1 4149 102 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 2 3675 28 INFLAMMATION AND HISTONE MODIFICATION IN CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS HAVE GREAT POTENTIAL IN THE FIELD OF PAIN. THE CHANGES AND ROLES OF EPIGENETICS OF THE SPINAL CORD AND DORSAL ROOT GANGLIA IN THE CHRONIC PAIN PROCESS MAY PROVIDE BROAD INSIGHTS FOR FUTURE PAIN MANAGEMENT. PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES RELEASED BY MICROGLIA AND ASTROCYTES, AS WELL AS BLOOD-DERIVED MACROPHAGES, PLAY CRITICAL ROLES IN INDUCING AND MAINTAINING CHRONIC PAIN, WHILE HISTONE MODIFICATIONS MAY PLAY AN IMPORTANT ROLE IN INFLAMMATORY METABOLISM. THIS REVIEW PROVIDES AN OVERVIEW OF NEUROINFLAMMATION AND CHRONIC PAIN, AND WE SYSTEMATICALLY DISCUSS THE REGULATION OF NEUROINFLAMMATION AND HISTONE MODIFICATIONS IN THE CONTEXT OF CHRONIC PAIN. SPECIFICALLY, WE ANALYZED THE ROLE OF EPIGENETICS IN ALLEVIATING OR EXACERBATING CHRONIC PAIN BY MODULATING MICROGLIA, ASTROCYTES, AND THE PROINFLAMMATORY MEDIATORS THEY RELEASE. THIS REVIEW AIMED TO CONTRIBUTE TO THE DISCOVERY OF NEW THERAPEUTIC TARGETS FOR CHRONIC PAIN. 2022 3 4333 33 MICRORNAS: KEY PLAYERS IN MICROGLIA AND ASTROCYTE MEDIATED INFLAMMATION IN CNS PATHOLOGIES. THE SIGNIFICANCE OF MICROGLIA AND ASTROCYTES IN NEURAL DEVELOPMENT, IN MAINTAINING SYNAPTIC CONNECTIONS AND HOMEOSTASIS IN THE HEALTHY BRAIN IS WELL ESTABLISHED. MICROGLIA ARE DYNAMIC IMMUNE CELLS OF THE BRAIN THAT ELICIT AN IMMUNE RESPONSE DURING BRAIN DAMAGE AND ALSO PARTICIPATE IN TISSUE REPAIR AND REGENERATION, WHILE ASTROCYTES CONTRIBUTE TO THE LOCAL INFLAMMATORY RESPONSE BY PRODUCING PROINFLAMMATORY CYTOKINES AND RESOLVING NEURONAL DAMAGE THROUGH PRODUCTION OF ANTI-INFLAMMATORY CYTOKINES AND NEUROTROPHIC FACTORS. RECENT EFFORTS HAVE FOCUSED ON ELUCIDATING THE EPIGENETIC MECHANISMS WHICH REGULATE GLIAL CELL BEHAVIOR IN NORMAL AND PATHOLOGIC STATES. AN IMPORTANT CLASS OF EPIGENETIC REGULATORS IS MICRORNAS (MIRNAS) WHICH ARE SMALL NON-CODING RNA MOLECULES THAT REGULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY. CERTAIN DYSREGULATED MIRNAS CONTRIBUTE TO CHRONIC MICROGLIAL INFLAMMATION IN THE BRAIN, THEREBY LEADING TO PROGRESSION OF NEUROLOGICAL DISEASES LIKE ALZHEIMER'S DISEASE, TRAUMATIC INJURY, AMYOTROPHIC LATERAL SCLEROSIS AND STROKE. FURTHER, SEVERAL MIRNAS ARE DIFFERENTIALLY EXPRESSED IN ASTROCYTES AFTER ISCHEMIA AND SPINAL CORD INJURY. DESPITE KNOWLEDGE ABOUT MIRNAS IN NEUROINFLAMMATION, LITTLE IS KNOWN ABOUT EFFECTIVE DELIVERY ROUTES AND PHARMACOKINETIC DATA FOR MIRNA BASED THERAPEUTICS. THIS REVIEW SUMMARIZES THE CURRENT RESEARCH ON THE ROLE OF MIRNAS IN PROMOTING AND INHIBITING INFLAMMATORY RESPONSE OF MICROGLIA AND ASTROCYTES IN A DISEASE-SPECIFIC MANNER. IN ADDITION, MIRNA DELIVERY AS A THERAPEUTIC STRATEGY TO TREAT NEUROINFLAMMATION IS DISCUSSED. 2016 4 2214 40 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 5 2194 29 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015 6 5778 23 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 7 789 38 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 8 5369 27 RECENT ADVANCES IN UNDERSTANDING NEUROPATHIC PAIN: GLIA, SEX DIFFERENCES, AND EPIGENETICS. NEUROPATHIC PAIN RESULTS FROM DISEASES OR TRAUMA AFFECTING THE NERVOUS SYSTEM. THIS PAIN CAN BE DEVASTATING AND IS POORLY CONTROLLED. THE PATHOPHYSIOLOGY IS COMPLEX, AND IT IS ESSENTIAL TO UNDERSTAND THE UNDERLYING MECHANISMS IN ORDER TO IDENTIFY THE RELEVANT TARGETS FOR THERAPEUTIC INTERVENTION. IN THIS ARTICLE, WE FOCUS ON THE RECENT RESEARCH INVESTIGATING NEURO-IMMUNE COMMUNICATION AND EPIGENETIC PROCESSES, WHICH GAIN PARTICULAR ATTENTION IN THE CONTEXT OF NEUROPATHIC PAIN. SPECIFICALLY, WE ANALYZE THE ROLE OF GLIAL CELLS, INCLUDING MICROGLIA, ASTROCYTES, AND OLIGODENDROCYTES, IN THE MODULATION OF THE CENTRAL NERVOUS SYSTEM INFLAMMATION TRIGGERED BY NEUROPATHY. CONSIDERING EPIGENETICS, WE ADDRESS DNA METHYLATION, HISTONE MODIFICATIONS, AND THE NON-CODING RNAS IN THE REGULATION OF ION CHANNELS, G-PROTEIN-COUPLED RECEPTORS, AND TRANSMITTERS FOLLOWING NEURONAL DAMAGE. THE GOAL WAS NOT ONLY TO HIGHLIGHT THE EMERGING CONCEPTS BUT ALSO TO DISCUSS CONTROVERSIES, METHODOLOGICAL COMPLICATIONS, AND INTRIGUING OPINIONS. 2016 9 842 34 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 10 5926 32 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. CHRONIC PAIN IS A MULTIFACETED AND COMPLEX CONDITION. BROADLY CLASSIFIED INTO SOMATIC, VISCERAL, OR NEUROPATHIC PAIN, IT IS POORLY MANAGED DESPITE ITS PREVALENCE. CURRENT DRUGS USED FOR THE TREATMENT OF CHRONIC PAIN ARE LIMITED BY TOLERANCE WITH LONG-TERM USE, ABUSE POTENTIAL, AND MULTIPLE ADVERSE SIDE EFFECTS. THE PERSISTENT NATURE OF PAIN SUGGESTS THAT EPIGENETIC MACHINERY MAY BE A CRITICAL FACTOR DRIVING CHRONIC PAIN. IN THIS REVIEW, WE DISCUSS THE LATEST INSIGHTS INTO EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, AND WE DESCRIBE THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF CHRONIC PAIN AND WHETHER EPIGENETIC MODIFICATIONS COULD BE APPLIED AS FUTURE THERAPEUTIC TARGETS FOR CHRONIC PAIN. WE PROVIDE EVIDENCE FROM EXPERIMENTAL MODELS AND TRANSLATIONAL RESEARCH IN HUMAN TISSUE THAT HAVE ENHANCED OUR UNDERSTANDING OF EPIGENETIC PROCESSES MEDIATING NOCICEPTION, AND WE THEN SPECULATE ON THE POTENTIAL FUTURE USE OF MORE SPECIFIC AND SELECTIVE AGENTS THAT TARGET EPIGENETIC MECHANISMS TO ATTENUATE PAIN. 2016 11 5419 29 REGULATION OF GENE EXPRESSION AND PAIN STATES BY EPIGENETIC MECHANISMS. THE INDUCTION OF INFLAMMATORY OR NEUROPATHIC PAIN STATES IS KNOWN TO INVOLVE MOLECULAR ACTIVITY IN THE SPINAL SUPERFICIAL DORSAL HORN AND DORSAL ROOT GANGLIA, INCLUDING INTRACELLULAR SIGNALING EVENTS WHICH LEAD TO CHANGES IN GENE EXPRESSION. THESE CHANGES ULTIMATELY CAUSE ALTERATIONS IN MACROMOLECULAR SYNTHESIS, SYNAPTIC TRANSMISSION, AND STRUCTURAL ARCHITECTURE WHICH SUPPORT CENTRAL SENSITIZATION, A PROCESS REQUIRED FOR THE ESTABLISHMENT OF LONG-TERM PAIN STATES. EPIGENETIC MECHANISMS ARE ESSENTIAL FOR LONG-TERM SYNAPTIC PLASTICITY AND MODULATION OF GENE EXPRESSION. THIS IS BECAUSE EPIGENETIC MODIFICATIONS ARE KNOWN TO REGULATE GENE TRANSCRIPTION BY AIDING THE PHYSICAL RELAXATION OR CONDENSATION OF CHROMATIN. THESE PROCESSES ARE THEREFORE POTENTIAL REGULATORS OF THE MOLECULAR CHANGES UNDERLYING PERMANENT PAIN STATES. A HANDFUL OF STUDIES HAVE EMERGED IN THE FIELD OF PAIN EPIGENETICS; HOWEVER, THE FIELD IS STILL VERY MUCH IN ITS INFANCY. THIS CHAPTER DRAWS UPON OTHER SPECIALITIES WHICH HAVE EXTENSIVELY INVESTIGATED EPIGENETIC MECHANISMS, SUCH AS LEARNING AND MEMORY AND ONCOLOGY. AFTER DEFINING EPIGENETICS AS WELL AS THE RECENT FIELD OF "NEUROEPIGENETICS" AND THE MAIN MOLECULAR MECHANISMS INVOLVED, THIS CHAPTER DESCRIBES THE ROLE OF THESE MECHANISMS IN THE SYNAPTIC PLASTICITY SEEN IN LEARNING AND MEMORY, AND ADDRESS THOSE EPIGENETIC MECHANISMS THAT HAVE BEEN LINKED WITH THE DEVELOPMENT OF ACUTE AND PROLONGED PAIN STATES. FINALLY, THE IDEA THAT LONG-LASTING EPIGENETIC MODIFICATIONS COULD CONTRIBUTE TO THE TRANSITION FROM ACUTE TO CHRONIC PAIN STATES BY SUPPORTING MALADAPTIVE MOLECULAR CHANGES IS DISCUSSED. 2015 12 2176 23 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 13 4278 28 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES. 2021 14 5928 21 TARGETING EPIGENETIC MECHANISMS FOR PAIN RELIEF. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS TO CHROMATIN THAT MODULATE GENE ACTIVITY WITHOUT ALTERING THE DNA SEQUENCE. WHILE RESEARCH ON EPIGENETICS HAS GROWN EXPONENTIALLY OVER THE PAST FEW YEARS, VERY FEW STUDIES HAVE INVESTIGATED EPIGENETIC MECHANISMS IN RELATION TO PAIN STATES. HOWEVER, EPIGENETIC MECHANISMS ARE CRUCIAL TO MEMORY FORMATION THAT REQUIRES SIMILAR SYNAPTIC PLASTICITY TO PAIN PROCESSING, INDICATING THAT THEY MAY PLAY A KEY ROLE IN THE CONTROL OF PAIN STATES. THIS ARTICLE REVIEWS THE EARLY EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS ARE ENGAGED AFTER INJURY AND IN CHRONIC PAIN STATES, AND THAT DRUGS USED CLINICALLY TO TARGET THE EPIGENETIC MACHINERY FOR THE TREATMENT OF CANCER MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. 2012 15 2310 33 EPIGENETIC REGULATION OF CHRONIC PAIN. CHRONIC PAIN ARISING FROM PERIPHERAL INFLAMMATION AND TISSUE OR NERVE INJURY IS A COMMON CLINICAL SYMPTOM. ALTHOUGH INTENSIVE RESEARCH ON THE NEUROBIOLOGICAL MECHANISMS OF CHRONIC PAIN HAS BEEN CARRIED OUT DURING PREVIOUS DECADES, THIS DISORDER IS STILL POORLY MANAGED BY CURRENT DRUGS SUCH AS OPIOIDS AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. INFLAMMATION, TISSUE INJURY AND/OR NERVE INJURY-INDUCED CHANGES IN GENE EXPRESSION IN SENSORY NEURONS OF THE DORSAL ROOT GANGLION, SPINAL CORD DORSAL HORN AND PAIN-ASSOCIATED BRAIN REGIONS ARE THOUGHT TO PARTICIPATE IN CHRONIC PAIN GENESIS; HOWEVER, HOW THESE CHANGES OCCUR IS STILL ELUSIVE. EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION AND COVALENT HISTONE MODIFICATIONS CONTROL GENE EXPRESSION. RECENT STUDIES HAVE SHOWN THAT PERIPHERAL NOXIOUS STIMULATION CHANGES DNA METHYLATION AND HISTONE MODIFICATIONS AND THAT THESE CHANGES MAY BE RELATED TO THE INDUCTION OF PAIN HYPERSENSITIVITY UNDER CHRONIC PAIN CONDITIONS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE AND PROGRESS IN EPIGENETIC RESEARCH IN CHRONIC PAIN AND DISCUSSES THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS AS THERAPEUTIC ANTINOCICEPTIVE TARGETS IN THIS DISORDER. 2015 16 2354 18 EPIGENETIC REGULATION OF PERSISTENT PAIN. PERSISTENT OR CHRONIC PAIN IS TIGHTLY ASSOCIATED WITH VARIOUS ENVIRONMENTAL CHANGES AND LINKED TO ABNORMAL GENE EXPRESSION WITHIN CELLS PROCESSING NOCICEPTIVE SIGNALING. EPIGENETIC REGULATION GOVERNS GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL CUES. RECENT ANIMAL MODEL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC REGULATION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OR MAINTENANCE OF PERSISTENT PAIN AND POSSIBLY THE TRANSITION OF ACUTE PAIN TO CHRONIC PAIN, THUS SHEDDING LIGHT IN A DIRECTION FOR DEVELOPMENT OF NEW THERAPEUTICS FOR PERSISTENT PAIN. 2015 17 4969 28 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 18 1686 32 DRUGGING THE PAIN EPIGENOME. MORE THAN 20% OF ADULTS WORLDWIDE EXPERIENCE DIFFERENT TYPES OF CHRONIC PAIN, WHICH ARE FREQUENTLY ASSOCIATED WITH SEVERAL COMORBIDITIES AND A DECREASE IN QUALITY OF LIFE. SEVERAL APPROVED PAINKILLERS ARE AVAILABLE, BUT CURRENT ANALGESICS ARE OFTEN HAMPERED BY INSUFFICIENT EFFICACY AND/OR SEVERE ADVERSE EFFECTS. CONSEQUENTLY, NOVEL STRATEGIES FOR SAFE, HIGHLY EFFICACIOUS TREATMENTS ARE HIGHLY DESIRABLE, PARTICULARLY FOR CHRONIC PAIN. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNAS (MIRNAS) STRONGLY AFFECT THE REGULATION OF GENE EXPRESSION, POTENTIALLY FOR LONG PERIODS OVER YEARS OR EVEN GENERATIONS, AND HAVE BEEN ASSOCIATED WITH PATHOPHYSIOLOGICAL PAIN. SEVERAL STUDIES, MOSTLY IN ANIMALS, REVEALED THAT INHIBITORS OF DNA METHYLATION, ACTIVATORS AND INHIBITORS OF HISTONE MODIFICATION AND MODULATORS OF MIRNAS REVERSE A NUMBER OF PATHOLOGICAL CHANGES IN THE PAIN EPIGENOME, WHICH ARE ASSOCIATED WITH ALTERED EXPRESSION OF PAIN-RELEVANT GENES. THIS EPIGENETIC MODULATION MIGHT THEN REDUCE THE NOCICEPTIVE RESPONSE AND PROVIDE NOVEL THERAPEUTIC OPTIONS FOR ANALGESIC THERAPY OF CHRONIC PAIN STATES. HOWEVER, A NUMBER OF CHALLENGES, SUCH AS NONSPECIFIC EFFECTS AND POOR DELIVERY TO TARGET CELLS AND TISSUES, HINDER THE RAPID DEVELOPMENT OF SUCH ANALGESICS. IN THIS REVIEW, WE CRITICALLY SUMMARIZE DATA ON EPIGENETICS AND PAIN, FOCUSING ON CHALLENGES IN CLINICAL DEVELOPMENT AS WELL AS POSSIBLE NEW APPROACHES TO THE DRUG MODULATION OF THE PAIN EPIGENOME. 2017 19 6124 28 THE EPIGENETIC MECHANISMS INVOLVED IN CHRONIC PAIN IN RODENTS: A MINI- REVIEW. CHRONIC PAIN IS A COMMON DISTRESSING NEUROLOGICAL DISORDER AND ABOUT 30% OF THE GLOBAL POPULATION SUFFERS FROM IT. IN ADDITION TO BEING HIGHLY PREVALENT, CHRONIC PAIN CAUSES A HEAVY ECONOMIC AND SOCIAL BURDEN. ALTHOUGH SUBSTANTIAL PROGRESS HAS BEEN ACHIEVED TO DISSECT THE UNDERLYING MECHANISM OF CHRONIC PAIN IN THE PAST FEW DECADES, THE INCIDENCE AND TREATMENT OF THIS NEUROLOGICAL ILLNESS IS YET NOT PROPERLY MANAGED IN CLINICAL PRACTICE. WHILE NERVE INJURY-, CHEMOTHERAPY- OR INFLAMMATION-INDUCED FUNCTIONAL REGULATION OF GENE EXPRESSION IN THE DORSAL ROOT GANGLION AND SPINAL CORD ARE EXTENSIVELY REPORTED TO BE INVOLVED IN THE PATHOGENIC PROCESS OF CHRONIC PAIN, THE SPECIFIC MECHANISM OF THESE ALTERED TRANSCRIPTIONAL PROFILE STILL REMAINS UNCLEAR. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MECHANISMS, INCLUDING DNA/RNA METHYLATION, HISTONE MODIFICATION AND CIRCULAR RNAS REGULATION, ARE INVOLVED IN THE OCCURRENCE AND DEVELOPMENT OF CHRONIC PAIN. IN THIS REVIEW, WE PROVIDE A DESCRIPTION OF RESEARCH ON THE ROLE OF EPIGENETIC MECHANISM IN CHRONIC PAIN, SUMMARIZE THE LATEST CLINICAL AND PRECLINICAL ADVANCE IN THIS FIELD, AND PROPOSE THE POTENTIAL DIRECTIONS FOR FURTHER RESEARCH TO ELUCIDATE THE MOLECULAR MECHANISM UNDERLYING THE PATHOGENESIS OF CHRONIC PAIN. 2022 20 1509 21 DNA METHYLATION AND NON-CODING RNAS DURING TISSUE-INJURY ASSOCIATED PAIN. WHILE ABOUT HALF OF THE POPULATION EXPERIENCE PERSISTENT PAIN ASSOCIATED WITH TISSUE DAMAGES DURING THEIR LIFETIME, CURRENT SYMPTOM-BASED APPROACHES OFTEN FAIL TO REDUCE SUCH PAIN TO A SATISFACTORY LEVEL. TO PROVIDE BETTER PATIENT CARE, MECHANISM-BASED ANALGESIC APPROACHES MUST BE DEVELOPED, WHICH NECESSITATES A COMPREHENSIVE UNDERSTANDING OF THE NOCICEPTIVE MECHANISM LEADING TO TISSUE INJURY-ASSOCIATED PERSISTENT PAIN. EPIGENETIC EVENTS LEADING THE ALTERED TRANSCRIPTION IN THE NERVOUS SYSTEM ARE PIVOTAL IN THE MAINTENANCE OF PAIN IN TISSUE INJURY. HOWEVER, THE MECHANISMS THROUGH WHICH THOSE EVENTS CONTRIBUTE TO THE PERSISTENCE OF PAIN ARE NOT FULLY UNDERSTOOD. THIS REVIEW PROVIDES A SUMMARY AND CRITICAL EVALUATION OF TWO EPIGENETIC MECHANISMS, DNA METHYLATION AND NON-CODING RNA EXPRESSION, ON TRANSCRIPTIONAL MODULATION IN NOCICEPTIVE PATHWAYS DURING THE DEVELOPMENT OF TISSUE INJURY-ASSOCIATED PAIN. WE ASSESS THE PRE-CLINICAL DATA AND THEIR TRANSLATIONAL IMPLICATION AND EVALUATE THE POTENTIAL OF CONTROLLING DNA METHYLATION AND NON-CODING RNA EXPRESSION AS NOVEL ANALGESIC APPROACHES AND/OR BIOMARKERS OF PERSISTENT PAIN. 2022