1 400 135 ANALGESIA INDUCED BY THE EPIGENETIC DRUG, L-ACETYLCARNITINE, OUTLASTS THE END OF TREATMENT IN MOUSE MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN. BACKGROUND L-ACETYLCARNITINE, A DRUG MARKETED FOR THE TREATMENT OF CHRONIC PAIN, CAUSES ANALGESIA BY EPIGENETICALLY UP-REGULATING TYPE-2 METABOTROPIC GLUTAMATE (MGLU2) RECEPTORS IN THE SPINAL CORD. BECAUSE THE EPIGENETIC MECHANISMS ARE TYPICALLY LONG-LASTING, WE HYPOTHESIZED THAT ANALGESIA COULD OUTLAST THE DURATION OF L-ACETYLCARNITINE TREATMENT IN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN. RESULTS A SEVEN-DAY TREATMENT WITH L-ACETYLCARNITINE (100 MG/KG, ONCE A DAY, I.P.) PRODUCED AN ANTIALLODYNIC EFFECT IN THE COMPLETE FREUND ADJUVANT MOUSE MODEL OF CHRONIC INFLAMMATORY PAIN. L-ACETYLCARNITINE-INDUCED ANALGESIA PERSISTED FOR AT LEAST 14 DAYS AFTER DRUG WITHDRAWAL. IN CONTRAST, THE ANALGESIC EFFECT OF PREGABALIN, AMITRYPTILINE, CEFTRIAXONE, AND N-ACETYLCYSTEINE DISAPPEARED SEVEN DAYS AFTER DRUG WITHDRAWAL. L-ACETYLCARNITINE TREATMENT ENHANCED MGLU2/3 RECEPTOR PROTEIN LEVELS IN THE DORSAL REGION OF THE SPINAL CORD. THIS EFFECT ALSO PERSISTED FOR TWO WEEKS AFTER DRUG WITHDRAWAL AND WAS ASSOCIATED WITH INCREASED LEVELS OF ACETYLATED HISTONE H3 BOUND TO THE GRM2 GENE PROMOTER IN THE DORSAL ROOT GANGLIA. A LONG-LASTING ANALGESIC EFFECT OF L-ACETYLCARNITINE WAS ALSO OBSERVED IN MICE SUBJECTED TO CHRONIC CONSTRICTION INJURY OF THE SCIATIC NERVE. IN THESE ANIMALS, A 14-DAY TREATMENT WITH PREGABALIN, AMITRYPTILINE, TRAMADOL, OR L-ACETYLCARNITINE PRODUCED A SIGNIFICANT ANTIALLODYNIC EFFECT, WITH PREGABALIN DISPLAYING THE GREATEST EFFICACY. IN MICE TREATED WITH PREGABALIN, TRAMADOL OR L-ACETYLCARNITINE THE ANALGESIC EFFECT WAS STILL VISIBLE 15 DAYS AFTER THE END OF DRUG TREATMENT. HOWEVER, ONLY IN MICE TREATED WITH L-ACETYLCARNITINE ANALGESIA PERSISTED 37 DAYS AFTER DRUG WITHDRAWAL. THIS EFFECT WAS ASSOCIATED WITH AN INCREASE IN MGLU2/3 RECEPTOR PROTEIN LEVELS IN THE DORSAL HORNS OF THE SPINAL CORD. CONCLUSIONS OUR FINDINGS SUGGEST THAT L-ACETYLCARNITINE HAS THE UNIQUE PROPERTY TO CAUSE A LONG-LASTING ANALGESIC EFFECT THAT MIGHT REDUCE RELAPSES IN PATIENTS SUFFERING FROM CHRONIC PAIN. 2017 2 6536 36 TRANSCRIPTIONAL REGULATION OF TYPE-2 METABOTROPIC GLUTAMATE RECEPTORS: AN EPIGENETIC PATH TO NOVEL TREATMENTS FOR CHRONIC PAIN. ACTIVATION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS INHIBITS PAIN TRANSMISSION AT THE SYNAPSES BETWEEN PRIMARY AFFERENT FIBERS AND NEURONS IN THE DORSAL HORN OF THE SPINAL CORD. IN ADDITION, MGLU2 RECEPTORS ARE FOUND IN PERIPHERAL NOCICEPTORS, AND IN PAIN-REGULATORY CENTERS OF THE BRAIN STEM AND FOREBRAIN. MGLU2 RECEPTOR AGONISTS PRODUCE ANALGESIA IN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN, BUT THEIR USE IS LIMITED BY THE DEVELOPMENT OF TOLERANCE. A NEW THERAPEUTIC STRATEGY COULD BE BASED ON THE TRANSCRIPTIONAL REGULATION OF MGLU2 RECEPTORS VIA THE ACETYLATION-PROMOTED ACTIVATION OF THE P65/RELA TRANSCRIPTION FACTOR. "EPIGENETIC" DRUGS THAT INCREASE MGLU2 RECEPTOR EXPRESSION, INCLUDING L-ACETYLCARNITINE AND INHIBITORS OF HISTONE DEACETYLASES, HAVE A DIFFERENT ANALGESIC PROFILE WITH NO TOLERANCE TO THE THERAPEUTIC EFFECT AFTER REPEATED DOSING. 2010 3 2249 52 EPIGENETIC MODULATION OF MGLU2 RECEPTORS BY HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF INFLAMMATORY PAIN. KNOWING THAT EXPRESSION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS IN THE DORSAL ROOT GANGLIA IS REGULATED BY ACETYLATION MECHANISMS, WE EXAMINED THE EFFECT OF TWO SELECTIVE AND CHEMICALLY UNRELATED HISTONE DEACETYLASE (HDAC) INHIBITORS, N-(2-AMINOPHENYL)-4-[N-(PYRIDINE-3-YLMETHOXY-CARBONYL)AMINOMETHYL]BENZAMIDE (MS-275) AND SUBEROYLANILIDE HYDROAMIC ACID (SAHA), IN A MOUSE MODEL OF PERSISTENT INFLAMMATORY PAIN. ALTHOUGH A SINGLE SUBCUTANEOUS INJECTION OF MS-275 (3 MG/KG) OR SAHA (5-50 MG/KG) WAS INEFFECTIVE, A 5-DAY TREATMENT WITH EITHER OF THE TWO HDAC INHIBITORS SUBSTANTIALLY REDUCED THE NOCICEPTIVE RESPONSE IN THE SECOND PHASE OF THE FORMALIN TEST, WHICH REFLECTS THE DEVELOPMENT OF CENTRAL SENSITIZATION IN THE DORSAL HORN OF THE SPINAL CORD. ANALGESIA WAS ABROGATED BY A SINGLE INJECTION OF THE MGLU2/3 RECEPTOR ANTAGONIST (ALPHAS)-ALPHA-AMINO-ALPHA-[(1S,2S)-2-CARBOXYCYCLOPROPYL]-9H-XANTINE-9-PROPANOIC ACID (LY341495; 1 MG/KG, I.P.), WHICH WAS INACTIVE PER SE. BOTH MS-275 AND SAHA UP-REGULATED THE EXPRESSION OF MGLU2 RECEPTORS IN THE DORSAL ROOT GANGLION (DRG) AND SPINAL CORD UNDER CONDITIONS IN WHICH THEY CAUSED ANALGESIA, WITHOUT CHANGING THE EXPRESSION OF MGLU1A, MGLU4, OR MGLU5 RECEPTORS. INDUCTION OF DRG MGLU2 RECEPTORS IN RESPONSE TO SAHA WAS ASSOCIATED WITH INCREASED ACETYLATION OF P65/RELA ON LYSINE 310, A PROCESS THAT ENHANCES THE TRANSCRIPTIONAL ACTIVITY OF P65/RELA AT NUCLEAR FACTOR-KAPPAB-REGULATED GENES. TRANSCRIPTION OF THE MGLU2 RECEPTOR GENE IS KNOWN TO BE ACTIVATED BY P65/RELA IN DRG NEURONS. WE CONCLUDE THAT HDAC INHIBITION PRODUCES ANALGESIA BY UP-REGULATING MGLU2 RECEPTOR EXPRESSION IN THE DRG, AN EFFECT THAT RESULTS FROM THE AMPLIFICATION OF NF-KAPPAB TRANSCRIPTIONAL ACTIVITY. THESE DATA PROVIDE THE FIRST EVIDENCE THAT HDAC INHIBITORS CAUSE ANALGESIA AND SUGGEST THAT HDACS ARE POTENTIAL TARGETS FOR THE EPIGENETIC TREATMENT OF PAIN. 2009 4 3892 46 L-ACETYLCARNITINE CAUSES RAPID ANTIDEPRESSANT EFFECTS THROUGH THE EPIGENETIC INDUCTION OF MGLU2 RECEPTORS. EPIGENETIC MECHANISMS ARE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSIVE DISORDERS AND ARE UNIQUE POTENTIAL TARGETS FOR THERAPEUTIC INTERVENTION. THE ACETYLATING AGENT L-ACETYLCARNITINE (LAC), A WELL-TOLERATED DRUG, BEHAVES AS AN ANTIDEPRESSANT BY THE EPIGENETIC REGULATION OF TYPE 2 METABOTROPIC GLUTAMATE (MGLU2) RECEPTORS. IT CAUSED A RAPID AND LONG-LASTING ANTIDEPRESSANT EFFECT IN FLINDERS SENSITIVE LINE RATS AND IN MICE EXPOSED TO CHRONIC UNPREDICTABLE STRESS, WHICH, RESPECTIVELY, MODEL GENETIC AND ENVIRONMENTALLY INDUCED DEPRESSION. IN BOTH MODELS, LAC INCREASED LEVELS OF ACETYLATED H3K27 BOUND TO THE GRM2 PROMOTER AND ALSO INCREASED ACETYLATION OF NF-KB-P65 SUBUNIT, THEREBY ENHANCING THE TRANSCRIPTION OF GRM2 GENE ENCODING FOR THE MGLU2 RECEPTOR IN HIPPOCAMPUS AND PREFRONTAL CORTEX. IMPORTANTLY, LAC REDUCED THE IMMOBILITY TIME IN THE FORCED SWIM TEST AND INCREASED SUCROSE PREFERENCE AS EARLY AS 3 D OF TREATMENT, WHEREAS 14 D OF TREATMENT WERE NEEDED FOR THE ANTIDEPRESSANT EFFECT OF CHLORIMIPRAMINE. MOREOVER, THERE WAS NO TOLERANCE TO THE ACTION OF LAC, AND THE ANTIDEPRESSANT EFFECT WAS STILL SEEN 2 WK AFTER DRUG WITHDRAWAL. CONVERSELY, NF-KB INHIBITION PREVENTED THE INCREASE IN MGLU2 EXPRESSION INDUCED BY LAC, WHEREAS THE USE OF A HISTONE DEACETYLASE INHIBITOR SUPPORTED THE EPIGENETIC CONTROL OF MGLU2 EXPRESSION. FINALLY, LAC HAD NO EFFECT ON MGLU2 KNOCKOUT MICE EXPOSED TO CHRONIC UNPREDICTABLE STRESS, AND A SINGLE INJECTION OF THE MGLU2/3 RECEPTOR ANTAGONIST LY341495 PARTIALLY BLOCKED LAC ACTION. THE RAPID AND LONG-LASTING ANTIDEPRESSANT ACTION OF LAC STRONGLY SUGGESTS A UNIQUE APPROACH TO EXAMINE THE EPIGENETIC HYPOTHESIS OF DEPRESSIVE DISORDERS IN HUMANS, PAVING THE WAY FOR MORE EFFICIENT ANTIDEPRESSANTS WITH FASTER ONSET OF ACTION. 2013 5 3194 37 HDAC INHIBITORS ATTENUATE THE DEVELOPMENT OF HYPERSENSITIVITY IN MODELS OF NEUROPATHIC PAIN. 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. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER THESE COMPOUNDS COULD ALSO AFFECT NEUROPATHIC PAIN. DIFFERENT CLASS I HDACIS WERE DELIVERED INTRATHECALLY INTO RAT SPINAL CORD IN MODELS OF TRAUMATIC NERVE INJURY AND ANTIRETROVIRAL DRUG-INDUCED PERIPHERAL NEUROPATHY (STAVUDINE, D4T). MECHANICAL AND THERMAL HYPERSENSITIVITY WAS ATTENUATED BY 40% TO 50% AS A RESULT OF HDACI TREATMENT, BUT ONLY IF STARTED BEFORE ANY INSULT. THE DRUGS GLOBALLY INCREASED HISTONE ACETYLATION IN THE SPINAL CORD, BUT APPEARED TO HAVE NO MEASURABLE EFFECTS IN RELEVANT DORSAL ROOT GANGLIA IN THIS TREATMENT PARADIGM, SUGGESTING THAT ANY POTENTIAL MECHANISM SHOULD BE SOUGHT IN THE CENTRAL NERVOUS SYSTEM. MICROARRAY ANALYSIS OF DORSAL CORD RNA REVEALED THE SIGNATURE OF THE SPECIFIC COMPOUND USED (MS-275) AND SUGGESTED THAT ITS MAIN EFFECT WAS MEDIATED THROUGH HDAC1. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE ACETYLATION IN THE EMERGENCE OF NEUROPATHIC PAIN. 2013 6 3191 50 HDAC AND HAT INHIBITORS DIFFERENTLY AFFECT ANALGESIA MEDIATED BY GROUP II METABOTROPIC GLUTAMATE RECEPTORS. BACKGROUND: HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYLTRANSFERASES (HATS) ARE KEY PLAYERS IN EPIGENETIC REGULATION OF GENE EXPRESSION. ANALGESIC ACTIVITY BY HDAC INHIBITORS HAS BEEN REPORTED IN DIFFERENT PAIN MODELS INCLUDING INFLAMMATORY AND NEUROPATHIC PAIN. THESE DRUGS INTERFERE WITH GENE EXPRESSION THROUGH DIFFERENT MECHANISMS INCLUDING CHROMATIN REMODELING AND/OR ACTIVATION OF TRANSCRIPTION FACTORS. AMONG OTHER TARGETS, HDAC INHIBITORS REGULATE METABOTROPIC GLUTAMATE RECEPTORS TYPE 2 (MGLU2) EXPRESSION IN CENTRAL AND PERIPHERAL CENTRAL NERVOUS SYSTEM. HOWEVER WHETHER INHIBITION OF HAT ACTIVITY ALSO REGULATES MGLU2 EXPRESSION HAS NOT BEEN REPORTED. FINDINGS: HERE WE REPORT THAT CURCUMIN (CUR), A NATURALLY OCCURRING COMPOUND ENDOWED WITH P300/CREB-BINDING PROTEIN HAT INHIBITORY ACTIVITY, IS ABLE TO INDUCE A DRASTIC DOWN-REGULATION OF THE MGLU2 RECEPTOR IN THE MOUSE SPINAL CORD AFTER SYSTEMIC ADMINISTRATION TOGETHER WITH A MARKED HYPOACETYLATION OF HISTONES H3 AND H4 IN DORSAL ROOT GANGLIA (DRG). FURTHERMORE, THE ANALGESIC ACTIVITY OF THE MGLU2/3 AGONIST, LY379268 IS LOST AFTER A 3-DAY TREATMENT WITH CUR. CONVERSELY THE ANALGESIC ACTIVITY OF LY379268 IS POTENTIATED IN MICE PRETREATED FOR 5 CONSECUTIVE DAYS WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), KNOWN TO INDUCE MGLU2-UPREGULATION. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT SYSTEMICALLY INJECTED CUR IS ABLE TO INHIBIT H3 AND H4 ACETYLATION IN THE DRG AND TO DOWN-REGULATE MGLU2 RECEPTORS IN THE SPINAL CORD. WE ALSO DEMONSTRATE THAT LONG TERM MODIFICATION OF THE MGLU2 EXPRESSION AFFECTS THE ANALGESIC PROPERTIES OF THE ORTHOSTERIC MGLU2/3 AGONIST, LY379268. THESE DATA OPEN UP THE POSSIBILITY THAT EPIGENETIC MODULATORS MIGHT BE GIVEN IN COMBINATION WITH "TRADITIONAL" DRUGS IN A CONTEXT OF A MULTI TARGET APPROACH FOR A BETTER ANALGESIC EFFICACY. 2014 7 1003 46 CHRONIC TREATMENT WITH FLUOXETINE INDUCES SEX-DEPENDENT ANALGESIC EFFECTS AND MODULATES HDAC2 AND MGLU2 EXPRESSION IN FEMALE MICE. GENDER AND SEX DIFFERENCES IN PAIN RECOGNITION AND DRUG RESPONSES HAVE BEEN REPORTED IN CLINICAL TRIALS AND EXPERIMENTAL MODELS OF PAIN. AMONG ANTIDEPRESSANTS, CONTRADICTORY RESULTS HAVE BEEN OBSERVED IN PATIENTS TREATED WITH SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS). THIS STUDY EVALUATED SEX DIFFERENCES IN RESPONSE TO THE SSRI FLUOXETINE AFTER CHRONIC ADMINISTRATION IN THE MOUSE FORMALIN TEST. ADULT MALE AND FEMALE CD1 MICE WERE INTRAPERITONEALLY INJECTED WITH FLUOXETINE (10 MG/KG) FOR 21 DAYS AND SUBJECTED TO PAIN ASSESSMENT. FLUOXETINE TREATMENT REDUCED THE SECOND PHASE OF THE FORMALIN TEST ONLY IN FEMALE MICE WITHOUT PRODUCING BEHAVIORAL CHANGES IN MALES. WE ALSO OBSERVED THAT FLUOXETINE WAS ABLE TO SPECIFICALLY INCREASE THE EXPRESSION OF METABOTROPIC GLUTAMATE RECEPTOR TYPE-2 (MGLU2) IN FEMALES. ALSO A REDUCED EXPRESSION OF THE EPIGENETIC MODIFYING ENZYME, HISTONE DEACETYLASE 2 (HDAC2), IN DORSAL ROOT GANGLIA (DRG) AND DORSAL HORN (DH) TOGETHER WITH AN INCREASE HISTONE 3 ACETYLATION (H3) LEVEL WAS OBSERVED IN FEMALES BUT NOT IN MALES. WITH THIS STUDY WE PROVIDE EVIDENCE THAT FLUOXETINE INDUCES SEX SPECIFIC CHANGES IN HDAC2 AND MGLU2 EXPRESSION IN THE DH OF THE SPINAL CORD AND IN DRGS AND SUGGESTS A MOLECULAR EXPLANATION FOR THE ANALGESIC EFFECTS IN FEMALE MICE. 2017 8 5877 46 SYNERGIC ACTION OF L-ACETYLCARNITINE AND L-METHYLFOLATE IN MOUSE MODELS OF STRESS-RELATED DISORDERS AND HUMAN IPSC-DERIVED DOPAMINERGIC NEURONS. THE EPIGENETIC AGENTS, L-ACETYLCARNITINE (LAC) AND L-METHYLFOLATE (MF) ARE PUTATIVE CANDIDATES AS ADD-ON DRUGS IN DEPRESSION. WE EVALUATED THE EFFECT OF A COMBINED TREATMENT WITH LAC AND MF IN TWO DIFFERENT PARADIGMS OF CHRONIC STRESS IN MICE AND IN HUMAN INDUCIBLE PLURIPOTENT STEM CELLS (HIPSCS) DIFFERENTIATED INTO DOPAMINERGIC NEURONS. TWO GROUPS OF MICE WERE EXPOSED TO CHRONIC UNPREDICTABLE STRESS (CUS) FOR 28 DAYS OR CHRONIC RESTRAINT STRESS (CRS) FOR 21 DAY, AND LAC (30 OR 100 MG/KG) AND/OR MF (0.75 OR 3 MG/KG) WERE ADMINISTERED I.P. ONCE A DAY FOR 14 DAYS, STARTING FROM THE LAST WEEK OF STRESS. IN BOTH STRESS PARADIGMS, LAC AND MF ACTED SYNERGISTICALLY IN REDUCING THE IMMOBILITY TIME IN THE FORCED SWIM TEST AND ENHANCING BDNF PROTEIN LEVELS IN THE FRONTAL CORTEX AND HIPPOCAMPUS. IN ADDITION, LAC AND MF ACTED SYNERGISTICALLY IN ENHANCING TYPE-2 METABOTROPIC GLUTAMATE RECEPTOR (MGLU2) PROTEIN LEVELS IN THE HIPPOCAMPUS OF MICE EXPOSED TO CRS. INTERESTINGLY, CRS MICE TREATED WITH MF SHOWED AN UP-REGULATION OF NFKAPPAB P65, WHICH IS A SUBSTRATE FOR LAC-INDUCED ACETYLATION. WE COULD ALSO DEMONSTRATE A SYNERGISM BETWEEN LAC AND MF IN CULTURED HIPSCS DIFFERENTIATED INTO DOPAMINE NEURONS, BY MEASURING DENDRITE LENGTH AND NUMBER, AND AREA OF THE CELL SOMA AFTER 3 DAYS OF DRUG EXPOSURE. THESE FINDINGS SUPPORT THE COMBINED USE OF LAC AND MF IN THE TREATMENT OF MDD AND OTHER STRESS-RELATED DISORDERS. 2022 9 5851 37 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 10 2353 43 EPIGENETIC REGULATION OF OPIOID-INDUCED HYPERALGESIA, DEPENDENCE, AND TOLERANCE IN MICE. REPEATED ADMINISTRATION OF OPIOIDS SUCH AS MORPHINE INDUCES PERSISTENT BEHAVIORAL CHANGES INCLUDING OPIOID-INDUCED HYPERALGESIA (OIH), TOLERANCE, AND PHYSICAL DEPENDENCE. IN THE CURRENT WORK WE EXPLORED HOW THE BALANCE OF HISTONE ACETYLTRANSFERASE (HAT) VERSUS HISTONE DEACETYLASE (HDAC) MIGHT REGULATE THESE MORPHINE-INDUCED CHANGES. NOCICEPTIVE THRESHOLDS, ANALGESIA, AND PHYSICAL DEPENDENCE WERE ASSESSED DURING AND FOR A PERIOD OF SEVERAL WEEKS AFTER MORPHINE EXPOSURE. TO PROBE THE ROLES OF HISTONE ACETYLATION, THE HAT INHIBITOR CURCUMIN OR A SELECTIVE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WAS ADMINISTERED DAILY TO GROUPS OF ANIMALS. HISTONE ACETYLATION IN SPINAL CORD WAS ASSESSED BY WESTERN BLOT AND IMMUNOHISTOCHEMISTRY. CONCURRENT ADMINISTRATION OF CURCUMIN WITH MORPHINE FOR 4 DAYS SIGNIFICANTLY REDUCED DEVELOPMENT OF OPIOID-INDUCED MECHANICAL ALLODYNIA, THERMAL HYPERALGESIA, TOLERANCE, AND PHYSICAL DEPENDENCE. CONVERSELY, THE HDAC INHIBITOR SAHA ENHANCED THESE RESPONSES. INTERESTINGLY, SAHA TREATMENT AFTER THE TERMINATION OF OPIOID ADMINISTRATION SUSTAINED THESE BEHAVIORAL CHANGES FOR AT LEAST 4 WEEKS. HISTONE H3 ACETYLATION IN THE DORSAL HORN OF THE SPINAL CORD WAS INCREASED AFTER CHRONIC MORPHINE TREATMENT, BUT H4 ACETYLATION WAS UNCHANGED. MOREOVER, WE OBSERVED A DECREASE IN HDAC ACTIVITY IN THE SPINAL CORDS OF MORPHINE-TREATED MICE WHILE OVERALL HAT ACTIVITY WAS UNCHANGED, SUGGESTING A SHIFT TOWARD A STATE OF ENHANCED HISTONE ACETYLATION. PERSPECTIVE: THE CURRENT STUDY INDICATES THAT EPIGENETIC MECHANISMS PLAY A CRUCIAL ROLE IN OPIOID-INDUCED LONG-LASTING NEUROPLASTICITY. THESE RESULTS PROVIDE NEW SIGHT INTO UNDERSTANDING THE MECHANISMS OF OPIOID-INDUCED NEUROPLASTICITY AND SUGGEST NEW STRATEGIES TO LIMIT OPIOID ABUSE POTENTIAL AND INCREASE THE VALUE OF THESE DRUGS AS ANALGESICS. 2013 11 2785 38 EZH2 REGULATES SPINAL NEUROINFLAMMATION IN RATS WITH NEUROPATHIC PAIN. ALTERATION IN GENE EXPRESSION ALONG THE PAIN SIGNALING PATHWAY IS A KEY MECHANISM CONTRIBUTING TO THE GENESIS OF NEUROPATHIC PAIN. ACCUMULATING STUDIES HAVE SHOWN THAT EPIGENETIC REGULATION PLAYS A CRUCIAL ROLE IN NOCICEPTIVE PROCESS IN THE SPINAL DORSAL HORN. IN THIS PRESENT STUDY, WE INVESTIGATED THE ROLE OF ENHANCER OF ZESTE HOMOLOG-2 (EZH2), A SUBUNIT OF THE POLYCOMB REPRESSIVE COMPLEX 2, IN THE SPINAL DORSAL HORN IN THE GENESIS OF NEUROPATHIC PAIN IN RATS INDUCED BY PARTIAL SCIATIC NERVE LIGATION. EZH2 IS A HISTONE METHYLTRANSFERASE, WHICH CATALYZES THE METHYLATION OF HISTONE H3 ON K27 (H3K27), RESULTING IN GENE SILENCING. WE FOUND THAT LEVELS OF EZH2 AND TRI-METHYLATED H3K27 (H3K27TM) IN THE SPINAL DORSAL HORN WERE INCREASED IN RATS WITH NEUROPATHIC PAIN ON DAY 3 AND DAY 10 POST NERVE INJURIES. EZH2 WAS PREDOMINANTLY EXPRESSED IN NEURONS IN THE SPINAL DORSAL HORN UNDER NORMAL CONDITIONS. THE NUMBER OF NEURONS WITH EZH2 EXPRESSION WAS INCREASED AFTER NERVE INJURY. MORE STRIKINGLY, NERVE INJURY DRASTICALLY INCREASED THE NUMBER OF MICROGLIA WITH EZH2 EXPRESSION BY MORE THAN SEVENFOLD. INTRATHECAL INJECTION OF THE EZH2 INHIBITOR ATTENUATED THE DEVELOPMENT AND MAINTENANCE OF MECHANICAL AND THERMAL HYPERALGESIA IN RATS WITH NERVE INJURY. SUCH ANALGESIC EFFECTS WERE CONCURRENTLY ASSOCIATED WITH THE REDUCED LEVELS OF EZH2, H3K27TM, IBA1, GFAP, TNF-ALPHA, IL-1BETA, AND MCP-1 IN THE SPINAL DORSAL HORN IN RATS WITH NERVE INJURY. OUR RESULTS HIGHLY SUGGEST THAT TARGETING THE EZH2 SIGNALING PATHWAY COULD BE AN EFFECTIVE APPROACH FOR THE MANAGEMENT OF NEUROPATHIC PAIN. 2017 12 1238 29 CURCUMIN BLOCKS CHRONIC MORPHINE ANALGESIC TOLERANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR UPREGULATION. THIS STUDY WAS CARRIED OUT BASED ON THE ASSUMPTION THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MAY COUNTERBALANCE THE ACTION OF MORPHINE IN THE BRAIN. MORPHINE ANALGESIC TOLERANCE AFTER DAILY ADMINISTRATIONS FOR SIX DAYS WAS BLOCKED BY INTRACEREBROVENTRICULAR INJECTION OF ANTI-BDNF IGG ON DAY 5, BUT NOT BY ADMINISTRATIONS ON DAYS 1-4. CHRONIC MORPHINE TREATMENT SIGNIFICANTLY INCREASED THE EXPRESSION OF EXON I AND IV BDNF TRANSCRIPTS, INDICATING DIFFERENTIAL REGULATION OF BDNF GENE EXPRESSION. DAILY ADMINISTRATION OF THE CREB-BINDING PROTEIN INHIBITOR CURCUMIN ABOLISHED THE UPREGULATION OF BDNF TRANSCRIPTION AND MORPHINE ANALGESIC TOLERANCE. THESE RESULTS SUGGEST THAT CURCUMIN MIGHT BE A PROMISING ADJUVANT TO REDUCE MORPHINE ANALGESIC TOLERANCE, AND THAT EPIGENETIC CONTROL COULD BE A NEW STRATEGY USEFUL FOR THE CONTROL OF THIS PROBLEM. 2009 13 2300 45 EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS KNOWN TO BE UP-REGULATED IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, AND TO CONTRIBUTE TO NEUROPATHIC PAIN. HERE, WE FOUND THAT THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AT DAY 7 POST-INJURY WERE INHIBITED ONLY WHEN ANTI-BDNF ANTIBODY WAS INTRATHECALLY ADMINISTRATED AT DAY 2 POST-INJURY. CONSISTENT WITH BEHAVIORAL RESULTS, WESTERN BLOT ANALYSIS SHOWED THAT THE EXPRESSION LEVELS OF BDNF PROTEIN IN THE SPINAL DORSAL HORN WERE MARKEDLY INDUCED DURING EARLY STAGE POST-INJURY. MOREOVER, THE MAXIMAL INCREASE IN BDNF MRNA EXPRESSION IN THE DRG WAS OBSERVED AT DAY 1 POST-INJURY, AND SIGNIFICANTLY ELEVATED LEVELS WERE SUSTAINED FOR AT LEAST 14 DAYS. FOUR OF FIVE BDNF MRNA TRANSCRIPTS WERE UP-REGULATED AFTER NERVE INJURY, AND THE MOST INDUCIBLE TRANSCRIPT WAS EXON I. USING A CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, WE FOUND THAT NERVE INJURY PROMOTES HISTONE H3 AND H4 ACETYLATION, TRANSCRIPTIONALLY ACTIVE MODIFICATIONS, AT BDNF PROMOTER I AT DAY 1 POST-INJURY, AND THE LEVELS OF HISTONE ACETYLATION REMAIN ELEVATED FOR AT LEAST 7 DAYS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT AN INITIAL INCREASE IN BDNF EXON I EXPRESSION CONTROLLED BY EPIGENETIC MECHANISMS MIGHT HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF NEUROPATHIC PAIN. 2013 14 5781 39 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 15 4617 42 NERVE INJURY-INDUCED CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT DNA METHYLATION REPROGRAMMING IN DORSAL ROOT GANGLION. NERVE INJURY-INDUCED HYPERACTIVITY OF PRIMARY SENSORY NEURONS IN THE DORSAL ROOT GANGLION (DRG) CONTRIBUTES TO CHRONIC PAIN DEVELOPMENT, BUT THE UNDERLYING EPIGENETIC MECHANISMS REMAIN POORLY UNDERSTOOD. HERE WE DETERMINED GENOME-WIDE CHANGES IN DNA METHYLATION IN THE NERVOUS SYSTEM IN NEUROPATHIC PAIN. SPINAL NERVE LIGATION (SNL), BUT NOT PACLITAXEL TREATMENT, IN MALE SPRAGUE DAWLEY RATS INDUCED A CONSISTENT LOW-LEVEL HYPOMETHYLATION IN THE CPG SITES IN THE DRG DURING THE ACUTE AND CHRONIC PHASES OF NEUROPATHIC PAIN. DNA METHYLATION REMODELING IN THE DRG OCCURRED EARLY AFTER SNL AND PERSISTED FOR AT LEAST 3 WEEKS. SNL CAUSED DNA METHYLATION CHANGES AT 8% OF CPG SITES WITH PREVAILING HYPOMETHYLATION OUTSIDE OF CPG ISLANDS, IN INTRONS, INTERGENIC REGIONS, AND REPETITIVE SEQUENCES. IN CONTRAST, SNL CAUSED MORE GAINS OF METHYLATION IN THE SPINAL CORD AND PREFRONTAL CORTEX. THE DNA METHYLATION CHANGES IN THE INJURED DRGS RECAPITULATED DEVELOPMENTAL REPROGRAMMING AT THE NEONATAL STAGE. METHYLATION REPROGRAMMING WAS CORRELATED WITH INCREASED GENE EXPRESSION VARIABILITY. A DIET DEFICIENT IN METHYL DONORS INDUCED HYPOMETHYLATION AND PAIN HYPERSENSITIVITY. INTRATHECAL ADMINISTRATION OF THE DNA METHYLTRANSFERASE INHIBITOR RG108 CAUSED LONG-LASTING PAIN HYPERSENSITIVITY. DNA METHYLATION REPROGRAMMING IN THE DRG THUS CONTRIBUTES TO NERVE INJURY-INDUCED CHRONIC PAIN. RESTORING DNA METHYLATION MAY REPRESENT A NEW THERAPEUTIC APPROACH TO TREAT NEUROPATHIC PAIN.SIGNIFICANCE STATEMENT EPIGENETIC MECHANISMS ARE CRITICALLY INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN AFTER NERVE INJURY. HOWEVER, GENOME-WIDE CHANGES IN DNA METHYLATION IN THE NERVOUS SYSTEM AND THEIR ROLES IN NEUROPATHIC PAIN DEVELOPMENT REMAIN UNCLEAR. HERE WE USED DIGITAL RESTRICTION ENZYME ANALYSIS OF METHYLATION TO QUANTITATIVELY DETERMINE GENOME-WIDE DNA METHYLATION CHANGES CAUSED BY NERVE INJURY. WE SHOWED THAT NERVE INJURY CAUSED DNA METHYLATION CHANGES AT 8% OF CPG SITES WITH PREVAILING HYPOMETHYLATION OUTSIDE OF CPG ISLANDS IN THE DORSAL ROOT GANGLION. REDUCING DNA METHYLATION INDUCED PAIN HYPERSENSITIVITY, WHEREAS INCREASING DNA METHYLATION ATTENUATED NEUROPATHIC PAIN. THESE FINDINGS EXTEND OUR UNDERSTANDING OF THE EPIGENETIC MECHANISM OF CHRONIC NEUROPATHIC PAIN AND SUGGEST NEW STRATEGIES TO TREAT NERVE INJURY-INDUCED CHRONIC PAIN. 2018 16 4614 36 NERVE EXCITABILITY AND NEUROPATHIC PAIN IS REDUCED BY BET PROTEIN INHIBITION AFTER SPARED NERVE INJURY. NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE PATHOPHYSIOLOGICAL CHANGES THAT UNDERLIE THE GENERATION AND MAINTENANCE OF NEUROPATHIC PAIN REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. IN PARTICULAR, THERE IS AN INDUCTION OF PRO-INFLAMMATORY NEUROMODULATORS LEVELS, AND CHANGES IN THE EXPRESSION OF ION CHANNELS AND OTHER FACTORS INTERVENING IN THE DETERMINATION OF THE MEMBRANE POTENTIAL IN NEURONAL CELLS. WE HAVE PREVIOUSLY FOUND THAT INHIBITION OF THE BET PROTEINS EPIGENETIC READERS REDUCED NEUROINFLAMMATION AFTER SPINAL CORD INJURY. WITHIN THE PRESENT STUDY WE AIMED TO DETERMINE IF BET PROTEIN INHIBITION MAY ALSO AFFECT NEUROINFLAMMATION AFTER A PERIPHERAL NERVE INJURY, AND IF THIS WOULD BENEFICIALLY ALTER NEURONAL EXCITABILITY AND NEUROPATHIC PAIN. FOR THIS PURPOSE, C57BL/6 FEMALE MICE UNDERWENT SPARED NERVE INJURY (SNI), AND WERE TREATED WITH THE BET INHIBITOR JQ1, OR VEHICLE. ELECTROPHYSIOLOGICAL AND ALGESIMETRY TESTS WERE PERFORMED ON THESE MICE. WE ALSO DETERMINED THE EFFECTS OF JQ1 TREATMENT AFTER INJURY ON NEUROINFLAMMATION, AND THE EXPRESSION OF NEURONAL COMPONENTS IMPORTANT FOR THE MAINTENANCE OF AXON MEMBRANE POTENTIAL. WE FOUND THAT TREATMENT WITH JQ1 AFFECTED NEURONAL EXCITABILITY AND MECHANICAL HYPERALGESIA AFTER SNI IN MICE. BET PROTEIN INHIBITION REGULATED CYTOKINE EXPRESSION AND REDUCED MICROGLIAL REACTIVITY AFTER INJURY. IN ADDITION, JQ1 TREATMENT ALTERED THE EXPRESSION OF SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 AND HCN2 ION CHANNELS, AS WELL AS THE EXPRESSION OF THE NA(+)/K(+) ATPASE PUMP SUBUNITS. IN CONCLUSION, BOTH, ALTERATION OF INFLAMMATION, AND NEURONAL TRANSCRIPTION, COULD BE THE RESPONSIBLE EPIGENETIC MECHANISMS FOR THE REDUCTION OF EXCITABILITY AND HYPERALGESIA OBSERVED AFTER BET INHIBITION. INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. PERSPECTIVE: NEUROPATHIC PAIN IS A COMMON DISABILITY PRODUCED BY ENHANCED NEURONAL EXCITABILITY AFTER NERVOUS SYSTEM INJURY. THE UNDERLYING PATHOPHYSIOLOGICAL CHANGES REQUIRE MODIFICATIONS OF TRANSCRIPTIONAL PROGRAMS. THIS STUDY NOTES THAT INHIBITION OF BET PROTEINS IS A PROMISING THERAPY FOR REDUCING NEUROPATHIC PAIN AFTER NEURAL INJURY. 2021 17 2253 34 EPIGENETIC MODULATION OF WNT SIGNALING CONTRIBUTES TO NEUROPATHIC PAIN IN RATS. PREVIOUS STUDIES HAVE DEMONSTRATED THAT THE WNT/BETA?CATENIN SIGNALING PATHWAY IS CRITICAL TO THE INDUCTION AND MAINTENANCE OF CHRONIC NEUROPATHIC PAIN CAUSED BY PERIPHERAL INFLAMMATION AND NERVE DAMAGE. EMERGING EVIDENCE FROM RECENT STUDIES SUGGESTS THAT EPIGENETIC MECHANISMS MAY ALSO BE CRITICAL TO THE PATHOGENESIS OF CHRONIC PAIN. THE PRESENT STUDY AIMED TO ELUCIDATE THE EPIGENETIC MECHANISMS UNDERLYING ALTERED WNT SIGNALING AND THEIR INVOLVEMENT IN CCI?INDUCED NEUROPATHIC PAIN IN RAT SCIATIC NERVES. THE RESULTS OF THE PRESENT STUDY DEMONSTRATED A SIGNIFICANT INCREASE IN THE EXPRESSION LEVELS OF WNT3A IN THE DORSAL HORN OF THE RATS WITH CCI. IN ADDITION, A SIGNIFICANT INCREASE IN HISTONE H3 ACETYLATION, AND A SIGNIFICANT DECREASE IN CYTOSINE METHYLATION IN THE PROMOTER REGION OF WNT3A WAS OBSERVED IN THE DORSAL HORN OF THE RATS WITH CCI. INTRATHECAL APPLICATION OF XAV939, WHICH ACTS AS AN INHIBITOR OF WNT SIGNALING, SIGNIFICANTLY DECREASED THE EXPRESSION LEVELS OF ACTIVE BETA?CATENIN, AND ATTENUATED THE RAT BEHAVIORAL RESPONSES TO THERMAL AND MECHANICAL PAIN STIMULI. THESE RESULTS SUGGEST THAT THE EPIGENETIC UPREGULATION OF WNT3A IN THE DORSAL HORN CONTRIBUTES TO THE MAINTENANCE OF PAIN?INDUCED BEHAVIOR IN RATS WITH CCI. 2015 18 3319 29 HISTONE ACETYLATION AND HISTONE DEACETYLATION IN NEUROPATHIC PAIN: AN UNRESOLVED PUZZLE? CHRONIC PAIN IS BROADLY CLASSIFIED INTO SOMATIC, VISCERAL OR NEUROPATHIC PAIN DEPENDING UPON THE LOCATION AND EXTENT OF PAIN PERCEPTION. EVIDENCES FROM DIFFERENT ANIMAL STUDIES SUGGEST THAT INFLAMMATORY OR NEUROPATHIC PAIN IS ASSOCIATED WITH ALTERED ACETYLATION AND DEACETYLATION OF HISTONE PROTEINS, WHICH RESULT IN ABNORMAL TRANSCRIPTION OF NOCICEPTIVE PROCESSING GENES. THERE HAVE BEEN A NUMBER OF STUDIES INDICATING THAT NERVE INJURY UP-REGULATES HISTONE DEACETYLASE ENZYMES, WHICH LEADS TO INCREASED HISTONE DEACETYLATION AND INDUCE CHRONIC PAIN. TREATMENT WITH HISTONE DEACETYLASE INHIBITORS RELIEVES PAIN BY NORMALIZING NERVE INJURY-INDUCED DOWN REGULATION OF METABOTROPIC GLUTAMATE RECEPTORS, GLUTAMATE TRANSPORTERS, GLUTAMIC ACID DECARBOXYLASE 65, NEURON RESTRICTIVE SILENCER FACTOR AND SERUM AND GLUCOCORTICOID INDUCIBLE KINASE 1. ON THE OTHER HAND, A FEW STUDIES REFER TO INCREASED EXPRESSION OF HISTONE ACETYLASE ENZYMES IN RESPONSE TO NERVE INJURY THAT PROMOTES HISTONE ACETYLATION LEADING TO PAIN INDUCTION. TREATMENT WITH HISTONE ACETYL TRANSFERASE INHIBITORS HAVE BEEN REPORTED TO RELIEVE CHRONIC PAIN BY BLOCKING THE UP-REGULATION OF CHEMOKINES AND CYCLOOXYGENASE-2, THE CRITICAL FACTORS ASSOCIATED WITH HISTONE ACETYLATION-INDUCED PAIN. THE PRESENT REVIEW DESCRIBES THE DUAL ROLE OF HISTONE ACETYLATION/DEACETYLATION IN DEVELOPMENT OR ATTENUATION OF NEUROPATHIC PAIN ALONG WITH THE UNDERLYING MECHANISMS. 2017 19 2363 40 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 20 5954 37 TBI-INDUCED NOCICEPTIVE SENSITIZATION IS REGULATED BY HISTONE ACETYLATION. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. IN THESE STUDIES WE PURSUED THE HYPOTHESIS THAT TBI PAIN SENSITIZATION IS ASSOCIATED WITH HISTONE ACETYLATION IN THE RAT LATERAL FLUID PERCUSSION MODEL. SOME ANIMALS RECEIVED HINDPAW INCISIONS IN ADDITION TO TBI TO MIMIC POLYTRAUMA. NEUROPATHOLOGICAL ANALYSIS OF BRAIN TISSUE FROM SHAM AND TBI ANIMALS REVEALED EVIDENCE OF BLEEDING, BREAKDOWN OF THE BLOOD BRAIN BARRIER, IN THE CORTEX, HIPPOCAMPUS, THALAMUS AND OTHER STRUCTURES RELATED TO PAIN SIGNAL PROCESSING. MECHANICAL ALLODYNIA WAS MEASURED IN THESE ANIMALS FOR UP TO EIGHT WEEKS POST-INJURY. INHIBITORS OF HISTONE ACETYLTRANSFERASE (HAT) AND HISTONE DEACETYLASE (HDAC) WERE USED TO PROBE THE ROLE OF HISTONE ACETYLATION IN SUCH PAIN PROCESSING. WE FOLLOWED SERUM MARKERS INCLUDING GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), NEURON-SPECIFIC ENOLASE 2 (NSE) MYELIN BASIC PROTEIN (MBP) AND S100BETA TO GAUGE TBI INJURY SEVERITY. OUR RESULTS SHOWED THAT TBI CAUSED MECHANICAL ALLODYNIA IN THE HINDPAWS OF THE RATS LASTING SEVERAL WEEKS. HINDPAWS CONTRALATERAL TO TBI SHOWED MORE RAPID AND PROFOUND SENSITIZATION THAN IPSILATERAL HINDPAWS. THE INHIBITION OF HAT USING CURCUMIN 50 MG/KG S.C REDUCED MECHANICAL SENSITIZATION WHILE THE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID 50 MG/KG I.P. PROLONGED SENSITIZATION IN THE TBI RATS. IMMUNOHISTOCHEMICAL ANALYSES OF SPINAL CORD TISSUE LOCALIZED CHANGES IN THE LEVEL OF ACETYLATION OF THE H3K9 HISTONE MARK TO DORSAL HORN NEURONS. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE THAT TBI INDUCES SUSTAINED NOCICEPTIVE SENSITIZATION, AND CHANGES IN SPINAL NEURONAL HISTONE PROTEINS MAY PLAY AN IMPORTANT ROLE. 2017