1 4644 86 NEUROPATHIC PAIN TREATMENT: STILL A CHALLENGE. NEUROPATHIC PAIN (NP) IS THE RESULT OF A SERIES OF CONDITIONS CAUSED BY DISEASES OR LESIONS TO THE SOMATOSENSORY SYSTEM. DUE TO THE BETTER UNDERSTANDING OF NP PATHOPHYSIOLOGY PREVIOUSLY UNEXPLORED THERAPIES HAVE BEEN USED WITH ENCOURAGING RESULTS. IN THIS GROUP, ACETYL-L-CARNITINE, ALPHA-LIPOIC-ACID, CANNABINOIDS, CLONIDINE, EMA401, BOTULINUM TOXIN TYPE A AND NEW VOLTAGE-GATED SODIUM CHANNEL BLOCKERS, CAN BE INCLUDED. BESIDES, CHANGING PARADIGMS MAY OCCUR WITH THE ADVENT OF OPTOGENETICS AND A BETTER UNDERSTANDING OF EPIGENETIC REGULATION. WE REVIEWED THE PUBLISHED LITERATURE ON THE PHARMACOLOGICAL TREATMENT OF NP. DESPITE THE INTERESTING RESULTS, RANDOMIZED CONTROLLED TRIALS ARE DEMANDED THE MAJORITY OF THE THERAPIES PREVIOUSLY MENTIONED. IN SPITE OF SEVERAL STUDIES FOR THE RELIEF OF NP, PAIN CONTROL CONTINUES BEING A CHALLENGE. 2016 2 1881 71 EMERGING TREATMENTS FOR NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A SERIES OF WELL-KNOWN CONDITIONS CAUSED BY DISEASES OR LESIONS TO THE SOMATOSENSORY SYSTEM. DUE TO THE BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF NEUROPATHIC PAIN, PREVIOUSLY UNEXPLORED THERAPIES HAVE BEEN USED WITH ENCOURAGING RESULTS. AS SUCH, ACETYL-L-CARNITINE (ALC), ALPHA-LIPOIC-ACID (ALA), CANNABINOIDS, CLONIDINE, EMA401, BOTULINUM TOXIN TYPE A, AND NEW VOLTAGE-GATED SODIUM CHANNEL BLOCKERS, CAN BE CITED. FURTHERMORE, NEW MODALITIES IN NEUROMODULATION SUCH AS HIGH-FREQUENCY SPINAL CORD STIMULATION, BURST STIMULATION, DORSAL ROOT GANGLION STIMULATION, TRANSCRANIAL DIRECT CURRENT STIMULATION, AND MANY OTHERS HAVE BEEN SHOWING EXCITING RESULTS. BESIDES, CHANGING PARADIGMS MAY OCCUR WITH THE ADVENT OF OPTOGENETICS AND A BETTER UNDERSTANDING OF EPIGENETIC REGULATION. THIS ARTICLE REVIEWS THE PUBLISHED LITERATURE ON THE TREATMENT OF NP. DESPITE THE INTERESTING RESULTS, RANDOMIZED CONTROLLED TRIALS ARE DEMANDED FOR THE MAJORITY OF THE THERAPIES PREVIOUSLY MENTIONED. 2015 3 1612 26 DNA METHYLATION: A TARGET IN NEUROPATHIC PAIN. NEUROPATHIC PAIN (NP), CAUSED BY AN INJURY OR A DISEASE AFFECTING THE SOMATOSENSORY NERVOUS SYSTEM OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS, HAS BECOME A GLOBAL HEALTH CONCERN. RECENT STUDIES HAVE DEMONSTRATED THAT EPIGENETIC MECHANISMS ARE AMONG THOSE THAT UNDERLIE NP; THUS, ELUCIDATING THE MOLECULAR MECHANISM OF DNA METHYLATION IS CRUCIAL TO DISCOVERING NEW THERAPEUTIC METHODS FOR NP. IN THIS REVIEW, WE FIRST BRIEFLY DISCUSS DNA METHYLATION, DEMETHYLATION, AND THE ASSOCIATED KEY ENZYMES, SUCH AS METHYLASES AND DEMETHYLASES. WE THEN DISCUSS THE RELATIONSHIP BETWEEN NP AND DNA METHYLATION, FOCUSING ON DNA METHYLTRANSFERASES INCLUDING METHYL-CPG-BINDING DOMAIN (MBD) FAMILY PROTEINS AND TEN-ELEVEN TRANSLOCATION (TET) ENZYMES. BASED ON EXPERIMENTAL RESULTS OF NEURALGIA IN ANIMAL MODELS, THE MECHANISM OF DNA METHYLATION-RELATED NEURALGIA IS SUMMARIZED, AND USEFUL TARGETS FOR EARLY DRUG INTERVENTION IN NP ARE DISCUSSED. 2022 4 6828 19 [GLOBAL UNDERSTANDING OF PAIN]. CLINICALLY, IT IS WELL-KNOWN THAT CHRONIC PAIN INDUCES DEPRESSION, ANXIETY, AND REDUCED QUALITY OF LIFE. NEUROPATHIC PAIN, WHICH IS CHARACTERIZED BY SPONTANEOUS BURNING PAIN, HYPERALGESIA AND ALLODYNIA, IS THE MOST DIFFICULT PAIN TO MANAGE IN THE PAIN CLINIC. HOWEVER, THE COMPLICATED PATHOPHYSIOLOGY OF NEUROPATHIC PAIN IS NOT YET UNDERSTOOD. A BETTER UNDERSTANDING OF ITS PATHOPHYSIOLOGY HAS GIVEN US MORE INSIGHT INTO ITS VARIOUS MECHANISMS AND POSSIBLE TREATMENT OPTIONS. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF PAIN, WITH A FOCUS ON TRANSCRIPTIONAL RESEARCH, EPIGENETIC RESEARCH AND POST-TRANSCRIPTIONAL RESEARCH. FOR A GLOBAL UNDERSTANDING OF THE PAIN, IT IS NECESSARY TO ANALYZE THE CORRELATION BETWEEN THESE TEMPORAL PARAMETERS AND PHENOMICS. 2012 5 2220 23 EPIGENETIC MODIFICATIONS IN NEUROPATHIC PAIN. NEUROPATHIC PAIN (NP) IS A COMMON SYMPTOM IN MANY DISEASES OF THE SOMATOSENSORY NERVOUS SYSTEM, WHICH SEVERELY AFFECTS THE PATIENT'S QUALITY OF LIFE. EPIGENETICS ARE HERITABLE ALTERATIONS IN GENE EXPRESSION THAT DO NOT CAUSE PERMANENT CHANGES IN THE DNA SEQUENCE. EPIGENETIC MODIFICATIONS CAN AFFECT GENE EXPRESSION AND FUNCTION AND CAN ALSO MEDIATE CROSSTALK BETWEEN GENES AND THE ENVIRONMENT. INCREASING EVIDENCE SHOWS THAT EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA, AND RNA MODIFICATION, ARE INVOLVED IN THE DEVELOPMENT AND MAINTENANCE OF NP. IN THIS REVIEW, WE FOCUS ON THE CURRENT KNOWLEDGE OF EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT AND MAINTENANCE OF NP. THEN, WE ILLUSTRATE DIFFERENT FACETS OF EPIGENETIC MODIFICATIONS THAT REGULATE GENE EXPRESSION AND THEIR CROSSTALK. FINALLY, WE DISCUSS THE BURGEONING EVIDENCE SUPPORTING THE POTENTIAL OF EMERGING EPIGENETIC THERAPIES, WHICH HAS BEEN VALUABLE IN UNDERSTANDING MECHANISMS AND OFFERS NOVEL AND POTENT TARGETS FOR NP THERAPY. 2021 6 6124 23 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 7 189 18 ACETYL-L-CARNITINE IN CHRONIC PAIN: A NARRATIVE REVIEW. ACETYL-L-CARNITINE (ALC) IS AN ENDOGENOUS MOLECULE THAT NOT ONLY PLAYS A ROLE IN ENERGY METABOLISM, BUT ALSO HAS ANTIOXIDANT PROPERTIES, PROTECTS FROM OXIDATIVE STRESS, MODULATES BRAIN NEUROTRANSMITTERS SUCH AS ACETYLCHOLINE, SEROTONIN AND DOPAMINE, AND ACTS ON NEUROTROPHIC FACTORS SUCH AS NERVE GROWTH FACTOR (NGF) AND METABOTROPIC GLUTAMATE (MGLU) RECEPTORS BY MEANS OF EPIGENETIC MECHANISMS. IMPORTANTLY, IT INDUCES MGLU2 EXPRESSION AT NERVE TERMINALS, THUS GIVING RISE TO ANALGESIA AND PREVENTING SPINAL SENSITISATION. IT HAS ALSO BEEN FOUND TO HAVE EVEN LONG-TERM NEUROTROPHIC AND ANALGESIC ACTIVITY IN EXPERIMENTAL MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN. THE AIM OF THIS NARRATIVE REVIEW IS TO SUMMARISE THE CURRENT EVIDENCE REGARDING THE USE OF ALC IN PATIENTS WITH CHRONIC PAIN, AND COGNITIVE AND MOOD DISORDERS, AND INVESTIGATE THE RATIONALE UNDERLYING ITS USE IN PATIENTS WITH FIBROMYALGIA SYNDROME, WHICH IS CHARACTERISED BY NOCIPLASTIC CHANGES THAT INCREASE THE SENSITIVITY OF THE NERVOUS SYSTEM TO PAIN. 2021 8 5369 25 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 5038 23 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 10 5926 28 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 5778 19 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 12 191 25 ACETYL-L-CARNITINE: FROM A BIOLOGICAL CURIOSITY TO A DRUG FOR THE PERIPHERAL NERVOUS SYSTEM AND BEYOND. ACETYL-L-CARNITINE (ALC) IS A MOLECULE DERIVED FROM ACETYLATION OF CARNITINE IN THE MITOCHONDRIA. CARNITINE ACETYLATION ENABLES THE FUNCTION OF COA AND FACILITATES ELIMINATION OF OXIDATIVE PRODUCTS. BEYOND THIS METABOLIC ACTIVITY, ALC PROVIDES ACETYL GROUPS FOR ACETYLCHOLINE SYNTHESIS, EXERTS A CHOLINERGIC EFFECT AND OPTIMIZES THE BALANCE OF ENERGY PROCESSES. ACETYLCARNITINE SUPPLEMENTATION INDUCES NEUROPROTECTIVE, NEUROTROPHIC AND ANALGESIC EFFECTS IN THE PERIPHERAL NERVOUS SYSTEM. IN THE RECENT STUDIES, ALC, BY ACTING AS A DONOR OF ACETYL GROUPS TO NF-KB P65/RELA, ENHANCED THE TRANSCRIPTION OF THE GRM2 GENE ENCODING THE MGLU2 RECEPTORS, INDUCING LONG-TERM UPREGULATION OF THE MGLUR2, EVIDENCING THEREFORE THAT ITS LONG-TERM ANALGESIC EFFECTS ARE DEPENDENT ON EPIGENETIC MODIFICATIONS. SEVERAL STUDIES, INCLUDING DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP STUDIES AND FEW OPEN STUDIES SHOWED THE EFFECT OF ALC IN DISEASES CHARACTERIZED BY NEUROPATHIES AND NEUROPATHIC PAIN: THE STUDIES INCLUDED DIABETIC NEUROPATHY, HIV AND ANTIRETROVIRAL THERAPY-INDUCED NEUROPATHIES, NEUROPATHIES DUE TO COMPRESSION AND CHEMOTHERAPEUTIC AGENTS. DOUBLE-BLINDED STUDIES INVOLVED 1773 PATIENTS. STATISTICAL EVALUATIONS EVIDENCED REDUCTION OF PAIN, IMPROVEMENTS OF NERVE FUNCTION AND TROPHISM. IN CONCLUSION, ALC REPRESENTS A CONSISTENT THERAPEUTIC OPTION FOR PERIPHERAL NEUROPATHIES, AND ITS COMPLEX EFFECTS, NEUROTROPHIC AND ANALGESIC, BASED ON EPIGENETIC MECHANISM, OPEN NEW PATHWAYS IN THE STUDY OF PERIPHERAL NERVE DISEASE MANAGEMENT. 2013 13 1509 18 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 14 1686 26 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 15 2194 25 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 16 2611 25 EPIGENETICS: A PROMISING PARADIGM FOR BETTER UNDERSTANDING AND MANAGING PAIN. EPIGENETIC REGULATION OF GENE EXPRESSION IS A RAPIDLY GROWING AREA OF RESEARCH. CONSIDERING THE LONGEVITY AND PLASTICITY OF NEURONS, THE STUDIES ON EPIGENETIC PATHWAYS IN THE NERVOUS SYSTEM SHOULD BE OF SPECIAL INTEREST FOR BOTH EPIGENETICISTS AND NEUROSCIENTISTS. ACTIVATION OR INACTIVATION OF DIFFERENT EPIGENETIC PATHWAYS BECOMES MORE PRONOUNCED WHEN THE CELLS EXPERIENCE RAPID CHANGES IN THEIR ENVIRONMENT, AND SUCH CHANGES CAN BE EASILY CAUSED BY INJURY AND INFLAMMATION, RESULTING IN PAIN PERCEPTION OR DISTORTION OF PAIN PERCEPTION (EG, HYPERALGESIA). THEREFORE, IN THIS REGARD, THE FIELD OF PAIN IS AT AN ADVANTAGE TO STUDY THE EPIGENETIC PATHWAYS. MORE IMPORTANTLY, UNDERSTANDING PAIN FROM AN EPIGENETICS POINT OF VIEW WOULD PROVIDE A NEW PARADIGM FOR DEVELOPING DRUGS OR STRATEGIES FOR PAIN MANAGEMENT. IN THIS REVIEW, WE INTRODUCE BASIC CONCEPTS OF EPIGENETICS, INCLUDING CHROMATIN DYNAMICS, HISTONE MODIFICATIONS, DNA METHYLATION, AND RNA-INDUCED GENE SILENCING. IN ADDITION, WE PROVIDE EVIDENCE FROM PUBLISHED STUDIES SUGGESTING WIDE IMPLICATION OF DIFFERENT EPIGENETIC PATHWAYS WITHIN PAIN PATHWAYS. PERSPECTIVE: THIS ARTICLE PROVIDES A BRIEF OVERVIEW OF EPIGENETIC PATHWAYS FOR GENE REGULATION AND HIGHLIGHTS THEIR INVOLVEMENT IN PAIN. OUR GOAL IS TO EXPOSE THE READERS TO THESE CONCEPTS SO THAT PAIN-RELATED PHENOTYPES CAN BE INVESTIGATED FROM THE EPIGENETIC POINT OF VIEW. 2013 17 789 25 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 18 5928 20 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 19 6807 19 [EPIGENETICS AND PAIN]. CHRONIC PAIN AFFECTS APPROXIMATELY 20 % OF ADULTS WORLDWIDE AND IS OFTEN ASSOCIATED WITH A DECREASE IN THE QUALITY OF LIFE AND VARIOUS COMORBIDITIES. CONVENTIONAL ANALGESIC THERAPIES ARE FREQUENTLY INSUFFICIENT AND SOMETIMES LEAD TO SEVERE SIDE EFFECTS. THEREFORE, GREAT EFFORTS ARE STILL BEING MADE TO ELUCIDATE THE SIGNALLING PATHWAYS IN PAIN AND TO DEVELOP NEW, SAFE AND EFFECTIVE THERAPIES. EPIGENETIC MECHANISMS WHICH INTERFERE WITH THE REGULATION OF GENE EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OF SEVERAL DISEASES AND ARE GAINING INCREASING IMPETUS IN MEDICAL RESEARCH. AS THEY ARE ALSO INVOLVED IN PAIN PROCESSING, A MODULATION OF THESE MECHANISMS MIGHT REPRESENT A NOVEL OPTION FOR THE THERAPY OF PAIN PATIENTS. 2014 20 1204 26 COULD TARGETING EPIGENETIC PROCESSES RELIEVE CHRONIC PAIN STATES? PURPOSE OF REVIEW: ABERRATIONS IN THE EPIGENETIC LANDSCAPE HAVE PREVIOUSLY BEEN ASSOCIATED WITH HUMAN DISEASES SUCH AS CANCER AND SCHIZOPHRENIA, AND DRUGS THAT TARGET EPIGENETIC PROCESSES ARE CURRENTLY USED AS THERAPEUTIC AGENTS. THIS ARTICLE WILL REVIEW THE EVIDENCE OBTAINED FROM ANIMAL STUDIES INDICATING THAT EPIGENETIC PROCESSES MIGHT REGULATE LONG-TERM PAIN STATES AND THEN DISCUSS THE POSSIBILITY THAT TARGETING EPIGENETIC MECHANISMS MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. RECENT FINDINGS: RECENT ANIMAL STUDIES HAVE REPORTED INJURY-INDUCED CHANGES IN EPIGENETIC PROCESSES IN THE CENTRAL NERVOUS SYSTEM. THE PICTURE THAT HAS EMERGED IS THAT OF VERY COMPLEX EPIGENETIC PROGRAMS THAT DEPEND ON THE INJURY. HOWEVER, SOME STUDIES HAVE REPORTED THE SUCCESSFUL USE OF NONSPECIFIC EPIGENETIC TOOLS TO IMPROVE THE HYPERSENSITIVITY THAT DEVELOPS IN ANIMAL MODELS OF LONG-TERM PAIN STATES. SUMMARY: THE FIELD OF EPIGENETICS AND PAIN IS RAPIDLY EMERGING BUT FURTHER INVESTIGATION IS NEEDED TO FULLY COMPREHEND THE CONTRIBUTION OF EPIGENETIC PROCESSES TO CHRONIC PAIN STATES. ALTHOUGH THERAPEUTIC APPROACHES TARGETING THESE MECHANISMS MIGHT SEEM WORTHWHILE, WE CANNOT ASSERT THAT CURRENTLY AVAILABLE GLOBAL TOOLS SUCH AS HISTONE DEACETYLASE INHIBITORS CAN BE USED SUCCESSFULLY FOR THE LONG-TERM TREATMENT OF CHRONIC PAIN STATES. 2015