AFTER INTRAPLANTAR INJECTION OF COMPLETE FREUND'S ADJUVANT, THERE WAS AN IPSILATERAL INCREASE IN THE MOST IMPORTANT NO-PRODUCING ENZYME IN PAIN STATES, NITRIC OXIDE SYNTHASE (NNOS), ACCOMPANIED BY AN INCREASE IN HDAC2 S-NITROSYLATION. MOREOVER, A SUBSET OF NNOS-POSITIVE NEURONS EXPRESSED CFOS, A KNOWN TARGET OF HDAC2, SUGGESTING THAT DEREPRESSION OF CFOS EXPRESSION FOLLOWING HDAC2 S-NITROSYLATION MIGHT OCCUR AFTER NOXIOUS STIMULATION. WE SAW NO CHANGE IN GLOBAL HDAC2 EXPRESSION IN BOTH SHORT- AND LONG-TERM PAIN STATES. HOWEVER, HDAC2 WAS INCREASED IN ASTROCYTES 7 DAYS AFTER NEUROPATHIC INJURY SUGGESTING THAT HDAC2 MIGHT INHIBIT ASTROCYTIC GENE EXPRESSION IN NEUROPATHIC PAIN STATES. ALL TOGETHER, OUR RESULTS INDICATE THAT THE EPIGENETIC REGULATION OF TRANSCRIPTIONAL PROGRAMMES IN THE DORSAL HORN AFTER INJURY IS CELL SPECIFIC. MOREOVER, THE PROMINENT ROLE OF NO IN PERSISTENT PAIN STATES SUGGESTS THAT HDAC2 S-NITROSYLATION COULD PLAY A CRUCIAL ROLE IN THE REGULATION OF GENE EXPRESSION LEADING TO HYPERSENSITIVITY. OUR MANUSCRIPT DESCRIBES FOR THE FIRST TIME THE REGULATION OF THE MEMORY REGULATOR HISTONE DEACETYLASE 2 (HDAC2) IN THE SUPERFICIAL DORSAL HORN OF ADULT RATS FOLLOWING PERIPHERAL INJURY. OUR CELL-SPECIFIC APPROACH HAS REVEALED A COMPLEX PATTERN OF EXPRESSION OF SPINAL HDAC2 THAT DEPENDS ON THE INJURY AND THE CELL TYPE, SUGGESTING A SOPHISTICATED REGULATION OF GENE EXPRESSION BY HDAC2. 2016 14 3810 27 INTRATHECAL 5-AZACYTIDINE INHIBITS GLOBAL DNA METHYLATION AND METHYL- CPG-BINDING PROTEIN 2 EXPRESSION AND ALLEVIATES NEUROPATHIC PAIN IN RATS FOLLOWING CHRONIC CONSTRICTION INJURY. THE PATHOGENESIS OF NEUROPATHIC PAIN REMAINS LARGELY UNKNOWN. EPIGENETIC MECHANISMS MAY PLAY A MAJOR ROLE IN REGULATING EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM IN VERTEBRATES, AND METHYL- CPG-BINDING PROTEIN 2 (MECP2) IS DIRECTLY INVOLVED IN METHYLATION-MEDIATED GENE SILENCING. TO DETERMINE HOW CHANGES IN GLOBAL DNA METHYLATION AND MECP2 EXPRESSION OCCUR FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) AND HOW REPRESSION OF DNA METHYLATION AFFECTS THESE CHANGES AND ATTENUATES NEUROPATHIC PAIN, WE USED INTRATHECAL 5-AZACYTIDINE, A DNA METHYLTRANSFERASE INHIBITOR, IN CCI RATS. RATS RECEIVED 0.9% SALINE OR 5-AZACYTIDINE (10MUMOL.D(-1)) VIA SPINAL INJECTION ONCE DAILY FROM DAY 3 TO DAY 14 AFTER CCI SURGERY. GLOBAL DNA METHYLATION AND MECP2 EXPRESSION INCREASED IN THE SPINAL CORD IN CCI RATS ON DAY 14 AFTER CCI SURGERY. MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA INDUCED BY CCI WERE ATTENUATED BY INTRATHECAL 5-AZACYTIDINE FROM DAY 5 TO DAY 14 AFTER CCI SURGERY. THE INCREASES IN GLOBAL DNA METHYLATION AND MECP2 EXPRESSION IN THE SPINAL CORD IN CCI RATS WERE ALSO SIGNIFICANTLY INHIBITED BY INTRATHECAL 5-AZACYTIDINE. THESE RESULTS DEMONSTRATE THAT INCREASED GLOBAL DNA METHYLATION AND MECP2 EXPRESSION IN THE SPINAL CORD AFTER NERVE DAMAGE MAY PLAY AN IMPORTANT ROLE IN NEUROPATHIC PAIN. 5-AZACYTIDINE SHOWS POTENTIAL FOR TREATING NEUROPATHIC PAIN. 2011 15 5865 25 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 16 6172 26 THE HDAC1/C-JUN COMPLEX IS ESSENTIAL IN THE PROMOTION OF NERVE INJURY-INDUCED NEUROPATHIC PAIN THROUGH JNK SIGNALING. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. ADMINISTRATION OF A SELECTIVE HDAC1 INHIBITOR (LG325) IN SNI-SUBJECTED MICE SIGNIFICANTLY ATTENUATED BEHAVIOR RELATED TO INJURY-INDUCED PAIN. UNDERSTANDING THE HDAC1 PATHWAY IN EPIGENETIC REGULATION OF PATHOLOGICAL PAIN IS OF GREAT MEDICAL RELEVANCE. SPARED NERVE INJURY (SNI) MICE SHOWED A SIGNIFICANT INCREASE IN THE HDAC1 PROTEIN LEVELS WITHIN SPINAL CORD IN COINCIDENCE WITH THE NOCICEPTIVE PHENOTYPE AT 1 AND 3 WEEKS AFTER NERVE INJURY. NO VARIATION IN HDAC3, DNMT3A, ACH3, MBD3 AND MECP2 LEVELS WAS DETECTED. INCREASED EXPRESSION OF HDAC1 IS ACCOMPANIED BY ACTIVATION OF THE JNK-C-JUN SIGNALING PATHWAY. A ROBUST SPINAL JNK-1 OVERPHOSPHORYLATION WAS OBSERVED POST NERVE-INJURY ALONG WITH A SELECTIVE JNK-DEPENDENT INCREASE IN P-C-JUN AND HDAC1 PROTEIN LEVELS. CO-IMMUNOPRECIPITATION EXPERIMENTS SHOWED THE PRESENCE OF A HETERODIMERIC COMPLEX BETWEEN HDAC1 AND C-JUN IN SNI MICE INDICATING THAT THESE TRANSCRIPTION FACTORS CAN ACT TOGETHER TO REGULATE TRANSCRIPTION THROUGH HETERODIMERIZATION. STIMULATION OF C-JUN PHOSPHORYLATION WAS PREVENTED BY THE SELECTIVE HDAC1 INHIBITOR LG325. WE FOUND THAT HDAC1 WAS ASSOCIATED WITH C-JUN IN NUCLEI OF SPINAL DORSAL HORN ASTROCYTES EXPRESSING JNK. ON THE OTHER HAND, THE PRESENCE OF HDAC1 AND C-JUN INTERACTION WAS NOT DETECTED IN CONTROL MICE. THESE FINDINGS PROVIDE NEW INSIGHTS INTO THE MECHANISMS UNDERLYING THE ANTI-NOCICEPTIVE ACTIVITY OF HDAC INHIBITORS. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE DEACETYLASE IN THE EMERGENCE OF NEUROPATHIC PAIN. 2018 17 5851 24 SUBEROYLANILIDE HYDROXAMIC ACID TRIGGERS AUTOPHAGY BY INFLUENCING THE MTOR PATHWAY IN THE SPINAL DORSAL HORN IN A RAT NEUROPATHIC PAIN MODEL. HISTONE ACETYLATION LEVELS CAN BE UPREGULATED BY TREATING CELLS WITH HISTONE DEACETYLASE INHIBITORS (HDACIS), WHICH CAN INDUCE AUTOPHAGY. AUTOPHAGY FLUX IN THE SPINAL CORD OF RATS FOLLOWING THE LEFT FIFTH LUMBER SPINAL NERVE LIGATION (SNL) IS INVOLVED IN THE PROGRESSION OF NEUROPATHIC PAIN. SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), ONE OF THE HDACIS CAN INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION, WHICH HAS BEEN SHOWN TO EASE NEUROPATHIC PAIN. RECENT RESEARCH SUGGEST THAT SAHA CAN STIMULATE AUTOPHAGY VIA THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) PATHWAY IN SOME TYPES OF CANCER CELLS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLE OF SAHA AND AUTOPHAGY IN NEUROPATHIC PAIN AFTER NERVE INJURY. IN THE PRESENT STUDY, WE AIM TO INVESTIGATE AUTOPHAGY FLUX AND THE ROLE OF THE MTOR PATHWAY ON SPINAL CELLS AUTOPHAGY ACTIVATION IN NEUROPATHIC PAIN INDUCED BY SNL IN RATS THAT RECEIVED SAHA TREATMENT. AUTOPHAGY-RELATED PROTEINS AND MTOR OR ITS ACTIVE FORM WERE ASSESSED BY USING WESTERN BLOT, IMMUNOHISTOCHEMISTRY, DOUBLE IMMUNOFLUORESCENCE STAINING AND TRANSMISSION ELECTRON MICROSCOPY (TEM). WE FOUND THAT SAHA DECREASED THE PAW MECHANICAL WITHDRAWAL THRESHOLD (PMWT) OF THE LOWER COMPARED WITH SNL. AUTOPHAGY FLUX WAS MAINLY DISRUPTED IN THE ASTROCYTES AND NEURONAL CELLS OF THE SPINAL CORD DORSAL HORN ON POSTSURGICAL DAY 28 AND WAS REVERSED BY DAILY INTRATHECAL INJECTION OF SAHA (N = 100 NMOL/DAY OR N = 200 NMOL/DAY). SAHA ALSO DECREASED MTOR AND PHOSPHORYLATED MTOR (P-MTOR) EXPRESSION, ESPECIALLY P-MTOR EXPRESSION IN ASTROCYTES AND NEURONAL CELLS OF THE SPINAL DORSAL HORN. THESE RESULTS SUGGEST THAT SAHA ATTENUATES NEUROPATHIC PAIN AND CONTRIBUTES TO AUTOPHAGY FLUX IN ASTROCYTES AND NEURONAL CELLS OF THE SPINAL DORSAL HORN VIA THE MTOR SIGNALING PATHWAY. 2019 18 1630 26 DNMT3A CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF BONE CANCER PAIN BY SILENCING KV1.2 EXPRESSION IN SPINAL CORD DORSAL HORN. METASTATIC BONE TUMOR-INDUCED CHANGES IN GENE TRANSCRIPTION AND TRANSLATION IN PAIN-RELATED REGIONS OF THE NERVOUS SYSTEM MAY PARTICIPATE IN THE DEVELOPMENT AND MAINTENANCE OF BONE CANCER PAIN. EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION REGULATE GENE TRANSCRIPTION. HERE, WE REPORT THAT INTRATHECAL INJECTION OF DECITABINE, A DNA METHYLTRANSFERASE (DNMT) INHIBITOR, DOSE DEPENDENTLY ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF BONE CANCER PAIN INDUCED BY INJECTING PROSTATE CANCER CELLS INTO THE TIBIA. THE LEVEL OF THE DE NOVO DNMT3A, BUT NOT DNMT3B, TIME DEPENDENTLY INCREASED IN THE IPSILATERAL L4/5 DORSAL HORN (NOT L4/5 DORSAL ROOT GANGLION) AFTER PROSTATE CANCER CELLS INJECTION. BLOCKING THIS INCREASE THROUGH MICROINJECTION OF RECOMBINANT ADENO-ASSOCIATED VIRUS 5 (AAV5) EXPRESSING DNMT3A SHRNA INTO DORSAL HORN RESCUED PROSTATE CANCER CELLS-INDUCED DOWNREGULATION OF DORSAL HORN KV1.2 EXPRESSION AND IMPAIRED PROSTATE CANCER CELLS-INDUCED PAIN HYPERSENSITIVITY. IN TURN, MIMICKING THIS INCREASE THROUGH MICROINJECTION OF AAV5 EXPRESSING FULL-LENGTH DNMT3A INTO DORSAL HORN REDUCED DORSAL HORN KV1.2 EXPRESSION AND PRODUCED PAIN HYPERSENSITIVITY IN THE ABSENCE OF PROSTATE CANCER CELLS INJECTION. ADMINISTRATION OF NEITHER DECITABINE NOR VIRUS AFFECTED LOCOMOTOR FUNCTION AND ACUTE RESPONSES TO MECHANICAL, THERMAL, OR COLD STIMULI. GIVEN THAT DNMT3A MRNA IS CO-EXPRESSED WITH KCNA2 MRNA (ENCODING KV1.2) IN INDIVIDUAL DORSAL HORN NEURONS, OUR FINDINGS SUGGEST THAT INCREASED DORSAL HORN DNMT3A CONTRIBUTES TO BONE CANCER PAIN THROUGH SILENCING DORSAL HORN KV1.2 EXPRESSION. DNMT3A MAY REPRESENT A POTENTIAL NEW TARGET FOR CANCER PAIN MANAGEMENT. 2017 19 2452 30 EPIGENETIC SUPPRESSION OF POTASSIUM-CHLORIDE CO-TRANSPORTER 2 EXPRESSION IN INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND'S ADJUVANT (CFA). BACKGROUND: MULTIPLE MECHANISMS CONTRIBUTE TO THE STIMULUS-EVOKED PAIN HYPERSENSITIVITY THAT MAY BE EXPERIENCED AFTER PERIPHERAL INFLAMMATION. PERSISTENT PATHOLOGICAL STIMULI IN MANY PAIN CONDITIONS AFFECT THE EXPRESSION OF CERTAIN GENES THROUGH EPIGENETIC ALTERNATIONS. THE MAIN PURPOSE OF OUR STUDY WAS TO INVESTIGATE THE ROLE OF EPIGENETIC MODIFICATION ON POTASSIUM-CHLORIDE CO-TRANSPORTER 2 (KCC2) GENE EXPRESSION IN THE PERSISTENCE OF INFLAMMATORY PAIN. METHODS: PERSISTENT INFLAMMATORY PAIN WAS INDUCED THROUGH THE INJECTION OF COMPLETE FREUND'S ADJUVANT (CFA) IN THE LEFT HIND PAW OF RATS. ACETYL-HISTONE H3 AND H4 LEVEL WAS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION IN THE SPINAL DORSAL HORN. PAIN BEHAVIOUR AND INHIBITORY SYNAPTIC FUNCTION OF SPINAL CORD WERE DETERMINED BEFORE AND AFTER CFA INJECTION. KCC2 EXPRESSION WAS DETERMINED BY REAL TIME RT-PCR AND WESTERN BLOT. INTRATHECAL KCC2 SIRNA (2 MUG PER 10 MUL PER RAT) OR HDAC INHIBITOR (10 MUG PER 10 MUL PER RAT) WAS INJECTED ONCE DAILY FOR 3 DAYS BEFORE CFA INJECTION. RESULTS: PERSISTENT INFLAMMATORY PAIN EPIGENETICALLY SUPPRESSED KCC2 EXPRESSION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN DECREASED INHIBITORY SIGNALLING EFFICACY. KCC2 KNOCK-DOWN CAUSED BY INTRATHECAL ADMINISTRATION OF KCC2 SIRNA IN NAIVE RATS REDUCED KCC2 EXPRESSION IN THE SPINAL CORD, LEADING TO SENSITIZED PAIN BEHAVIOURS AND IMPAIRED INHIBITORY SYNAPTIC TRANSMISSION IN THEIR SPINAL CORDS. MOREOVER, INTRATHECAL HDAC INHIBITOR INJECTION IN CFA RATS INCREASED KCC2 EXPRESSION, PARTIALLY RESTORING THE SPINAL INHIBITORY SYNAPTIC TRANSMISSION AND RELIEVING THE SENSITIZED PAIN BEHAVIOUR. CONCLUSION: THESE FINDINGS SUGGEST THAT THE TRANSCRIPTION OF SPINAL KCC2 IS REGULATED BY HISTONE ACETYLATION EPIGENETICALLY FOLLOWING CFA. SIGNIFICANCE: PERSISTENT PAIN SUPPRESSES KCC2 EXPRESSION THROUGH HDAC-MEDIATED HISTONE HYPOACETYLATION AND CONSEQUENTLY IMPAIRS THE INHIBITORY FUNCTION OF INHIBITORY INTERNEURONS. DRUGS SUCH AS HDAC INHIBITORS THAT SUPPRESS THE INFLUENCES OF PERSISTENT PAIN ON THE EXPRESSION OF KCC2 MAY SERVE AS A NOVEL ANALGESIC. 2017 20 5781 30 SPINAL SIRT1 ACTIVATION ATTENUATES NEUROPATHIC PAIN IN MICE. ABNORMAL HISTONE ACETYLATION OCCURS DURING NEUROPATHIC PAIN THROUGH AN EPIGENETIC MECHANISM. SILENT INFORMATION REGULATOR 1 (SIR2 OR SIRT1), A NAD-DEPENDENT DEACETYLASE, PLAYS COMPLEX SYSTEMIC ROLES IN A VARIETY OF PROCESSES THROUGH DEACETYLATING ACETYLATED HISTONE AND OTHER SPECIFIC SUBSTRATES. BUT THE ROLE OF SIRT1 IN NEUROPATHIC PAIN IS NOT WELL ESTABLISHED YET. THE PRESENT STUDY WAS INTENDED TO DETECT SIRT1 CONTENT AND ACTIVITY, NICOTINAMIDE (NAM) AND NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) IN THE SPINAL CORD USING IMMUNOBLOTTING OR MASS SPECTROSCOPY OVER TIME IN MICE FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) OR SHAM SURGERY. IN ADDITION, THE EFFECT OF INTRATHECAL INJECTION OF NAD OR RESVERATROL ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA WAS EVALUATED IN CCI MICE. FINALLY, WE INVESTIGATED WHETHER SIRT1 INHIBITOR EX-527 COULD REVERSE THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. IT WAS FOUND THAT SPINAL SIRT1 EXPRESSION, DEACETYLASE ACTIVITY AND NAD/NAM DECREASED SIGNIFICANTLY 1, 3, 7, 14 AND 21 DAYS AFTER CCI SURGERY AS COMPARED WITH SHAM GROUP. IN ADDITION, DAILY INTRATHECAL INJECTION OF 5 MICROL 800 MM NAD 1 H BEFORE AND 1 DAY AFTER CCI SURGERY OR SINGLE INTRATHECAL INJECTION OF 5 MICROL 90 MM RESVERATROL 1 H BEFORE CCI SURGERY PRODUCED A TRANSIENT INHIBITORY EFFECT ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA IN CCI MICE. FINALLY, AN INTRATHECAL INJECTION OF 5 MICROL 1.2 MM EX-527 1 H BEFORE NAD OR RESVERATROL ADMINISTRATION REVERSED THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. THESE DATA INDICATE THAT THE REDUCTION IN SIRT1 DEACETYLASE ACTIVITY MAY BE A FACTOR CONTRIBUTING TO THE DEVELOPMENT OF NEUROPATHIC PAIN IN CCI MICE. OUR FINDINGS SUGGEST THAT THE ENHANCEMENT OF SPINAL NAD/NAM AND/OR SIRT1 ACTIVITY MAY BE A POTENTIALLY PROMISING STRATEGY FOR THE PREVENTION OR TREATMENT OF NEUROPATHIC PAIN. 2014