1 3332 136 HISTONE DEACETYLASE INHIBITOR-INDUCED EMERGENCE OF SYNAPTIC DELTA-OPIOID RECEPTORS AND BEHAVIORAL ANTINOCICEPTION IN PERSISTENT NEUROPATHIC PAIN. THE EFFICACY OF OPIOIDS IN PATIENTS WITH CHRONIC NEUROPATHIC PAIN REMAINS CONTROVERSIAL. ALTHOUGH ACTIVATION OF DELTA-OPIOID RECEPTORS (DORS) IN THE BRAINSTEM REDUCES INFLAMMATION-INDUCED PERSISTENT HYPERALGESIA, IT IS NOT EFFECTIVE UNDER PERSISTENT NEUROPATHIC PAIN CONDITIONS AND THESE CLINICAL PROBLEMS REMAIN LARGELY UNKNOWN. IN THIS STUDY, BY USING A CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN RATS, WE FOUND THAT IN THE BRAINSTEM NUCLEUS RAPHE MAGNUS (NRM), DORS EMERGED ON THE SURFACE MEMBRANE OF CENTRAL SYNAPTIC TERMINALS ON DAY 3 AFTER CCI SURGERY AND DISAPPEARED ON DAY 14. HISTONE DEACETYLASE (HDAC) INHIBITORS MICROINJECTED INTO THE NRM IN VIVO INCREASED THE LEVEL OF SYNAPTOSOMAL DOR PROTEIN AND NRM INFUSION OF DOR AGONISTS PRODUCING AN ANTINOCICEPTIVE EFFECT IN A NERVE GROWTH FACTOR (NGF) SIGNALING-DEPENDENT MANNER. IN VITRO, IN CCI RAT SLICES INCUBATED WITH HDAC INHIBITORS, DOR AGONISTS SIGNIFICANTLY INHIBITED EPSCS. THIS EFFECT WAS BLOCKED BY TYROSINE RECEPTOR KINASE A ANTAGONISTS. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT NRM INFUSION OF HDAC INHIBITORS IN CCI RATS INCREASED THE LEVEL OF HISTONE H4 ACETYLATION AT NGF GENE PROMOTER REGIONS. NGF WAS INFUSED INTO THE NRM OR INCUBATED CCI RAT SLICES DROVE DORS TO THE SURFACE MEMBRANE OF SYNAPTIC TERMINALS. TAKEN TOGETHER, EPIGENETIC UPREGULATION OF NGF ACTIVITY BY HDAC INHIBITORS IN THE NRM PROMOTES THE TRAFFICKING OF DORS TO PAIN-MODULATING NEURONAL SYNAPSES UNDER NEUROPATHIC PAIN CONDITIONS, LEADING TO DELTA-OPIOID ANALGESIA. THESE FINDINGS INDICATE THAT THERAPEUTIC USE OF DOR AGONISTS COMBINED WITH HDAC INHIBITORS MIGHT BE EFFECTIVE IN CHRONIC NEUROPATHIC PAIN MANAGEMENTS. 2016 2 3201 48 HDAC2 IN PRIMARY SENSORY NEURONS CONSTITUTIVELY RESTRAINS CHRONIC PAIN BY REPRESSING ALPHA2DELTA-1 EXPRESSION AND ASSOCIATED NMDA RECEPTOR ACTIVITY. ALPHA2DELTA-1 (ENCODED BY THE CACNA2D1 GENE) IS A NEWLY DISCOVERED NMDA RECEPTOR-INTERACTING PROTEIN AND IS THE THERAPEUTIC TARGET OF GABAPENTINOIDS (E.G., GABAPENTIN AND PREGABALIN) FREQUENTLY USED FOR TREATING PATIENTS WITH NEUROPATHIC PAIN. NERVE INJURY CAUSES SUSTAINED ALPHA2DELTA-1 UPREGULATION IN THE DORSAL ROOT GANGLION (DRG), WHICH PROMOTES NMDA RECEPTOR SYNAPTIC TRAFFICKING AND ACTIVATION IN THE SPINAL DORSAL HORN, A HALLMARK OF CHRONIC NEUROPATHIC PAIN. HOWEVER, LITTLE IS KNOWN ABOUT HOW NERVE INJURY INITIATES AND MAINTAINS THE HIGH EXPRESSION LEVEL OF ALPHA2DELTA-1 TO SUSTAIN CHRONIC PAIN. HERE, WE SHOW THAT NERVE INJURY CAUSED HISTONE HYPERACETYLATION AND DIMINISHED ENRICHMENT OF HISTONE DEACETYLASE-2 (HDAC2), BUT NOT HDAC3, AT THE CACNA2D1 PROMOTER IN THE DRG. STRIKINGLY, HDAC2 KNOCKDOWN OR CONDITIONAL KNOCKOUT IN DRG NEURONS IN MALE AND FEMALE MICE CONSISTENTLY INDUCED LONG-LASTING MECHANICAL PAIN HYPERSENSITIVITY, WHICH WAS READILY REVERSED BY BLOCKING NMDA RECEPTORS, INHIBITING ALPHA2DELTA-1 WITH GABAPENTIN OR DISRUPTING THE ALPHA2DELTA-1-NMDA RECEPTOR INTERACTION AT THE SPINAL CORD LEVEL. HDAC2 DELETION IN DRG NEURONS INCREASED HISTONE ACETYLATION LEVELS AT THE CACNA2D1 PROMOTER, UPREGULATED ALPHA2DELTA-1 IN THE DRG, AND POTENTIATED ALPHA2DELTA-1-DEPENDENT NMDA RECEPTOR ACTIVITY AT PRIMARY AFFERENT CENTRAL TERMINALS IN THE SPINAL DORSAL HORN. CORRESPONDINGLY, HDAC2 KNOCKDOWN-INDUCED PAIN HYPERSENSITIVITY WAS BLUNTED IN CACNA2D1 KNOCKOUT MICE. THUS, OUR FINDINGS REVEAL THAT HDAC2 FUNCTIONS AS A PIVOTAL TRANSCRIPTIONAL REPRESSOR OF NEUROPATHIC PAIN VIA CONSTITUTIVELY SUPPRESSING ALPHA2DELTA-1 EXPRESSION AND ENSUING PRESYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD. HDAC2 ENRICHMENT LEVELS AT THE CACNA2D1 PROMOTER IN DRG NEURONS CONSTITUTE A UNIQUE EPIGENETIC MECHANISM THAT GOVERNS ACUTE-TO-CHRONIC PAIN TRANSITION.SIGNIFICANCE STATEMENT EXCESS ALPHA2DELTA-1 PROTEINS PRODUCED AFTER NERVE INJURY DIRECTLY INTERACT WITH GLUTAMATE NMDA RECEPTORS TO POTENTIATE SYNAPTIC NMDA RECEPTOR ACTIVITY IN THE SPINAL CORD, A PROMINENT MECHANISM OF NERVE PAIN. BECAUSE ALPHA2DELTA-1 UPREGULATION AFTER NERVE INJURY IS LONG LASTING, GABAPENTINOIDS RELIEVE PAIN SYMPTOMS ONLY TEMPORARILY. OUR STUDY DEMONSTRATES FOR THE FIRST TIME THE UNEXPECTED ROLE OF INTRINSIC HDAC2 ACTIVITY AT THE ALPHA2DELTA-1 GENE PROMOTER IN LIMITING ALPHA2DELTA-1 GENE TRANSCRIPTION, NMDA RECEPTOR-DEPENDENT SYNAPTIC PLASTICITY, AND CHRONIC PAIN DEVELOPMENT AFTER NERVE INJURY. THESE FINDINGS CHALLENGE THE PREVAILING VIEW ABOUT THE ROLE OF GENERAL HDAC ACTIVITY IN PROMOTING CHRONIC PAIN. RESTORING THE REPRESSIVE HDAC2 FUNCTION AND/OR REDUCING HISTONE ACETYLATION AT THE ALPHA2DELTA-1 GENE PROMOTER IN PRIMARY SENSORY NEURONS COULD LEAD TO LONG-LASTING RELIEF OF NERVE PAIN. 2022 3 687 60 BRAINSTEM BRAIN-DERIVED NEUROTROPHIC FACTOR SIGNALING IS REQUIRED FOR HISTONE DEACETYLASE INHIBITOR-INDUCED PAIN RELIEF. OUR PREVIOUS STUDY DEMONSTRATED THAT PERSISTENT PAIN CAN EPIGENETICALLY SUPPRESS THE TRANSCRIPTION OF GAD2 [ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)] AND CONSEQUENTLY IMPAIR THE INHIBITORY FUNCTION OF GABAERGIC SYNAPSES IN CENTRAL PAIN-MODULATING NEURONS. THIS CONTRIBUTES TO THE DEVELOPMENT OF PERSISTENT PAIN SENSITIZATION. HISTONE DEACETYLASE (HDAC) INHIBITORS INCREASED GAD65 ACTIVITY CONSIDERABLY, RESTORED GABA SYNAPTIC FUNCTION, AND RENDERED SENSITIZED PAIN BEHAVIOR LESS PRONOUNCED. HOWEVER, THE MOLECULAR MECHANISMS BY WHICH HDAC REGULATES GABAERGIC TRANSMISSION THROUGH GAD65 UNDER PAIN CONDITIONS ARE UNKNOWN. THIS WORK SHOWED THAT HDAC INHIBITOR-INDUCED INCREASES IN COLOCALIZATION OF GAD65 AND SYNAPTIC PROTEIN SYNAPSIN I ON THE PRESYNAPTIC AXON TERMINALS OF THE NUCLEUS RAPHE MAGNUS (NRM) WERE BLOCKED BY A TRKB RECEPTOR ANTAGONIST K252A [(9S,10R,12R)-2,3,9,10,11,12-HEXAHYDRO-10-HYDROXY-9-METHYL-1-OXO-9,12-EPOXY-1H-DIINDOLO[1,2,3-FG:3',2',1'-KL]PYRROLO[3,4-I][1,6]BENZODIAZOCINE-10-CARBOXYLIC ACID METHYL ESTER], INDICATING THAT BDNF-TRKB SIGNALING MAY BE REQUIRED IN GAD65 MODULATION OF GABA SYNAPTIC FUNCTION. AT THE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTER, HDAC INHIBITORS INDUCED SIGNIFICANT INCREASES IN H3 HYPERACETYLATION, CONSISTENT WITH THE INCREASE IN BDNF MRNA AND TOTAL PROTEINS. ALTHOUGH EXOGENOUS BDNF FACILITATED GABA MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS AND GAD65 ACCUMULATION IN NRM NEURONAL SYNAPSES IN NORMAL RATS, IT FAILED TO DO SO IN ANIMALS SUBJECTED TO PERSISTENT INFLAMMATION. IN ADDITION, BLOCKADE OF THE TRKB RECEPTOR WITH K252A HAS NO EFFECT ON MINIATURE INHIBITORY POSTSYNAPTIC CURRENTS AND SYNAPTIC GAD65 ACCUMULATION UNDER NORMAL CONDITIONS. IN ADDITION, THE ANALGESIC EFFECTS OF HDAC INHIBITORS ON BEHAVIOR WERE BLOCKED BY NRM INFUSION OF K252A. THESE FINDINGS SUGGEST THAT BDNF-TRKB SIGNALING IS REQUIRED FOR DRUGS THAT REVERSE THE EPIGENETIC EFFECTS OF CHRONIC PAIN AT THE GENE LEVEL, SUCH AS HDAC INHIBITORS. 2015 4 2448 37 EPIGENETIC SUPPRESSION OF GAD65 EXPRESSION MEDIATES PERSISTENT PAIN. CHRONIC PAIN IS A COMMON NEUROLOGICAL DISEASE INVOLVING LASTING, MULTIFACETED MALADAPTATIONS RANGING FROM GENE MODULATION TO SYNAPTIC DYSFUNCTION AND EMOTIONAL DISORDERS. SUSTAINED PATHOLOGICAL STIMULI IN MANY DISEASES ALTER THE OUTPUT ACTIVITIES OF CERTAIN GENES THROUGH EPIGENETIC MODIFICATIONS, BUT IT IS UNCLEAR HOW EPIGENETIC MECHANISMS OPERATE IN THE DEVELOPMENT OF CHRONIC PAIN. WE SHOW HERE THAT IN THE RAT BRAINSTEM NUCLEUS RAPHE MAGNUS, WHICH IS IMPORTANT FOR CENTRAL MECHANISMS OF CHRONIC PAIN, PERSISTENT INFLAMMATORY AND NEUROPATHIC PAIN EPIGENETICALLY SUPPRESSES GAD2 (ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)) TRANSCRIPTION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN IMPAIRED GAMMA-AMINOBUTYRIC ACID (GABA) SYNAPTIC INHIBITION. GAD2 KNOCKOUT MICE SHOWED SENSITIZED PAIN BEHAVIOR AND IMPAIRED GABA SYNAPTIC FUNCTION IN THEIR BRAINSTEM NEURONS. IN WILD-TYPE BUT NOT GAD2 KNOCKOUT MICE, HDAC INHIBITORS STRONGLY INCREASED GAD65 ACTIVITY, RESTORED GABA SYNAPTIC FUNCTION AND RELIEVED SENSITIZED PAIN BEHAVIOR. THESE FINDINGS SUGGEST GAD65 AND HDACS AS POTENTIAL THERAPEUTIC TARGETS IN AN EPIGENETIC APPROACH TO THE TREATMENT OF CHRONIC PAIN. 2011 5 1697 30 DYNAMIC DNA METHYLATION CONTROLS GLUTAMATE RECEPTOR TRAFFICKING AND SYNAPTIC SCALING. HEBBIAN PLASTICITY, INCLUDING LONG-TERM POTENTIATION AND LONG-TERM DEPRESSION, HAS LONG BEEN REGARDED AS IMPORTANT FOR LOCAL CIRCUIT REFINEMENT IN THE CONTEXT OF MEMORY FORMATION AND STABILIZATION. HOWEVER, CIRCUIT DEVELOPMENT AND STABILIZATION ADDITIONALLY RELIES ON NON-HEBBIAN, HOMEOSTATIC, FORMS OF PLASTICITY SUCH AS SYNAPTIC SCALING. SYNAPTIC SCALING IS INDUCED BY CHRONIC INCREASES OR DECREASES IN NEURONAL ACTIVITY. SYNAPTIC SCALING IS ASSOCIATED WITH CELL-WIDE ADJUSTMENTS IN POSTSYNAPTIC RECEPTOR DENSITY, AND CAN OCCUR IN A MULTIPLICATIVE MANNER RESULTING IN PRESERVATION OF RELATIVE SYNAPTIC STRENGTHS ACROSS THE ENTIRE NEURON'S POPULATION OF SYNAPSES. BOTH ACTIVE DNA METHYLATION AND DEMETHYLATION HAVE BEEN VALIDATED AS CRUCIAL REGULATORS OF GENE TRANSCRIPTION DURING LEARNING, AND SYNAPTIC SCALING IS KNOWN TO BE TRANSCRIPTIONALLY DEPENDENT. HOWEVER, IT HAS BEEN UNCLEAR WHETHER HOMEOSTATIC FORMS OF PLASTICITY SUCH AS SYNAPTIC SCALING ARE REGULATED VIA EPIGENETIC MECHANISMS. THIS REVIEW DESCRIBES EXCITING RECENT WORK THAT HAS DEMONSTRATED A ROLE FOR ACTIVE CHANGES IN NEURONAL DNA METHYLATION AND DEMETHYLATION AS A CONTROLLER OF SYNAPTIC SCALING AND GLUTAMATE RECEPTOR TRAFFICKING. THESE FINDINGS BRING TOGETHER THREE MAJOR CATEGORIES OF MEMORY-ASSOCIATED MECHANISMS THAT WERE PREVIOUSLY LARGELY CONSIDERED SEPARATELY: DNA METHYLATION, HOMEOSTATIC PLASTICITY, AND GLUTAMATE RECEPTOR TRAFFICKING. THIS REVIEW DESCRIBES EXCITING RECENT WORK THAT HAS DEMONSTRATED A ROLE FOR ACTIVE CHANGES IN NEURONAL DNA METHYLATION AND DEMETHYLATION AS A CONTROLLER OF SYNAPTIC SCALING AND GLUTAMATE RECEPTOR TRAFFICKING. THESE FINDINGS BRING TOGETHER THREE MAJOR CATEGORIES OF MEMORY-ASSOCIATED MECHANISMS THAT WERE PREVIOUSLY CONSIDERED SEPARATELY: GLUTAMATE RECEPTOR TRAFFICKING, DNA METHYLATION, AND HOMEOSTATIC PLASTICITY. 2016 6 6536 35 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 7 2214 37 EPIGENETIC MODIFICATIONS ASSOCIATED TO NEUROINFLAMMATION AND NEUROPATHIC PAIN AFTER NEURAL TRAUMA. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS LIE BEHIND THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. NEUROPATHIC PAIN IS USUALLY A CHRONIC CONDITION CAUSED BY A LESION, OR PATHOLOGICAL CHANGE, WITHIN THE NERVOUS SYSTEM. NEUROPATHIC PAIN APPEARS FREQUENTLY AFTER NERVE AND SPINAL CORD INJURIES OR DISEASES, PRODUCING A DEBILITATION OF THE PATIENT AND A DECREASE OF THE QUALITY OF LIFE. AT THE CELLULAR LEVEL, NEUROPATHIC PAIN IS THE RESULT OF NEURONAL PLASTICITY SHAPED BY AN INCREASE IN THE SENSITIVITY AND EXCITABILITY OF SENSORY NEURONS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. ONE OF THE MECHANISMS THOUGHT TO CONTRIBUTE TO HYPEREXCITABILITY AND THEREFORE TO THE ONTOGENY OF NEUROPATHIC PAIN IS THE ALTERED EXPRESSION, TRAFFICKING, AND FUNCTIONING OF RECEPTORS AND ION CHANNELS EXPRESSED BY PRIMARY SENSORY NEURONS. BESIDES, NEURONAL AND GLIAL CELLS, SUCH AS MICROGLIA AND ASTROCYTES, TOGETHER WITH BLOOD BORNE MACROPHAGES, PLAY A CRITICAL ROLE IN THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN BY RELEASING POWERFUL NEUROMODULATORS SUCH AS PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, WHICH ENHANCE NEURONAL EXCITABILITY. ALTERED GENE EXPRESSION OF NEURONAL RECEPTORS, ION CHANNELS, AND PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, HAVE BEEN ASSOCIATED TO EPIGENETIC ADAPTATIONS OF THE INJURED TISSUE. WITHIN THIS REVIEW, WE DISCUSS THE INVOLVEMENT OF THESE EPIGENETIC CHANGES, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNAS, AND ALTERATION OF CHROMATIN MODIFIERS, THAT HAVE BEEN SHOWN TO TRIGGER MODIFICATION OF NOCICEPTION AFTER NEURAL LESIONS. IN PARTICULAR, THE FUNCTION ON THESE PROCESSES OF EZH2, JMJD3, MECP2, SEVERAL HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYL TRANSFERASES (HATS), G9A, DNMT, REST AND DIVERSE NON-CODING RNAS, ARE DESCRIBED. DESPITE THE EFFORT ON DEVELOPING NEW THERAPIES, CURRENT TREATMENTS HAVE ONLY PRODUCED LIMITED RELIEF OF THIS PAIN IN A PORTION OF PATIENTS. THUS, THE PRESENT REVIEW AIMS TO CONTRIBUTE TO FIND NOVEL TARGETS FOR CHRONIC NEUROPATHIC PAIN TREATMENT. 2018 8 5018 54 PERSISTENT INFLAMMATION-INDUCED UP-REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTES SYNAPTIC DELIVERY OF ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTOR GLUA1 SUBUNITS IN DESCENDING PAIN MODULATORY CIRCUITS. THE ENHANCED AMPA RECEPTOR PHOSPHORYLATION AT GLUA1 SERINE 831 SITES IN THE CENTRAL PAIN-MODULATING SYSTEM PLAYS A PIVOTAL ROLE IN DESCENDING PAIN FACILITATION AFTER INFLAMMATION, BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. WE SHOW HERE THAT, IN THE RAT BRAIN STEM, IN THE NUCLEUS RAPHE MAGNUS, WHICH IS A CRITICAL RELAY IN THE DESCENDING PAIN-MODULATING SYSTEM OF THE BRAIN, PERSISTENT INFLAMMATORY PAIN INDUCED BY COMPLETE FREUND ADJUVANT (CFA) CAN ENHANCE AMPA RECEPTOR-MEDIATED EXCITATORY POSTSYNAPTIC CURRENTS AND THE GLUA2-LACKING AMPA RECEPTOR-MEDIATED RECTIFICATION INDEX. WESTERN BLOT ANALYSIS SHOWED AN INCREASE IN GLUA1 PHOSPHORYLATION AT SER-831 BUT NOT AT SER-845. THIS WAS ACCOMPANIED BY AN INCREASE IN DISTRIBUTION OF THE SYNAPTIC GLUA1 SUBUNIT. IN PARALLEL, THE LEVEL OF HISTONE H3 ACETYLATION AT BDNF GENE PROMOTER REGIONS WAS REDUCED SIGNIFICANTLY 3 DAYS AFTER CFA INJECTION, AS INDICATED BY CHIP ASSAYS. THIS WAS CORRELATED WITH AN INCREASE IN BDNF MRNA LEVELS AND BDNF PROTEIN LEVELS. SEQUESTERING ENDOGENOUS EXTRACELLULAR BDNF WITH TRKB-IGG IN THE NUCLEUS RAPHE MAGNUS DECREASED AMPA RECEPTOR-MEDIATED SYNAPTIC TRANSMISSION AND GLUA1 PHOSPHORYLATION AT SER-831 3 DAYS AFTER CFA INJECTION. UNDER THE SAME CONDITIONS, BLOCKADE OF TRKB RECEPTOR FUNCTIONS, PHOSPHOLIPASE C, OR PKC IMPAIRED GLUA1 PHOSPHORYLATION AT SER-831 AND DECREASED EXCITATORY POSTSYNAPTIC CURRENTS MEDIATED BY GLUA2-LACKING AMPA RECEPTORS. TAKEN TOGETHER, THESE RESULTS SUGGEST THAT EPIGENETIC UP-REGULATION OF BDNF BY PERIPHERAL INFLAMMATION INDUCES GLUR1 PHOSPHORYLATION AT SER-831 SITES THROUGH ACTIVATION OF THE PHOSPHOLIPASE C-PKC SIGNALING CASCADE, LEADING TO THE TRAFFICKING OF GLUA1 TO PAIN-MODULATING NEURONAL SYNAPSES. 2014 9 6139 28 THE ETIOLOGICAL CONTRIBUTION OF GABAERGIC PLASTICITY TO THE PATHOGENESIS OF NEUROPATHIC PAIN. NEUROPATHIC PAIN DEVELOPING AFTER PERIPHERAL OR CENTRAL NERVE INJURY IS THE RESULT OF PATHOLOGICAL CHANGES GENERATED THROUGH COMPLEX MECHANISMS. DISRUPTION IN THE HOMEOSTASIS OF EXCITATORY AND INHIBITORY NEURONS WITHIN THE CENTRAL NERVOUS SYSTEM IS A CRUCIAL FACTOR IN THE FORMATION OF HYPERALGESIA OR ALLODYNIA OCCURRING WITH NEUROPATHIC PAIN. THE CENTRAL GABAERGIC PATHWAY HAS RECEIVED ATTENTION FOR ITS EXTENSIVE DISTRIBUTION AND FUNCTION IN NEURAL CIRCUITS, INCLUDING THE GENERATION AND DEVELOPMENT OF NEUROPATHIC PAIN. GABAERGIC INHIBITORY CHANGES THAT OCCUR IN THE INTERNEURONS ALONG DESCENDING MODULATORY AND NOCICEPTIVE PATHWAYS IN THE CENTRAL NERVOUS SYSTEM ARE BELIEVED TO GENERATE NEURONAL PLASTICITY, SUCH AS SYNAPTIC PLASTICITY OR FUNCTIONAL PLASTICITY OF THE RELATED GENES OR PROTEINS, THAT IS THE FOUNDATION OF PERSISTENT NEUROPATHIC PAIN. THE PRIMARY GABAERGIC PLASTICITY OBSERVED IN NEUROPATHIC PAIN INCLUDES GABAERGIC SYNAPSE HOMO- AND HETEROSYNAPTIC PLASTICITY, DECREASED SYNTHESIS OF GABA, DOWN-EXPRESSION OF GLUTAMIC ACID DECARBOXYLASE AND GABA TRANSPORTER, ABNORMAL EXPRESSION OF NKCC1 OR KCC2, AND DISTURBED FUNCTION OF GABA RECEPTORS. IN THIS REVIEW, WE DESCRIBE POSSIBLE MECHANISMS ASSOCIATED WITH GABAERGIC PLASTICITY, SUCH AS CENTRAL SENSITIZATION AND GABAERGIC INTERNEURON APOPTOSIS, AND THE EPIGENETIC ETIOLOGIES OF GABAERGIC PLASTICITY IN NEUROPATHIC PAIN. MOREOVER, WE SUMMARIZE POTENTIAL THERAPEUTIC TARGETS OF GABAERGIC PLASTICITY THAT MAY ALLOW FOR SUCCESSFUL RELIEF OF HYPERALGESIA FROM NERVE INJURY. FINALLY, WE COMPARE THE EFFECTS OF THE GABAERGIC SYSTEM IN NEUROPATHIC PAIN TO OTHER TYPES OF CHRONIC PAIN TO UNDERSTAND THE CONTRIBUTION OF GABAERGIC PLASTICITY TO NEUROPATHIC PAIN. 2019 10 4420 22 MOLECULAR AND EPIGENETIC MECHANISMS FOR THE COMPLEX EFFECTS OF STRESS ON SYNAPTIC PHYSIOLOGY AND COGNITIVE FUNCTIONS. EVIDENCE OVER THE PAST DECADES HAS FOUND THAT STRESS, PARTICULARLY THROUGH THE CORTICOSTERONE STRESS HORMONES, PRODUCES COMPLEX CHANGES IN GLUTAMATERGIC SIGNALING IN PREFRONTAL CORTEX, WHICH LEADS TO THE ALTERATION OF COGNITIVE PROCESSES MEDICATED BY THIS BRAIN REGION. INTERESTINGLY, THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION APPEAR TO BE "U-SHAPED," DEPENDING UPON THE DURATION AND SEVERITY OF THE STRESSOR. THESE BIPHASIC EFFECTS OF ACUTE VS CHRONIC STRESS REPRESENT THE ADAPTIVE VS MALADAPTIVE RESPONSES TO STRESSFUL STIMULI. ANIMAL STUDIES SUGGEST THAT THE STRESS-INDUCED MODULATION OF EXCITATORY SYNAPTIC TRANSMISSION INVOLVES CHANGES IN PRESYNAPTIC GLUTAMATE RELEASE, POSTSYNAPTIC GLUTAMATE RECEPTOR MEMBRANE TRAFFICKING AND DEGRADATION, SPINE STRUCTURE AND CYTOSKELETON NETWORK, AND EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW WILL DISCUSS CURRENT FINDINGS ON THE KEY MOLECULES INVOLVED IN THE STRESS-INDUCED REGULATION OF PREFRONTAL CORTEX SYNAPTIC PHYSIOLOGY AND PREFRONTAL CORTEX-MEDIATED FUNCTIONS. UNDERSTANDING THE MOLECULAR AND EPIGENETIC MECHANISMS THAT UNDERLIE THE COMPLEX EFFECTS OF STRESS WILL HELP TO DEVELOP NOVEL STRATEGIES TO COPE WITH STRESS-RELATED MENTAL DISORDERS. 2017 11 3968 34 LONG-LASTING ANALGESIA VIA TARGETED IN SITU REPRESSION OF NA(V)1.7 IN MICE. CURRENT TREATMENTS FOR CHRONIC PAIN RELY LARGELY ON OPIOIDS DESPITE THEIR SUBSTANTIAL SIDE EFFECTS AND RISK OF ADDICTION. GENETIC STUDIES HAVE IDENTIFIED IN HUMANS KEY TARGETS PIVOTAL TO NOCICEPTIVE PROCESSING. IN PARTICULAR, A HEREDITARY LOSS-OF-FUNCTION MUTATION IN NA(V)1.7, A SODIUM CHANNEL PROTEIN ASSOCIATED WITH SIGNALING IN NOCICEPTIVE SENSORY AFFERENTS, LEADS TO INSENSITIVITY TO PAIN WITHOUT OTHER NEURODEVELOPMENTAL ALTERATIONS. HOWEVER, THE HIGH SEQUENCE AND STRUCTURAL SIMILARITY BETWEEN NA(V) SUBTYPES HAS FRUSTRATED EFFORTS TO DEVELOP SELECTIVE INHIBITORS. HERE, WE INVESTIGATED TARGETED EPIGENETIC REPRESSION OF NA(V)1.7 IN PRIMARY AFFERENTS VIA EPIGENOME ENGINEERING APPROACHES BASED ON CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)-DCAS9 AND ZINC FINGER PROTEINS AT THE SPINAL LEVEL AS A POTENTIAL TREATMENT FOR CHRONIC PAIN. TOWARD THIS END, WE FIRST OPTIMIZED THE EFFICIENCY OF NA(V)1.7 REPRESSION IN VITRO IN NEURO2A CELLS AND THEN, BY THE LUMBAR INTRATHECAL ROUTE, DELIVERED BOTH EPIGENOME ENGINEERING PLATFORMS VIA ADENO-ASSOCIATED VIRUSES (AAVS) TO ASSESS THEIR EFFECTS IN THREE MOUSE MODELS OF PAIN: CARRAGEENAN-INDUCED INFLAMMATORY PAIN, PACLITAXEL-INDUCED NEUROPATHIC PAIN, AND BZATP-INDUCED PAIN. OUR RESULTS SHOW EFFECTIVE REPRESSION OF NA(V)1.7 IN LUMBAR DORSAL ROOT GANGLIA, REDUCED THERMAL HYPERALGESIA IN THE INFLAMMATORY STATE, DECREASED TACTILE ALLODYNIA IN THE NEUROPATHIC STATE, AND NO CHANGES IN NORMAL MOTOR FUNCTION IN MICE. WE ANTICIPATE THAT THIS LONG-LASTING ANALGESIA VIA TARGETED IN VIVO EPIGENETIC REPRESSION OF NA(V)1.7 METHODOLOGY WE DUB PAIN LATER, MIGHT HAVE THERAPEUTIC POTENTIAL IN MANAGEMENT OF PERSISTENT PAIN STATES. 2021 12 2179 26 EPIGENETIC MECHANISMS OF NEURAL PLASTICITY IN CHRONIC NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A CHALLENGING CLINICAL PROBLEM AND REMAINS DIFFICULT TO TREAT. ALTERED GENE EXPRESSION IN PERIPHERAL SENSORY NERVES AND NEURONS DUE TO NERVE INJURY IS WELL DOCUMENTED AND CONTRIBUTES CRITICALLY TO THE SYNAPTIC PLASTICITY IN THE SPINAL CORD AND THE INITIATION AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS REGULATING THE TRANSCRIPTION OF PRO-NOCICEPTIVE (E.G., NMDA RECEPTORS AND ALPHA2DELTA-1) AND ANTINOCICEPTIVE (E.G., POTASSIUM CHANNELS AND OPIOID AND CANNABINOID RECEPTORS) GENES ARE STILL LIMITED. IN THIS REVIEW, WE SUMMARIZE RECENT STUDIES DETERMINING THE ROLES OF HISTONE MODIFICATIONS (INCLUDING METHYLATION, ACETYLATION, AND UBIQUITINATION), DNA METHYLATION, AND NONCODING RNAS IN NEUROPATHIC PAIN DEVELOPMENT. WE REVIEW THE EPIGENETIC WRITER, READER, AND ERASER PROTEINS THAT PARTICIPATE IN THE TRANSCRIPTIONAL CONTROL OF THE EXPRESSION OF KEY ION CHANNELS AND NEUROTRANSMITTER RECEPTORS IN THE DORSAL ROOT GANGLION AFTER TRAUMATIC NERVE INJURY, WHICH IS COMMONLY USED AS A PRECLINICAL MODEL OF NEUROPATHIC PAIN. A BETTER UNDERSTANDING OF EPIGENETIC REPROGRAMMING INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN COULD LEAD TO THE DEVELOPMENT OF NEW TREATMENTS FOR NEUROPATHIC PAIN. 2022 13 533 29 ASTROCYTIC TRANSCRIPTION FACTOR REST UPREGULATES GLUTAMATE TRANSPORTER EAAT2, PROTECTING DOPAMINERGIC NEURONS FROM MANGANESE-INDUCED EXCITOTOXICITY. CHRONIC EXPOSURE TO HIGH LEVELS OF MANGANESE (MN) LEADS TO MANGANISM, A NEUROLOGICAL DISORDER WITH SIMILAR SYMPTOMS TO THOSE INHERENT TO PARKINSON'S DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF THIS PATHOLOGICAL CONDITION HAVE YET TO BE ESTABLISHED. SINCE THE HUMAN EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) (GLUTAMATE TRANSPORTER 1 IN RODENTS) IS PREDOMINANTLY EXPRESSED IN ASTROCYTES AND ITS DYSREGULATION IS INVOLVED IN MN-INDUCED EXCITOTOXIC NEURONAL INJURY, CHARACTERIZATION OF THE MECHANISMS THAT MEDIATE THE MN-INDUCED IMPAIRMENT IN EAAT2 FUNCTION IS CRUCIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS AGAINST MN NEUROTOXICITY. REPRESSOR ELEMENT 1-SILENCING TRANSCRIPTION FACTOR (REST) EXERTS PROTECTIVE EFFECTS IN MANY NEURODEGENERATIVE DISEASES. BUT THE EFFECTS OF REST ON EAAT2 EXPRESSION AND ENSUING NEUROPROTECTION ARE UNKNOWN. GIVEN THAT THE EAAT2 PROMOTER CONTAINS REST BINDING SITES, THE PRESENT STUDY INVESTIGATED THE ROLE OF REST IN EAAT2 EXPRESSION AT THE TRANSCRIPTIONAL LEVEL IN ASTROCYTES AND MN-INDUCED NEUROTOXICITY IN AN ASTROCYTE-NEURON COCULTURE SYSTEM. THE RESULTS REVEAL THAT ASTROCYTIC REST POSITIVELY REGULATES EAAT2 EXPRESSION WITH THE RECRUITMENT OF AN EPIGENETIC MODIFIER, CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300, TO ITS CONSENSUS BINDING SITES IN THE EAAT2 PROMOTER. MOREOVER, ASTROCYTIC OVEREXPRESSION OF REST ATTENUATES MN-INDUCED REDUCTION IN EAAT2 EXPRESSION, LEADING TO ATTENUATION OF GLUTAMATE-INDUCED NEUROTOXICITY IN THE ASTROCYTE-NEURON COCULTURE SYSTEM. OUR FINDINGS DEMONSTRATE THAT ASTROCYTIC REST PLAYS A CRITICAL ROLE IN PROTECTION AGAINST MN-INDUCED NEUROTOXICITY BY ATTENUATING MN-INDUCED EAAT2 REPRESSION AND THE ENSUING EXCITOTOXIC DOPAMINERGIC NEURONAL INJURY. THIS INDICATES THAT ASTROCYTIC REST COULD BE A POTENTIAL MOLECULAR TARGET FOR THE TREATMENT OF MN TOXICITY AND OTHER NEUROLOGICAL DISORDERS ASSOCIATED WITH EAAT2 DYSREGULATION. 2021 14 4149 30 MECHANISTIC INSIGHT INTO THE EFFECTS OF CURCUMIN ON NEUROINFLAMMATION-DRIVEN CHRONIC PAIN. CHRONIC PAIN IS A PERSISTENT AND UNREMITTING CONDITION THAT HAS IMMENSE EFFECTS ON PATIENTS' QUALITY OF LIFE. STUDIES HAVE SHOWN THAT NEUROINFLAMMATION IS ASSOCIATED WITH THE INDUCTION AND PROGRESSION OF CHRONIC PAIN. THE ACTIVATION OF MICROGLIA AND ASTROCYTES IS THE MAJOR HALLMARK OF SPINAL NEUROINFLAMMATION LEADING TO NEURONAL EXCITABILITY IN THE PROJECTION NEURONS. EXCESSIVE ACTIVATION OF MICROGLIA AND ASTROCYTES IS ONE OF THE MAJOR CONTRIBUTING FACTORS TO THE EXACERBATION OF PAIN. HOWEVER, THE CURRENT CHRONIC PAIN TREATMENTS, MAINLY BY TARGETING THE NEURONAL CELLS, REMAIN INEFFECTIVE AND UNABLE TO MEET THE PATIENTS' NEEDS. CURCUMIN, A NATURAL PLANT PRODUCT FOUND IN THE CURCUMA GENUS, IMPROVES CHRONIC PAIN BY DIMINISHING THE RELEASE OF INFLAMMATORY MEDIATORS FROM THE SPINAL GLIA. THIS REVIEW DETAILS THE ROLE OF CURCUMIN IN MICROGLIA AND ASTROCYTES BOTH IN VITRO AND IN VIVO AND HOW IT IMPROVES PAIN. WE ALSO DESCRIBE THE MECHANISM OF CURCUMIN BY HIGHLIGHTING THE MAJOR GLIA-MEDIATED CASCADES IN PAIN. MOREOVER, THE ROLE OF CURCUMIN ON INFLAMMASOME AND EPIGENETIC REGULATION IS DISCUSSED. FURTHERMORE, WE DISCUSS THE STRATEGIES USED TO IMPROVE THE EFFICACY OF CURCUMIN. THIS REVIEW ILLUSTRATES THAT CURCUMIN MODULATING MICROGLIA AND ASTROCYTES COULD ASSURE THE TREATMENT OF CHRONIC PAIN BY SUPPRESSING SPINAL NEUROINFLAMMATION. 2021 15 5600 20 ROLES OF VOLTAGE-DEPENDENT SODIUM CHANNELS IN NEURONAL DEVELOPMENT, PAIN, AND NEURODEGENERATION. BESIDES INITIATING AND PROPAGATING ACTION POTENTIALS IN ESTABLISHED NEURONAL CIRCUITS, VOLTAGE-DEPENDENT SODIUM CHANNELS SCULPT AND BOLSTER THE FUNCTIONAL NEURONAL NETWORK FROM EARLY IN EMBRYONIC DEVELOPMENT THROUGH ADULTHOOD (E.G., DIFFERENTIATION OF OLIGODENDROCYTE PRECURSOR CELLS INTO OLIGODENDROCYTES, MYELINATING AXON; COMPETITION BETWEEN NEIGHBORING EQUIPOTENTIAL NEURITES FOR DEVELOPMENT INTO A SINGLE AXON; ENHANCING AND OPPOSING FUNCTIONAL INTERACTIONS WITH ATTRACTIVE AND REPULSIVE MOLECULES FOR AXON PATHFINDING; EXTENDING AND RETRACTING TERMINAL ARBORIZATION OF AXON FOR CORRECT SYNAPSE FORMATION; EXPERIENCE-DRIVEN COGNITION; NEURONAL SURVIVAL; AND REMYELINATION OF DEMYELINATED AXONS). SURPRISINGLY, DIFFERENT PATTERNS OF ACTION POTENTIALS DIRECT HOMEOSTASIS-BASED EPIGENETIC SELECTION FOR NEUROTRANSMITTER PHENOTYPE, THUS EXCITABILITY BY SODIUM CHANNELS SPECIFYING EXPRESSION OF INHIBITORY NEUROTRANSMITTERS. MECHANISMS FOR THESE PLEIOTROPIC EFFECTS OF SODIUM CHANNELS INCLUDE RECIPROCAL INTERACTIONS BETWEEN NEURONS AND GLIA VIA NEUROTRANSMITTERS, GROWTH FACTORS, AND CYTOKINES AT SYNAPSES AND AXONS. SODIUM CHANNELOPATHIES CAUSING PAIN (E.G., ALLODYNIA) AND NEURODEGENERATION (E.G., MULTIPLE SCLEROSIS) DERIVE FROM 1) ELECTROPHYSIOLOGICAL DISTURBANCES BY INSULTS (E.G., ISCHEMIA/HYPOXIA, TOXINS, AND ANTIBODIES); 2) LOSS-OF-PHYSIOLOGICAL FUNCTION OR GAIN-OF-PATHOLOGICAL FUNCTION OF MUTANT SODIUM CHANNEL PROTEINS; 3) SPATIOTEMPORAL INAPPROPRIATE EXPRESSION OF NORMAL SODIUM CHANNEL PROTEINS; OR 4) DE-REPRESSED EXPRESSION OF OTHERWISE SILENT SODIUM CHANNEL GENES. NA(V)1.7 PROVED TO ACCOUNT FOR PAIN IN HUMAN ERYTHERMALGIA AND INFLAMMATION, BEING THE CONVINCING MOLECULAR TARGET OF PAIN TREATMENT. 2006 16 842 33 CHEMOKINES IN CHRONIC PAIN: CELLULAR AND MOLECULAR MECHANISMS AND THERAPEUTIC POTENTIAL. CHRONIC PAIN RESULTING FROM NERVE INJURY, TISSUE INFLAMMATION, AND TUMOR INVASION OR TREATMENT, IS A MAJOR HEALTH PROBLEM IMPACTING THE QUALITY OF LIFE AND PRODUCING A SIGNIFICANT ECONOMIC AND SOCIAL BURDEN. HOWEVER, THE CURRENT ANALGESIC DRUGS INCLUDING NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS ARE INADEQUATE TO RELIEVE CHRONIC PAIN DUE TO THE LACK OF EFFICACY OR SEVERE SIDE-EFFECTS. CHEMOKINES ARE A FAMILY OF SMALL SECRETED PROTEINS THAT BIND TO G PROTEIN-COUPLED RECEPTORS TO TRIGGER INTRACELLULAR SIGNALING PATHWAYS AND DIRECT CELL MIGRATION, PROLIFERATION, SURVIVAL, AND INFLAMMATION UNDER HOMEOSTATIC AND PATHOLOGICAL CONDITIONS. ACCUMULATING EVIDENCE SUPPORTS THE IMPORTANT ROLE OF CHEMOKINES AND CHEMOKINE RECEPTORS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM IN MEDIATING CHRONIC PAIN VIA ENHANCING NEUROINFLAMMATION. IN THIS REVIEW, WE FOCUS ON RECENT PROGRESS IN UNDERSTANDING THE COMPREHENSIVE ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN THE GENERATION AND MAINTENANCE OF DIFFERENT TYPES OF CHRONIC PAIN, INCLUDING NEUROPATHIC PAIN, INFLAMMATORY PAIN, CANCER PAIN, AND VISCERAL PAIN. THE CURRENT REVIEW ALSO SUMMARIZES THE UPSTREAM SIGNALING OF TRANSCRIPTIONAL AND EPIGENETIC REGULATION ON THE EXPRESSION OF CHEMOKINES AND CHEMOKINE RECEPTORS AS WELL AS THE DOWNSTREAM SIGNALING OF CHEMOKINE RECEPTORS UNDERLYING CHRONIC PAIN. AS CHRONIC ITCH AND CHRONIC PAIN SHARE SOME COMMON MECHANISMS, WE ALSO DISCUSS THE EMERGING ROLES OF CHEMOKINES AND CHEMOKINE RECEPTORS IN CHRONIC ITCH. TARGETING SPECIFIC CHEMOKINES OR CHEMOKINE RECEPTORS BY SIRNAS, BLOCKING ANTIBODIES, OR SMALL-MOLECULE ANTAGONISTS MAY OFFER NEW THERAPEUTIC POTENTIAL FOR THE MANAGEMENT OF CHRONIC PAIN. 2020 17 3319 31 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 18 2772 29 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 19 6138 31 THE ETIOLOGICAL CHANGES OF ACETYLATION IN PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC HYPERSENSITIVITY. NEUROPATHIC PAIN IS A COMMON CHRONIC PAIN CONDITION WITH MECHANISMS FAR CLEARLY BEEN ELUCIDATED. MOUNTING PRECLINICAL AND CLINICAL STUDIES HAVE SHOWN NEUROPATHIC PAIN IS HIGHLY ASSOCIATED WITH HISTONE ACETYLATION MODIFICATION, WHICH FOLLOWS EXPRESSION REGULATION OF VARIOUS PAIN-RELATED MOLECULES SUCH AS MGLUR1/5, GLUTAMATE ASPARTATE TRANSPORTER, GLUTAMATE TRANSPORTER-1, GAD65, NA(V)1.8, KV4.3, MU-OPIOID RECEPTOR, BRAIN-DERIVED NEUROTROPHIC FACTOR, AND CERTAIN CHEMOKINES. AS TWO TYPES OF PIVOTAL ENZYMES INVOLVED IN HISTONE ACETYLATION, HISTONE DEACETYLASES INDUCE HISTONE DEACETYLATION TO SILENCE GENE EXPRESSION; IN CONTRAST, HISTONE ACETYL TRANSFERASES FACILITATE HISTONE ACETYLATION TO POTENTIATE GENE TRANSCRIPTION. ACCORDINGLY, UPREGULATION OR BLOCKADE OF ACETYLATION MAY BE A PROMISING INTERVENTION DIRECTION FOR NEUROPATHIC PAIN TREATMENT. IN FACT, NUMEROUS ANIMAL STUDIES HAVE SUGGESTED VARIOUS HISTONE DEACETYLASE INHIBITORS, SIRT (CLASS III HISTONE DEACETYLASES) ACTIVATORS, AND HISTONE ACETYL TRANSFERASES INHIBITORS ARE EFFECTIVE IN NEUROPATHIC PAIN TREATMENT VIA TARGETING SPECIFIC EPIGENETIC SITES. IN THIS REVIEW, WE SUMMARIZE THE CHARACTERISTICS OF THE MOLECULES AND MECHANISMS OF NEUROPATHY-RELATED ACETYLATION, AS WELL AS THE ACETYLATION UPREGULATION AND BLOCKADE FOR NEUROPATHIC PAIN THERAPY. FINALLY, WE WILL DISCUSS THE CURRENT DRUG ADVANCES FOCUSING ON NEUROPATHY-RELATED ACETYLATION ALONG WITH THE UNDERLYING TREATMENT MECHANISMS. 2018 20 5778 25 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015