1 5047 144 PHARMACOLOGICAL AND THERAPEUTIC APPROACHES IN THE TREATMENT OF EPILEPSY. EPILEPSY AFFECTS AROUND 50 MILLION PEOPLE ACROSS THE GLOBE AND IS THE THIRD MOST COMMON CHRONIC BRAIN DISORDER. IT IS A NON-COMMUNICABLE DISEASE OF THE BRAIN THAT AFFECTS PEOPLE OF ALL AGES. IT IS ACCOMPANIED BY DEPRESSION, ANXIETY, AND SUBSTANTIALLY INCREASED MORBIDITY AND MORTALITY. A LARGE NUMBER OF THIRD-GENERATION ANTI-EPILEPTIC DRUGS ARE AVAILABLE, BUT THEY HAVE MULTIPLE SIDE-EFFECTS CAUSING A DECLINE IN THE QUALITY OF LIFE. THE INHERITANCE AND ETIOLOGY OF EPILEPSY ARE COMPLEX WITH MULTIPLE UNDERLYING GENETIC AND EPIGENETIC MECHANISMS. DIFFERENT NEUROTRANSMITTERS PLAY INTRICATE FUNCTIONS TO MAINTAIN THE NORMAL PHYSIOLOGY OF VARIOUS NEURONS. IF THERE IS ANY DYSREGULATION OF NEUROTRANSMISSION DUE TO ABERRANT TRANSMITTER LEVELS OR THEIR RECEPTOR BIOLOGY, IT CAN RESULT IN SEIZURES. IN THIS REVIEW, WE HAVE DISCUSSED THE ROLES PLAYED BY VARIOUS NEUROTRANSMITTERS AND THEIR RECEPTORS IN THE PATHOPHYSIOLOGY OF EPILEPSY. DRUG-RESISTANT EPILEPSY (DRE) HAS REMAINED ONE OF THE FOREFRONT AREAS OF EPILEPSY RESEARCH FOR A LONG TIME. UNDERSTANDING THE MECHANISMS UNDERLYING DRE IS OF UTMOST IMPORTANCE BECAUSE OF ITS HIGH INCIDENCE RATE AMONG EPILEPSY PATIENTS AND INCREASED RISKS OF PSYCHOSOCIAL PROBLEMS AND PREMATURE DEATH. HERE WE HAVE ENUMERATED VARIOUS HYPOTHESES OF DRE. FURTHER, WE HAVE DISCUSSED DIFFERENT NON-CONVENTIONAL THERAPEUTIC STRATEGIES, INCLUDING COMBINATION THERAPY AND NON-DRUG TREATMENT. THE RECENT STUDIES SUPPORTING THE MODERN APPROACHES FOR THE TREATMENT OF EPILEPSY HAVE BEEN DELIBERATED WITH PARTICULAR REFERENCE TO THE MTOR PATHWAY, BREAKDOWN OF THE BLOOD-BRAIN BARRIER, AND INFLAMMATORY PATHWAYS. 2021 2 262 33 ADVANCES IN THE POTENTIAL BIOMARKERS OF EPILEPSY. EPILEPSY IS A GROUP OF CHRONIC NEUROLOGICAL DISORDERS CHARACTERIZED BY RECURRENT, SPONTANEOUS, AND UNPREDICTABLE SEIZURES. IT IS ONE OF THE MOST COMMON NEUROLOGICAL DISORDERS, AFFECTING TENS OF MILLIONS OF PEOPLE WORLDWIDE. COMPREHENSIVE STUDIES ON EPILEPSY IN RECENT DECADES HAVE REVEALED THE COMPLEXITY OF EPILEPTOGENESIS, IN WHICH IMMUNOLOGICAL PROCESSES, EPIGENETIC MODIFICATIONS, AND STRUCTURAL CHANGES IN NEURONAL TISSUES HAVE BEEN IDENTIFIED AS PLAYING A CRUCIAL ROLE. THIS REVIEW DISCUSSES THE RECENT ADVANCES IN THE BIOMARKERS OF EPILEPSY. WE EVALUATE THE POSSIBLE MOLECULAR BACKGROUND UNDERLYING THE CLINICAL CHANGES OBSERVED IN RECENT STUDIES, FOCUSING ON THERAPEUTIC INVESTIGATIONS, AND THE EVIDENCE OF THEIR SAFETY AND EFFICACY IN THE HUMAN POPULATION. THIS ARTICLE REVIEWS THE PATHOPHYSIOLOGY OF EPILEPSY, INCLUDING RECENT REPORTS ON THE EFFECTS OF OXIDATIVE STRESS AND HYPOXIA, AND FOCUSES ON SPECIFIC BIOMARKERS AND THEIR CLINICAL IMPLICATIONS, ALONG WITH FURTHER PERSPECTIVES IN EPILEPSY RESEARCH. 2019 3 2536 41 EPIGENETICS IN EPILEPSY. EPILEPSY AFFECTS OVER 50 MILLION INDIVIDUALS GLOBALLY, MAKING IT THE MOST PREVALENT CHRONIC AND SERIOUS NEUROLOGICAL CONDITION. A PRECISE THERAPEUTIC STRATEGY IS COMPLICATED BY POOR UNDERSTANDING OF THE PATHOLOGICAL CHANGES IN EPILEPSY THUS, 30% OF TLE PATIENTS ARE RESISTANT TO DRUG THERAPY. IN THE BRAIN, EPIGENETIC PROCESSES TRANSLATE INFORMATION FROM TRANSIENT CELLULAR IMPULSES AND ADJUSTMENTS IN NEURONAL ACTIVITY INTO LONG-LASTING IMPACTS ON GENE EXPRESSION. RESEARCH SUGGESTS THAT EPIGENETIC PROCESSES CAN BE MANIPULATED IN THE FUTURE TO TREAT OR PREVENT EPILEPSY AS EPIGENETICS HAS BEEN SHOWN TO HAVE A PROFOUND INFLUENCE ON HOW GENES ARE EXPRESSED IN EPILEPSY. AS WELL AS BEING POTENTIAL BIOMARKERS FOR EPILEPSY DIAGNOSIS, EPIGENETIC CHANGES CAN ALSO BE USED AS PROGNOSTIC INDICATORS OF TREATMENT RESPONSE. IN THIS CHAPTER, WE REVIEW THE MOST RECENT FINDINGS IN SEVERAL MOLECULAR PATHWAYS LINKED WITH THE PATHOGENESIS OF TLE THAT ARE CONTROLLED BY EPIGENETIC MECHANISMS HIGHLIGHTING THEIR POTENTIAL UTILITY AS BIOMARKERS FOR UPCOMING TREATMENT STRATEGIES. 2023 4 4128 39 MECHANISMS OF DRUG RESISTANCE IN THE PATHOGENESIS OF EPILEPSY: ROLE OF NEUROINFLAMMATION. A LITERATURE REVIEW. EPILEPSY IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRING SPONTANEOUS SEIZURES. DRUG RESISTANCE APPEARS IN 30% OF PATIENTS AND IT CAN LEAD TO PREMATURE DEATH, BRAIN DAMAGE OR A REDUCED QUALITY OF LIFE. THE PURPOSE OF THE STUDY WAS TO ANALYZE THE DRUG RESISTANCE MECHANISMS, ESPECIALLY NEUROINFLAMMATION, IN THE EPILEPTOGENESIS. THE INFORMATION BASES OF BIOMEDICAL LITERATURE SCOPUS, PUBMED, GOOGLE SCHOLAR AND SCIVERSE WERE USED. TO OBTAIN FULL-TEXT DOCUMENTS, ELECTRONIC RESOURCES OF PUBMED CENTRAL AND RESEARCH GATE WERE USED. THE ARTICLE EXAMINES THE RECENT RESEARCH OF THE MECHANISMS OF DRUG RESISTANCE IN EPILEPSY AND DISCUSSES THE HYPOTHESES OF DRUG RESISTANCE DEVELOPMENT (GENETIC, EPIGENETIC, TARGET HYPOTHESIS, ETC.). DRUG-RESISTANT EPILEPSY IS ASSOCIATED WITH NEUROINFLAMMATORY, AUTOIMMUNE AND NEURODEGENERATIVE PROCESSES. NEUROINFLAMMATION CAUSES IMMUNE, PATHOPHYSIOLOGICAL, BIOCHEMICAL AND PSYCHOLOGICAL CONSEQUENCES. FOCAL OR SYSTEMIC UNREGULATED INFLAMMATORY PROCESSES LEAD TO THE FORMATION OF ABERRANT NEURAL CONNECTIONS AND HYPEREXCITABLE NEURAL NETWORKS. INFLAMMATORY MEDIATORS AFFECT THE ENDOTHELIUM OF CEREBRAL VESSELS, DESTROY CONTACTS BETWEEN ENDOTHELIAL CELLS AND INDUCE ABNORMAL ANGIOGENESIS (THE FORMATION OF "LEAKY" VESSELS), THEREBY AFFECTING THE BLOOD-BRAIN BARRIER PERMEABILITY. THUS, THE ANALYSIS OF PRO-INFLAMMATORY AND OTHER COMPONENTS OF EPILEPTOGENESIS CAN CONTRIBUTE TO THE FURTHER DEVELOPMENT OF THE THERAPEUTIC TREATMENT OF DRUG-RESISTANT EPILEPSY. 2021 5 1329 45 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 6 2963 25 GENETIC AND EPIGENETIC MECHANISMS LINKING PAIN AND PSYCHIATRIC DISORDERS. THE NEUROPHYSIOLOGICAL LINK BETWEEN NEUROPATHIC PAIN AND DEPRESSION REMAINS UNKNOWN DESPITE EVIDENT HIGH COMORBIDITY OF THESE TWO DISORDERS. HOWEVER, THERE IS CONVINCING EVIDENCE THAT GENOTYPE PLAYS A ROLE IN BOTH PAIN AND DEPRESSION. USING VARIOUS TYPES OF GENETIC ANALYSIS - POPULATION GENETICS, CYTOGENETICS AND MOLECULAR TECHNOLOGIES - SPECIFIC GENES HAVE BEEN IMPLICATED IN MEDIATING ALMOST ALL ASPECTS OF NOCICEPTION AND MOOD DISORDERS. THE CURRENT REVIEW ATTEMPTS TO IDENTIFY SPECIFIC GENES AND EPIGENETIC MECHANISMS COMMON TO BOTH DISORDERS. IT IS CONCLUDED THAT EXTERNAL AND INTERNAL FACTORS (INFLAMMATION, STRESS, GENDER, ETC.) THAT CONTRIBUTE TO THE PATHOLOGIES MAY DO SO THROUGH EPIGENETIC MECHANISMS THAT MAY AFFECT EXPRESSION OF THESE PARTICULAR GENES. THE POSSIBLE INVOLVEMENT OF EPIGENETIC REGULATION IN PAIN AND PSYCHIATRIC DISORDERS SUGGESTS THAT TREATMENTS TARGETING EPIGENETIC MECHANISMS THAT MEDIATE ADVERSE LIFE EVENTS SHOULD BE CONSIDERED. 2015 7 2498 35 EPIGENETICS AND EPILEPSY PREVENTION: THE THERAPEUTIC POTENTIAL OF ADENOSINE AND METABOLIC THERAPIES. PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE MOST URGENT NEED FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT. NOVEL CONCEPTUAL ADVANCES ARE REQUIRED TO MEANINGFULLY ADDRESS THIS FUNDAMENTAL CHALLENGE. MALADAPTIVE EPIGENETIC CHANGES, WHICH INCLUDE METHYLATION OF DNA AND ACETYLATION OF HISTONES - AMONG OTHER MECHANISMS, ARE NOW WELL RECOGNIZED TO PLAY A FUNCTIONAL ROLE IN THE DEVELOPMENT OF EPILEPSY AND ITS PROGRESSION. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN THIS CONTEXT, GLOBAL DNA HYPERMETHYLATION IS PARTICULARLY ASSOCIATED WITH CHRONIC EPILEPSY. LIKEWISE, ACETYLATION CHANGES OF HISTONES HAVE BEEN LINKED TO EPILEPSY DEVELOPMENT. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATE THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY METABOLIC AND BIOCHEMICAL MANIPULATIONS THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS REVIEW WILL DISCUSS EPIGENETIC MECHANISMS IMPLICATED IN EPILEPSY DEVELOPMENT AS WELL AS METABOLIC AND BIOCHEMICAL INTERACTIONS THOUGHT TO DRIVE EPILEPTOGENESIS. THEREFORE, METABOLIC AND BIOCHEMICAL MECHANISMS ARE IDENTIFIED AS NOVEL TARGETS FOR EPILEPSY PREVENTION. WE WILL SPECIFICALLY DISCUSS ADENOSINE BIOCHEMISTRY AS A NOVEL THERAPEUTIC STRATEGY TO RECONSTRUCT THE DNA METHYLOME AS ANTIEPILEPTOGENIC STRATEGY AS WELL AS METABOLIC MEDIATORS, SUCH AS BETA-HYDROXYBUTYRATE, WHICH AFFECT HISTONE ACETYLATION. FINALLY, METABOLIC DIETARY INTERVENTIONS (SUCH AS THE KETOGENIC DIET) WHICH HAVE THE UNIQUE POTENTIAL TO PREVENT EPILEPTOGENESIS THROUGH RECENTLY IDENTIFIED EPIGENETIC MECHANISMS WILL BE REVIEWED. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED 'NEW EPILEPSY THERAPIES FOR THE 21ST CENTURY - FROM ANTISEIZURE DRUGS TO PREVENTION, MODIFICATION AND CURE OF EPILEPSY'. 2020 8 6260 29 THE MOLECULAR NEUROBIOLOGY OF CHRONIC PAIN-INDUCED DEPRESSION. THE INCREASING NUMBER OF INDIVIDUALS WITH COMORBIDITIES POSES AN URGENT NEED TO IMPROVE THE MANAGEMENT OF PATIENTS WITH MULTIPLE CO-EXISTING DISEASES. AMONG THESE COMORBIDITIES, CHRONIC PAIN AND MOOD DISORDERS, TWO LONG-LASTING DISABLING CONDITIONS THAT SIGNIFICANTLY REDUCE THE QUALITY OF LIFE, COULD BE CITED FIRST. THE RECENT DEVELOPMENT OF ANIMAL MODELS ACCELERATED THE STUDIES FOCUSING ON THE UNDERLYING MECHANISMS OF THE CHRONIC PAIN AND DEPRESSION/ANXIETY COMORBIDITY. THIS REVIEW PROVIDES AN OVERVIEW OF CLINICAL AND PRE-CLINICAL STUDIES PERFORMED OVER THE PAST TWO DECADES ADDRESSING THE MOLECULAR ASPECTS OF THE COMORBID RELATIONSHIP OF CHRONIC PAIN AND DEPRESSION. WE THUS FOCUSED ON THE STUDIES THAT INVESTIGATED THE MOLECULAR CHARACTERISTICS OF THE COMORBID RELATIONSHIP BETWEEN CHRONIC PAIN AND MOOD DISORDERS, ESPECIALLY MAJOR DEPRESSIVE DISORDERS, FROM THE GENETIC AND EPIGENETIC POINT OF VIEW TO KEY NEUROMODULATORS WHICH HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THIS COMORBIDITY. 2019 9 6676 30 USING EPIGENETIC TOOLS TO INVESTIGATE ANTIDEPRESSANT RESPONSE. MAJOR DEPRESSIVE DISORDER IS A CHRONIC AND DEBILITATING ILLNESS. IT IS MOST COMMONLY TREATED WITH ANTIDEPRESSANT DRUGS, HOWEVER, AS THE MAJORITY OF PATIENTS DO NOT RESPOND ON THEIR FIRST TRIAL OR FOLLOWING SEVERAL ADEQUATE TRIALS, THERE IS GREAT INTEREST IN IDENTIFYING BIOLOGICAL FACTORS THAT MAY HELP SELECT THE MOST APPROPRIATE TREATMENT FOR EACH PATIENT AND IN UNDERSTANDING BIOLOGICAL PROCESSES THAT MEDIATE TREATMENT RESPONSE. EPIGENETIC FACTORS, SUCH AS NON-CODING RNAS (NCRNAS), HOLD POTENTIAL AS BIOMARKERS OF ANTIDEPRESSANT RESPONSE. IN THIS CHAPTER, WE REVIEW KEY METHODOLOGICAL CONSIDERATIONS WHEN INVESTIGATING NCRNA BIOMARKERS, INCLUDING BIOLOGICAL SAMPLES AND TECHNOLOGIES WHICH HAVE BEEN USED IN THESE STUDIES. SECONDLY, WE SUMMARIZE FINDINGS FROM STUDIES INVESTIGATING NCRNAS IN ANTIDEPRESSANT TREATMENT RESPONSE. FINALLY, WE DISCUSS SOME OF THE FUTURE DIRECTIONS WHICH WILL BE NECESSARY FOR THE DEVELOPMENT OF CLINICALLY RELEVANT EPIGENETIC TOOLS. 2018 10 2412 47 EPIGENETIC SIDE-EFFECTS OF COMMON PHARMACEUTICALS: A POTENTIAL NEW FIELD IN MEDICINE AND PHARMACOLOGY. THE TERM "EPIGENETICS" REFERS TO DNA AND CHROMATIN MODIFICATIONS THAT PERSIST FROM ONE CELL DIVISION TO THE NEXT, DESPITE A LACK OF CHANGE IN THE UNDERLYING DNA SEQUENCE. THE "EPIGENOME" REFERS TO THE OVERALL EPIGENETIC STATE OF A CELL, AND SERVES AS AN INTERFACE BETWEEN THE ENVIRONMENT AND THE GENOME. THE EPIGENOME IS DYNAMIC AND RESPONSIVE TO ENVIRONMENTAL SIGNALS NOT ONLY DURING DEVELOPMENT, BUT ALSO THROUGHOUT LIFE; AND IT IS BECOMING INCREASINGLY APPARENT THAT CHEMICALS CAN CAUSE CHANGES IN GENE EXPRESSION THAT PERSIST LONG AFTER EXPOSURE HAS CEASED. HERE WE PRESENT THE HYPOTHESIS THAT COMMONLY-USED PHARMACEUTICAL DRUGS CAN CAUSE SUCH PERSISTENT EPIGENETIC CHANGES. DRUGS MAY ALTER EPIGENETIC HOMEOSTASIS BY DIRECT OR INDIRECT MECHANISMS. DIRECT EFFECTS MAY BE CAUSED BY DRUGS WHICH AFFECT CHROMATIN ARCHITECTURE OR DNA METHYLATION. FOR EXAMPLE THE ANTIHYPERTENSIVE HYDRALAZINE INHIBITS DNA METHYLATION. AN EXAMPLE OF AN INDIRECTLY ACTING DRUG IS ISOTRETINOIN, WHICH HAS TRANSCRIPTION FACTOR ACTIVITY. A TWO-TIER MECHANISM IS POSTULATED FOR INDIRECT EFFECTS IN WHICH ACUTE EXPOSURE TO A DRUG INFLUENCES SIGNALING PATHWAYS THAT MAY LEAD TO AN ALTERATION OF TRANSCRIPTION FACTOR ACTIVITY AT GENE PROMOTERS. THIS STIMULATION RESULTS IN THE ALTERED EXPRESSION OF RECEPTORS, SIGNALING MOLECULES, AND OTHER PROTEINS NECESSARY TO ALTER GENETIC REGULATORY CIRCUITS. WITH MORE CHRONIC EXPOSURE, CELLS ADAPT BY AN UNKNOWN HYPOTHETICAL PROCESS THAT RESULTS IN MORE PERMANENT MODIFICATIONS TO DNA METHYLATION AND CHROMATIN STRUCTURE, LEADING TO ENDURING ALTERATION OF A GIVEN EPIGENETIC NETWORK. THEREFORE, ANY EPIGENETIC SIDE-EFFECT CAUSED BY A DRUG MAY PERSIST AFTER THE DRUG IS DISCONTINUED. IT IS FURTHER PROPOSED THAT SOME IATROGENIC DISEASES SUCH AS TARDIVE DYSKINESIA AND DRUG-INDUCED SLE ARE EPIGENETIC IN NATURE. IF THIS HYPOTHESIS IS CORRECT THE CONSEQUENCES FOR MODERN MEDICINE ARE PROFOUND, SINCE IT WOULD IMPLY THAT OUR CURRENT UNDERSTANDING OF PHARMACOLOGY IS AN OVERSIMPLIFICATION. WE PROPOSE THAT EPIGENETIC SIDE-EFFECTS OF PHARMACEUTICALS MAY BE INVOLVED IN THE ETIOLOGY OF HEART DISEASE, CANCER, NEUROLOGICAL AND COGNITIVE DISORDERS, OBESITY, DIABETES, INFERTILITY, AND SEXUAL DYSFUNCTION. IT IS SUGGESTED THAT A SYSTEMS BIOLOGY APPROACH EMPLOYING MICROARRAY ANALYSES OF GENE EXPRESSION AND METHYLATION PATTERNS CAN LEAD TO A BETTER UNDERSTANDING OF LONG-TERM SIDE-EFFECTS OF DRUGS, AND THAT IN THE FUTURE, EPIGENETIC ASSAYS SHOULD BE INCORPORATED INTO THE SAFETY ASSESSMENT OF ALL PHARMACEUTICAL DRUGS. THIS NEW APPROACH TO PHARMACOLOGY HAS BEEN TERMED "PHAMACOEPIGENOMICS", THE IMPACT OF WHICH MAY BE EQUAL TO OR GREATER THAN THAT OF PHARMACOGENETICS. WE PROVIDE HERE AN OVERVIEW OF THIS POTENTIALLY MAJOR NEW FIELD IN PHARMACOLOGY AND MEDICINE. 2009 11 3404 32 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 12 6807 24 [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 13 2094 27 EPIGENETIC EFFECTS MEDIATED BY ANTIEPILEPTIC DRUGS AND THEIR POTENTIAL APPLICATION. AN EPIGENETIC EFFECT MAINLY REFERS TO A HERITABLE MODULATION IN GENE EXPRESSION IN THE SHORT TERM BUT DOES NOT INVOLVE ALTERATIONS IN THE DNA ITSELF. EPIGENETIC MOLECULAR MECHANISMS INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND UNTRANSLATED RNA REGULATION. ANTIEPILEPTIC DRUGS HAVE DRAWN ATTENTION TO BIOLOGICAL AND TRANSLATIONAL MEDICINE BECAUSE THEIR IMPACT ON EPIGENETIC MECHANISMS WILL LEAD TO THE IDENTIFICATION OF NOVEL BIOMARKERS AND POSSIBLE THERAPEUTIC STRATEGIES FOR THE PREVENTION AND TREATMENT OF VARIOUS DISEASES RANGING FROM NEUROPSYCHOLOGICAL DISORDERS TO CANCERS AND OTHER CHRONIC CONDITIONS. HOWEVER, THESE TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL ALTERATIONS CAN ALSO RESULT IN ADVERSE REACTIONS AND TOXICITY IN VITRO AND IN VIVO. HENCE, IN THIS REVIEW, WE FOCUS ON RECENT FINDINGS SHOWING EPIGENETIC PROCESSES MEDIATED BY ANTIEPILEPTIC DRUGS TO ELUCIDATE THEIR APPLICATION IN MEDICAL EXPERIMENTS AND SHED LIGHT ON EPIGENETIC RESEARCH FOR MEDICINAL PURPOSES. 2020 14 2611 28 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 15 6024 38 THE BIOCHEMISTRY AND EPIGENETICS OF EPILEPSY: FOCUS ON ADENOSINE AND GLYCINE. EPILEPSY, ONE OF THE MOST PREVALENT NEUROLOGICAL CONDITIONS, PRESENTS AS A COMPLEX DISORDER OF NETWORK HOMEOSTASIS CHARACTERIZED BY SPONTANEOUS NON-PROVOKED SEIZURES AND ASSOCIATED COMORBIDITIES. CURRENTLY USED ANTIEPILEPTIC DRUGS HAVE BEEN DESIGNED TO SUPPRESS NEURONAL HYPEREXCITABILITY AND THEREBY TO SUPPRESS EPILEPTIC SEIZURES. HOWEVER, THE CURRENT ARMAMENTARIUM OF ANTIEPILEPTIC DRUGS IS NOT EFFECTIVE IN OVER 30% OF PATIENTS, DOES NOT AFFECT THE COMORBIDITIES OF EPILEPSY, AND DOES NOT PREVENT THE DEVELOPMENT AND PROGRESSION OF EPILEPSY (EPILEPTOGENESIS). PREVENTION OF EPILEPSY AND ITS PROGRESSION REMAINS THE HOLY GRAIL FOR EPILEPSY RESEARCH AND THERAPY DEVELOPMENT, REQUIRING NOVEL CONCEPTUAL ADVANCES TO FIND A SOLUTION TO THIS URGENT MEDICAL NEED. THE METHYLATION HYPOTHESIS OF EPILEPTOGENESIS SUGGESTS THAT CHANGES IN DNA METHYLATION ARE IMPLICATED IN THE PROGRESSION OF THE DISEASE. IN PARTICULAR, GLOBAL DNA HYPERMETHYLATION APPEARS TO BE ASSOCIATED WITH CHRONIC EPILEPSY. CLINICAL AS WELL AS EXPERIMENTAL EVIDENCE DEMONSTRATES THAT EPILEPSY AND ITS PROGRESSION CAN BE PREVENTED BY BIOCHEMICAL MANIPULATIONS AND THOSE THAT TARGET PREVIOUSLY UNRECOGNIZED EPIGENETIC FUNCTIONS CONTRIBUTING TO EPILEPSY DEVELOPMENT AND MAINTENANCE OF THE EPILEPTIC STATE. THIS MINI-REVIEW WILL DISCUSS, EPIGENETIC MECHANISMS IMPLICATED IN EPILEPTOGENESIS AND BIOCHEMICAL INTERACTIONS BETWEEN ADENOSINE AND GLYCINE AS A CONCEPTUAL ADVANCE TO UNDERSTAND THE CONTRIBUTION OF MALADAPTIVE CHANGES IN BIOCHEMISTRY AS A MAJOR CONTRIBUTING FACTOR TO THE DEVELOPMENT OF EPILEPSY. NEW FINDINGS BASED ON BIOCHEMICAL MANIPULATION OF THE DNA METHYLOME SUGGEST THAT: (I) EPIGENETIC MECHANISMS PLAY A FUNCTIONAL ROLE IN EPILEPTOGENESIS; AND (II) THERAPEUTIC RECONSTRUCTION OF THE EPIGENOME IS AN EFFECTIVE ANTIEPILEPTOGENIC THERAPY. 2016 16 2526 34 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 17 5926 33 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 18 4277 37 MICROGLIA SEQUELAE: BRAIN SIGNATURE OF INNATE IMMUNITY IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A PSYCHIATRIC DISORDER WITH SIGNIFICANT IMPACT ON INDIVIDUALS AND SOCIETY. THE CURRENT PHARMACOLOGIC TREATMENT, WHICH PRINCIPALLY ALLEVIATES PSYCHOSIS, IS FOCUSED ON NEUROTRANSMITTERS MODULATION, RELYING ON DRUGS WITH SEVERE SIDE EFFECTS AND INEFFECTIVENESS IN A SIGNIFICANT PERCENTAGE OF CASES. THEREFORE, AND DUE TO DIFFICULTIES INHERENT TO DIAGNOSIS AND TREATMENT, IT IS VITAL TO REASSESS ALTERNATIVE CELLULAR AND MOLECULAR DRUG TARGETS. DISTINCT RISK FACTORS - GENETIC, DEVELOPMENTAL, EPIGENETIC, AND ENVIRONMENTAL - HAVE BEEN ASSOCIATED WITH DISEASE ONSET AND PROGRESSION, GIVING RISE TO THE PROPOSAL OF DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS AND PUTATIVE PHARMACOLOGICAL TARGETS. IMMUNITY IS INVOLVED AND, PARTICULARLY MICROGLIA - INNATE IMMUNE CELLS OF THE CENTRAL NERVOUS SYSTEM, CRITICALLY INVOLVED IN BRAIN DEVELOPMENT - HAVE CAPTURED ATTENTION AS CELLULAR PLAYERS. MICROGLIA UNDERGO MARKED MORPHOLOGIC AND FUNCTIONAL ALTERATIONS IN THE HUMAN DISEASE, AS WELL AS IN ANIMAL MODELS OF SCHIZOPHRENIA, AS REPORTED IN SEVERAL ORIGINAL PAPERS. WE CLUSTER THE MAIN FINDINGS OF CLINICAL STUDIES BY GROUPS OF PATIENTS: (1) AT ULTRA-HIGH RISK OF PSYCHOSIS, (2) WITH A FIRST EPISODE OF PSYCHOSIS OR RECENT-ONSET SCHIZOPHRENIA, AND (3) WITH CHRONIC SCHIZOPHRENIA; IN TRANSLATIONAL STUDIES, WE HIGHLIGHT THE TIME WINDOW OF APPEARANCE OF PARTICULAR MICROGLIA ALTERATIONS IN THE MOST WELL STUDIED ANIMAL MODEL IN THE FIELD (MATERNAL IMMUNE ACTIVATION). THE ORGANIZATION OF CLINICAL AND TRANSLATIONAL FINDINGS BASED ON SCHIZOPHRENIA-ASSOCIATED MICROGLIA CHANGES IN DIFFERENT PHASES OF THE DISEASE COURSE MAY HELP DEFINING A TEMPORAL PATTERN OF MICROGLIA CHANGES AND MAY DRIVE THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES. 2022 19 6447 33 THERAPEUTIC PROSPECTS FOR EPIGENETIC MODULATION. INTRODUCTION: EPIGENETICS DESCRIBES THE PHENOMENON OF HERITABLE CHANGES IN GENE REGULATION GOVERNED BY NON-MENDELIAN PROCESSES, PRIMARILY THROUGH BIOCHEMICAL MODIFICATIONS TO CHROMATIN THAT OCCUR DURING CELL DIFFERENTIATION AND DEVELOPMENT. ABNORMAL LEVELS OF DNA AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. DRUGS THAT TARGET THE PROTEINS CONTROLLING THESE CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS WITH SINGLE TARGET PHARMACOLOGIES THAT ARE SUSCEPTIBLE TO BIOCHEMICAL PATHWAY DEGENERACY. AREAS COVERED: THIS ARTICLE REVIEWS RESEARCH CHARACTERIZING DYSREGULATION OF EPIGENETIC PROCESSES IN CANCER, IMMUNO-INFLAMMATORY, PSYCHIATRIC, NEUROLOGICAL, METABOLIC AND VIROLOGY DISEASE AREAS, AND SUMMARIZES RECENT DEVELOPMENTS IN IDENTIFYING SMALL MOLECULE MODULATORS THAT ARE BEING USED TO INFORM TARGET DISCOVERY AND INITIATE DRUG DISCOVERY PROJECTS. EXPERT OPINION: THERE ARE NUMEROUS POTENTIAL OPPORTUNITIES FOR EPIGENETIC MODULATORS IN TREATING A WIDE RANGE OF CHRONIC DISEASES; HOWEVER, THE FIELD IS COMPLEX, INVOLVING > 300 PROTEINS, AND MUCH WORK IS STILL REQUIRED TO PROVIDE TOOLS TO UNRAVEL THE FUNCTIONS OF INDIVIDUAL PROTEINS, PARTICULARLY IN VIVO. THIS GROUNDWORK IS ESSENTIAL TO ALLOW THE DRUG DISCOVERY COMMUNITY TO FOCUS ON THOSE EPIGENETIC PROTEINS MOST LIKELY TO BE SUITABLE TARGETS FOR SAFE, EFFICACIOUS NEW THERAPIES. 2011 20 1686 35 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