1 2561 113 EPIGENETICS IN THE PERIOPERATIVE PERIOD. THE PERIOPERATIVE PERIOD IS CHARACTERIZED BY PROFOUND CHANGES IN THE BODY'S HOMOEOSTATIC PROCESSES. THIS REVIEW SEEKS TO ADDRESS WHETHER EPIGENETIC MECHANISMS MAY INFLUENCE AN INDIVIDUAL'S REACTION TO SURGERY AND ANAESTHESIA. EVIDENCE FROM ANIMAL AND HUMAN STUDIES SUGGESTS THAT EPIGENETIC MECHANISMS CAN EXPLAIN MANY FACETS OF SUSCEPTIBILITY TO ACUTE AND CHRONIC PAIN, MAKING THEM POTENTIAL THERAPEUTIC TARGETS. MODERN PAIN MANAGEMENT IS STILL BASED UPON OPIATES, AND BOTH THE DEVELOPMENTAL EXPRESSION OF OPIOID RECEPTORS AND OPIOID-INDUCED HYPERALGESIA HAVE BEEN LINKED TO EPIGENETIC MECHANISMS. IN GENERAL, OPIATES SEEM TO INCREASE GLOBAL DNA METHYLATION LEVELS. THIS IS IN CONTRAST TO LOCAL ANAESTHETICS, WHICH HAVE BEEN ASCRIBED A GLOBAL DEMETHYLATING EFFECT. EVEN THOUGH NO DIRECT INVESTIGATIONS HAVE BEEN CARRIED OUT, THE POTENTIAL INFLUENCE OF EPIGENETICS ON THE INFLAMMATORY RESPONSE THAT FOLLOWS SURGERY SEEMS A PROMISING AREA FOR RESEARCH. THERE IS A CONSIDERABLE BODY OF EVIDENCE THAT SUPPORTS THE INVOLVEMENT OF EPIGENETICS IN THE COMPLEX PROCESS OF WOUND HEALING. EPIGENETICS IS AN IMPORTANT EMERGING RESEARCH TOPIC IN PERIOPERATIVE MEDICINE, WITH A HUGE POTENTIAL TO POSITIVELY INFLUENCE PATIENT OUTCOME. 2015 2 3010 35 GENETICS AND EPIGENETICS IN PERIOPERATIVE MEDICINE. PURPOSE OF REVIEW: TO SUMMARIZE IS TO REVIEW RECENT PROGRESS IN 'GENOMIC' SCIENCE AND HOW THIS MAY BE APPLIED TO THE PERIOPERATIVE ENVIRONMENT. ALTHOUGH INVESTIGATIONS THAT RELATE GENETIC VARIATION TO PERIOPERATIVE OUTCOMES CONTINUE, IT IS INCREASINGLY APPARENT THAT EPIGENETIC MECHANISMS MAY CONTRIBUTE TO MUCH OF THE OBSERVED VARIATION IN COMPLEX OUTCOMES NOT OTHERWISE EXPLAINED BY DIFFERENCES IN GENETIC SEQUENCE. RECENT FINDINGS: EXAMPLES OF RECENT FINDINGS RELATING TO THE ROLE OF EPIGENETIC MODIFICATIONS IN COMPLEX DISEASE AND OUTCOMES ARE DERIVED FROM RESEARCH INTO TYPE 1 DIABETES, PAIN, AND THE HYPOXIC RESPONSE. THESE STUDIES PROVIDE MODELS FOR FUTURE COHORT STUDY DESIGN, POTENTIAL PERIOPERATIVE DRUG TARGETS, AND HYPOTHESIS DEVELOPMENT. GENETIC AND EPIGENETIC FACTORS COMBINE TO ALTER BOTH GENE EXPRESSION AND DRUG RESPONSES AT BOTH PHARMACOKINETIC AND PHARMACODYNAMIC LEVELS. THESE FACTORS IMPACT ON THE EFFICACY AND SAFETY OF MULTIPLE DRUG CLASSES USED IN PERIOPERATIVE MEDICINE. SUMMARY: ENHANCING OUR UNDERSTANDING OF THE WAY IN WHICH PATIENTS AS GENOMIC ORGANISMS INTERACT WITH THE PERIOPERATIVE ENVIRONMENT REQUIRES A MORE SOPHISTICATED APPRECIATION OF THE FACTORS GOVERNING GENE EXPRESSION THAN HAS BEEN THE CASE TO DATE. EPIGENETIC MECHANISMS ARE SURE TO PLAY A PIVOTAL ROLE IN WHAT IS ESSENTIALLY AN ACQUIRED PHENOTYPE. 2012 3 2523 40 EPIGENETICS AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN. OBJECTIVE: THE OBJECTIVE OF THIS STUDY WAS TO REVIEW THE EPIGENETIC MODIFICATIONS INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN AND TO IDENTIFY POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED PAIN THERAPEUTICS. BACKGROUND: EPIGENETICS IS THE STUDY OF HERITABLE MODIFICATIONS IN GENE EXPRESSION AND PHENOTYPE THAT DO NOT REQUIRE A CHANGE IN GENETIC SEQUENCE TO MANIFEST THEIR EFFECTS. ENVIRONMENTAL TOXINS, MEDICATIONS, DIET, AND PSYCHOLOGICAL STRESSES CAN ALTER EPIGENETIC PROCESSES SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND RNA INTERFERENCE. AS EPIGENETIC MODIFICATIONS POTENTIALLY PLAY AN IMPORTANT ROLE IN INFLAMMATORY CYTOKINE METABOLISM, STEROID RESPONSIVENESS, AND OPIOID SENSITIVITY, THEY ARE LIKELY KEY FACTORS IN THE DEVELOPMENT OF CHRONIC PAIN. ALTHOUGH OUR KNOWLEDGE OF THE HUMAN GENETIC CODE AND DISEASE-ASSOCIATED POLYMORPHISMS HAS GROWN SIGNIFICANTLY IN THE PAST DECADE, WE HAVE NOT YET BEEN ABLE TO ELUCIDATE THE MECHANISMS THAT LEAD TO THE DEVELOPMENT OF PERSISTENT PAIN AFTER NERVE INJURY OR SURGERY. DESIGN: THIS IS A FOCUSED LITERATURE REVIEW OF EPIGENETIC SCIENCE AND ITS RELATIONSHIP TO CHRONIC PAIN. RESULTS: SIGNIFICANT LABORATORY AND CLINICAL DATA SUPPORT THE NOTION THAT EPIGENETIC MODIFICATIONS ARE AFFECTED BY THE ENVIRONMENT AND LEAD TO DIFFERENTIAL GENE EXPRESSION. SIMILAR TO MECHANISMS INVOLVED IN THE DEVELOPMENT OF CANCER, NEURODEGENERATIVE DISEASE, AND INFLAMMATORY DISORDERS, THE LITERATURE ENDORSES AN IMPORTANT POTENTIAL ROLE FOR EPIGENETICS IN CHRONIC PAIN. CONCLUSIONS: EPIGENETIC ANALYSIS MAY IDENTIFY MECHANISMS CRITICAL TO THE DEVELOPMENT OF CHRONIC PAIN AFTER INJURY, AND MAY PROVIDE NEW PATHWAYS AND TARGET MECHANISMS FOR FUTURE DRUG DEVELOPMENT AND INDIVIDUALIZED MEDICINE. 2012 4 2611 37 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 5 3404 29 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 6 5928 25 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 7 2963 23 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 8 6185 32 THE IMPACT OF GENERAL ANESTHESIA ON REDOX STABILITY AND EPIGENETIC INFLAMMATION PATHWAYS: CROSSTALK ON PERIOPERATIVE ANTIOXIDANT THERAPY. WORLDWIDE, THE PREVALENCE OF SURGERY UNDER GENERAL ANESTHESIA HAS SIGNIFICANTLY INCREASED, BOTH BECAUSE OF MODERN ANESTHETIC AND PAIN-CONTROL TECHNIQUES AND BECAUSE OF BETTER DIAGNOSIS AND THE INCREASED COMPLEXITY OF SURGICAL TECHNIQUES. APART FROM DEVELOPING NEW CONCEPTS IN THE SURGICAL FIELD, RESEARCHERS AND CLINICIANS ARE NOW WORKING ON MINIMIZING THE IMPACT OF SURGICAL TRAUMA AND OFFERING MINIMAL INVASIVE PROCEDURES DUE TO THE RECENT DISCOVERIES IN THE FIELD OF CELLULAR AND MOLECULAR MECHANISMS THAT HAVE REVEALED A SYSTEMIC INFLAMMATORY AND PRO-OXIDATIVE IMPACT NOT ONLY IN THE PERIOPERATIVE PERIOD BUT ALSO IN THE LONG TERM, CONTRIBUTING TO MORE DIFFICULT RECOVERY, INCREASED MORBIDITY AND MORTALITY, AND A NEGATIVE FINANCIAL IMPACT. DETAILED MOLECULAR AND CELLULAR ANALYSIS HAS SHOWN AN OVERPRODUCTION OF INFLAMMATORY AND PRO-OXIDATIVE SPECIES, RESPONSIBLE FOR AUGMENTING THE SYSTEMIC INFLAMMATORY STATUS AND MAKING POSTOPERATIVE RECOVERY MORE DIFFICULT. MOREOVER, THERE ARE A SERIES OF CHANGES IN CERTAIN EPIGENETIC STRUCTURES, THE MOST IMPORTANT BEING THE MICRORNAS. THIS REVIEW DESCRIBES THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS THAT IMPACT THE SURGICAL PATIENT UNDERGOING GENERAL ANESTHESIA, AND IT PRESENTS A SERIES OF ANTIOXIDANT THERAPIES THAT CAN REDUCE SYSTEMIC INFLAMMATION. 2022 9 5926 35 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 10 1204 34 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 11 6805 29 [EPIGENETICS : IMPORTANT ASPECTS FOR ANESTHESIOLOGISTS, PAIN AND INTENSIVE CARE PHYSICIANS]. EPIGENETICS, I.E. AN ALTERED READING OF THE GENOME WITHOUT ALTERING THE GENES THEMSELVES IS A GROWING SCIENTIFIC FIELD. A DISTINCTION IS MADE BETWEEN CHANGES IN THE DNA BY MODIFICATION OF THE HISTONES AND NON-CODING RNA THAT ALTER THE MESSENGER (M)RNAS. EPIGENETIC MODIFICATIONS CAN BE TRIGGERED BY PERSONAL CIRCUMSTANCES OR OTHER EXTERNAL FACTORS AND THEREFORE INFLUENCE THE OCCURRENCE OF DISEASES. EPIGENETICS ARE THEREFORE OF PARTICULAR INTEREST TO ANESTHESIOLOGISTS, PAIN SPECIALISTS AND INTENSIVE CARE PHYSICIANS, AS ANESTHETIC DRUGS MAY HAVE A LONG-TERM INFLUENCE ON PROTEIN TRANSCRIPTION LEADING FOR EXAMPLE TO ALTERATIONS IN NEUROCOGNITION AFTER ANESTHESIA, CHRONIFICATION OF POSTOPERATIVE PAIN AND IMMUNE RESPONSE IN SEPSIS. NON-CODING MICRORNAS KNOWN TO BE ALTERED IN A VARIETY OF PERIOPERATIVELY RELEVANT DISEASES E. G. HEART INFARCT, MIGHT SERVE AS PROGNOSTIC FACTORS OF PERIOPERATIVE OUTCOME. MOREOVER, THERE ARE WAYS TO INFLUENCE EPIGENETIC CHANGES THROUGH LIFE STYLE AND CERTAIN MEDICATIONS. IN THIS REVIEW ARTICLE, EXAMPLES OF ANESTHESIA, INTENSIVE CARE AND PAIN MEDICINE-RELEVANT DISEASES AND THE INFLUENCE OF EPIGENETICS ON THEM ARE PRESENTED. 2018 12 1686 30 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 13 2789 30 FACTORS INFLUENCING EPIGENETIC MECHANISMS: IS THERE A ROLE FOR BARIATRIC SURGERY? EPIGENETICS IS THE INTERACTION BETWEEN THE GENOME AND ENVIRONMENTAL STIMULI CAPABLE OF INFLUENCING GENE EXPRESSION DURING DEVELOPMENT AND AGING. A LARGE NUMBER OF STUDIES HAVE SHOWN THAT METABOLIC DISEASES ARE HIGHLY ASSOCIATED WITH EPIGENETIC ALTERATIONS, SUGGESTING THAT EPIGENETIC FACTORS MAY PLAY A CENTRAL ROLE IN OBESITY. TO INVESTIGATE THESE RELATIONSHIPS, WE FOCUS OUR ATTENTION ON THE MOST COMMON EPIGENETIC MODIFICATIONS THAT OCCUR IN OBESITY, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS OF HISTONES. WE ALSO CONSIDER BARIATRIC SURGERY AS AN EPIGENETIC FACTOR, EVALUATING HOW THE ANATOMIC AND PHYSIOLOGIC MODIFICATIONS INDUCED BY THESE SURGICAL TECHNIQUES CAN CHANGE GENE EXPRESSION. HERE WE DISCUSS THE IMPORTANCE OF EPIGENETIC MECHANISMS IN CHRONIC DISEASE AND CANCER, AND THE ROLE OF EPIGENETIC DISTURBANCES IN OBESITY, WITH A FOCUS ON THE ROLE OF BARIATRIC SURGERY. 2020 14 6211 28 THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTH AND DISEASE: POTENTIAL ROLE OF AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS. OXIDATIVE STRESS CAN BE INDUCED BY VARIOUS STIMULI AND ALTERED IN CERTAIN CONDITIONS, INCLUDING EXERCISE AND PAIN. ALTHOUGH MANY STUDIES HAVE INVESTIGATED OXIDATIVE STRESS IN RELATION TO EITHER EXERCISE OR PAIN, THE LITERATURE PRESENTS CONFLICTING RESULTS. THEREFORE, THIS REVIEW CRITICALLY DISCUSSES EXISTING LITERATURE ABOUT THIS TOPIC, AIMING TO PROVIDE A CLEAR OVERVIEW OF KNOWN INTERACTIONS BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTHY PEOPLE AS WELL AS IN PEOPLE WITH CHRONIC PAIN, AND TO HIGHLIGHT POSSIBLE CONFOUNDING FACTORS TO KEEP IN MIND WHEN REFLECTING ON THESE INTERACTIONS. IN ADDITION, AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS ARE PROPOSED AS POTENTIAL MECHANISMS OF ACTION UNDERLYING THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN. THIS REVIEW HIGHLIGHTS THAT THE RELATION BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IS POORLY UNDERSTOOD AND NOT STRAIGHTFORWARD, AS IT IS DEPENDENT ON THE CHARACTERISTICS OF EXERCISE, BUT ALSO ON WHICH POPULATION IS INVESTIGATED. TO BE ABLE TO COMPARE STUDIES ON THIS TOPIC, STRICT GUIDELINES SHOULD BE DEVELOPED TO LIMIT THE EFFECT OF SEVERAL CONFOUNDING FACTORS. THIS WAY, THE TRUE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN, AND THE UNDERLYING MECHANISMS OF ACTION CAN BE REVEALED AND VALIDATED VIA INDEPENDENT STUDIES. 2020 15 6807 20 [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 16 6905 24 [THE ROLE OF EPIGENETIC REGULATIONS IN EARLY CHILDHOOD DISEASES]. WITH THE ACCEPTANCE OF "THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" CONCEPT IN THE 1990S, IT BECAME CLEAR THAT EPIGENETIC INHERITANCE, WHICH DO NOT INVOLVE CHANGES IN THE DNA SEQUENCE HAS IMPORTANT ROLE IN THE PATHOGENESIS OF DISEASES. EPIGENETIC REGULATION SERVES THE ADAPTATION TO THE CHANGING ENVIRONMENT AND MAINTAINS THE REPRODUCTIVE FITNESS EVEN ON THE DRAWBACK OF INCREASED RISK OF DISEASES IN LATER LIFE. THE ROLE OF EPIGENETIC MECHANISMS IN CHRONIC NON-COMMUNICABLE DISEASES HAS BEEN WELL ESTABLISHED. RECENT STUDIES HAVE REVEALED THAT EPIGENETIC CHANGES HAVE ALSO CAUSAL ROLE IN CERTAIN PEDIATRIC DISEASES. THE REVIEW EVALUATES THE RECENT EPIGENETIC FINDINGS IN THE PATHOMECHANISM OF COMMON PEDIATRIC DISEASES. THE WIDE RANGE AND LONG-LASTING DURATION OF EPIGENETIC REGULATIONS GIVE IMPORTANCE TO THE SUBJECT. METHODS ARE ALREADY AVAILABLE TO EVALUATE A PART OF THE EPIGENETIC CHANGES IN THE CLINICAL PRACTICE, PRESENTLY AIMING PRIMARILY THE ESTIMATION OF THE DISEASE RISK OR DEFINITION OF DIAGNOSIS. FURTHERMORE, THERE ARE ALREADY AVAILABLE LIMITED MEANS TO INFLUENCE THE EPIGENETIC REGULATION. 2019 17 3108 24 GENOMICS OF PAIN IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) ACCOUNTS FOR THE MAJORITY OF THE DISEASE BURDEN FOR MUSCULOSKELETAL DISORDERS AND IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. THIS DISABILITY IS THE RESULT NOT OF THE CARTILAGE LOSS THAT DEFINES OA RADIOGRAPHICALLY, BUT OF THE CHRONIC PAIN WHOSE PRESENCE DEFINES SYMPTOMATIC OA. IT IS BECOMING CLEAR THAT MANY GENES, EACH WITH A SMALL EFFECT SIZE, CONTRIBUTE TO THE RISK OF DEVELOPING OA. HOWEVER, THE GENETICS OF OA PAIN ARE ONLY JUST STARTING TO BE EXPLORED. THIS REVIEW WILL DESCRIBE THE FIRST GENES TO HAVE BEEN IDENTIFIED IN GENOMIC STUDIES OF OA PAIN, AS WELL AS THE POSSIBLE DUAL ROLES OF GENES PREVIOUSLY IDENTIFIED IN GENOMIC STUDIES OF OA IN THE CONTEXT OF PAIN. DIFFICULTIES ASSOCIATED WITH ATTEMPTING TO CHARACTERISE THE GENETICS OF OA PAIN WILL BE DISCUSSED AND PROMISING FUTURE AVENUES OF RESEARCH INTO GENETIC AND EPIGENETIC FACTORS AFFECTING OA PAIN DESCRIBED. 2013 18 6391 28 THE ROLE OF THE GUT MICROBIOME AND MICROBIAL METABOLISM IN MEDIATING OPIOID-INDUCED CHANGES IN THE EPIGENOME. THE CURRENT OPIOID PANDEMIC IS A MAJOR PUBLIC HEALTH CRISIS IN THE UNITED STATES, AFFECTING MILLIONS OF PEOPLE AND IMPOSING SIGNIFICANT HEALTH AND SOCIOECONOMIC BURDENS. PRECLINICAL AND CLINICAL RESEARCH OVER THE PAST FEW DECADES HAS DELINEATED CERTAIN MOLECULAR MECHANISMS AND IDENTIFIED VARIOUS GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS RESPONSIBLE FOR THE PATHOPHYSIOLOGY AND COMORBIDITIES ASSOCIATED WITH OPIOID USE. OPIOID USE-INDUCED EPIGENETIC MODIFICATIONS HAVE BEEN IDENTIFIED AS ONE OF THE IMPORTANT FACTORS THAT MEDIATE GENETIC CHANGES IN BRAIN REGIONS THAT CONTROL REWARD AND DRUG-SEEKING BEHAVIOR AND ARE ALSO IMPLICATED IN THE DEVELOPMENT OF TOLERANCE. RECENTLY, IT HAS BEEN SHOWN THAT OPIOID USE RESULTS IN MICROBIAL DYSBIOSIS, LEADING TO GUT BARRIER DISRUPTION, WHICH DRIVES SYSTEMIC INFLAMMATION, IMPACTING THE PERCEPTION OF PAIN, THE DEVELOPMENT OF ANALGESIC TOLERANCE, AND BEHAVIORAL OUTCOMES. IN THIS REVIEW, WE HIGHLIGHT THE POTENTIAL ROLE OF MICROBIOTA AND MICROBIAL METABOLITES IN MEDIATING THE EPIGENETIC MODIFICATIONS INDUCED BY OPIOID USE. 2023 19 2412 38 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 20 6458 34 TIME COURSE OF DNA METHYLATION IN PAIN CONDITIONS: FROM EXPERIMENTAL MODELS TO HUMANS. BACKGROUND AND OBJECTIVE: THROUGHOUT THE LAST DECADE, RESEARCH HAS UNCOVERED ASSOCIATIONS BETWEEN PAIN AND EPIGENETIC ALTERATIONS CAUSED BY ENVIRONMENTAL FACTORS. SPECIFICALLY, STUDIES HAVE DEMONSTRATED CORRELATIONS BETWEEN PAIN CONDITIONS AND ALTERED DNA METHYLATION PATTERNS. THUS, DNA METHYLATION HAS BEEN REVEALED AS A POSSIBLE MODULATOR OR CONTRIBUTOR TO PAIN CONDITIONS, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR TREATMENT BY DNA METHYLATION MODIFICATION. TO DEVELOP SUCH TREATMENTS, IT IS NECESSARY TO CLARIFY A WIDE NUMBER OF ASPECTS ON HOW DNA METHYLATION AFFECTS PAIN PERCEPTION; FIRST AND FOREMOST, THE TEMPORAL DYNAMICS. THE OBJECTIVE OF THE PRESENT REVIEW IS TO PROVIDE AN OVERVIEW OF CURRENT KNOWLEDGE ON TEMPORAL DYNAMICS OF DNA METHYLATION IN RESPONSE TO PAIN, AND TO INVESTIGATE IF A TIMEFRAME CAN BE ESTABLISHED BASED ON THE DATA OF CURRENTLY PUBLISHED STUDIES. DATABASES AND DATA TREATMENT: PUBMED, MEDLINE, GOOGLE SCHOLAR AND EMBASE WERE SEARCHED COMPREHENSIVELY FOR STUDIES OF DNA METHYLATION IN NEUROPATHIC, INFLAMMATORY AND ALTERNATIVE ANIMAL PAIN MODELS, AND IN CHRONIC PAIN PATIENTS INCLUDING COMPLEX REGIONAL PAIN SYNDROME, CHRONIC POSTSURGICAL PAIN, CHRONIC WIDESPREAD PAIN, FIBROMYALGIA AND CROHN'S DISEASE. RESULTS: WE IDENTIFIED 34 ARTICLES HIGHLIGHTING VARIATIONS IN TEMPORAL DYNAMICS OF DNA METHYLATION ACROSS SPECIES AND BETWEEN DIFFERENT TYPES OF PAIN. THESE STUDIES REPRESENT A STARTING POINT TO UNCOVER NEW INSIGHTS IN THE DNA METHYLATION TIME COURSE IN PAIN. CONCLUSIONS: NO TIMEFRAME CAN CURRENTLY BE MADE FOR THE DNA METHYLATION RESPONSE TO PAIN IN ANY OF THE REVIEWED CONDITIONS, HIGHLIGHTING AN IMPORTANT FOCUS AREA FOR FUTURE RESEARCH. 2021