1 6916 115 [WHAT IS MIGRAINE?]. MIGRAINE IS A MULTIFACTORIAL AND HETEROGENEOUS DISORDER. DIAGNOSTIC CRITERIA HAVE BEEN ESTABLISHED BY THE INTERNATIONAL HEADACHE SOCIETY, HOWEVER THESE ARE ONLY SUPPORTIVE IN TERMS OF DEFINITION. THE PATHOPHYSIOLOGY INVOLVES NEURONAL AND VASCULAR PHENOMENA. THE FORMER IS SUPPORTED BY THE CORTICAL SPREADING DEPRESSION BEING THE AURA CORRELATE AND BY BRAINSTEM AND HYPOTHALAMIC ACTIVATION DURING THE PAIN PHASE; THE LATTER IS SUGGESTED BY THE ASSOCIATION BETWEEN MIGRAINE AND CARDIOVASCULAR DISEASE AND FINDINGS OF PATHOLOGICAL VASOREACTIVITY AND ENDOTHELIAL DYSFUNCTION. TRIPTANS AND CALCITONIN GENE-RELATED PEPTIDE RECEPTOR ANTAGONISTS SHOW ONLY A RELATIVE MIGRAINE-SPECIFIC ACTION; UP TO 30% OF PATIENTS ARE NONRESPONDERS. DESPITE A CLEAR GENETIC COMPONENT, THE DISCOVERY OF SPECIFIC GENES FOR COMMON FORMS OF MIGRAINE REMAINS ELUSIVE. ELECTROPHYSIOLOGICAL STUDIES CONSISTENTLY INDICATE A CHARACTERISTIC "DYSHABITUATION" CONCURRING WITH CLINICAL FEATURES OF ALTERED SENSORY PERCEPTION. THE AGE- AND SEX-SPECIFIC PATTERN ALONG WITH THE EFFECT OF EXTERNAL FACTORS ON THE COURSE OF MIGRAINE ARGUE IN FAVOR OF THE INVOLVEMENT OF EPIGENETIC MECHANISMS. KNOWLEDGE ABOUT MIGRAINE IS STILL LIMITED, WHICH HAMPERS A DEFINITION. 2009 2 6846 31 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 3 4139 27 MECHANISMS OF MIGRAINE AS A CHRONIC EVOLUTIVE CONDITION. UNDERSTANDING THE MECHANISMS OF MIGRAINE REMAINS CHALLENGING AS MIGRAINE IS NOT A STATIC DISORDER, AND EVEN IN ITS EPISODIC FORM MIGRAINE REMAINS AN "EVOLUTIVE" CHRONIC CONDITION. CONSIDERABLE PROGRESS HAS BEEN MADE IN ELUCIDATING THE PATHOPHYSIOLOGICAL MECHANISMS OF MIGRAINE, ASSOCIATED GENETIC FACTORS THAT MAY INFLUENCE SUSCEPTIBILITY TO THE DISEASE, AND FUNCTIONAL AND ANATOMICAL CHANGES DURING THE PROGRESSION OF A MIGRAINE ATTACK OR THE TRANSFORMATION OF EPISODIC TO CHRONIC MIGRAINE. MIGRAINE IS A LIFE SPAN NEUROLOGICAL DISORDER THAT FOLLOWS AN EVOLUTIVE AGE-DEPENDENT CHANGE IN ITS PREVALENCE AND EVEN CLINICAL PRESENTATIONS. AS A DISORDER, MIGRAINE INVOLVES RECURRENT INTENSE HEAD PAIN AND ASSOCIATED UNPLEASANT SYMPTOMS. MIGRAINE ATTACKS EVOLVE OVER DIFFERENT PHASES WITH SPECIFIC NEURAL MECHANISMS AND SYMPTOMS BEING INVOLVED DURING EACH PHASE. IN SOME PATIENTS, MIGRAINE CAN BE TRANSFORMED INTO A CHRONIC FORM WITH DAILY OR ALMOST DAILY HEADACHES. THE MECHANISMS BEHIND THIS EVOLUTIVE PROCESS REMAIN UNKNOWN, BUT GENETIC AND EPIGENETIC FACTORS, INFLAMMATORY PROCESSES AND CENTRAL SENSITIZATION MAY PLAY AN IMPORTANT ROLE. 2019 4 2029 20 EPIGENETIC CHANGES IN HEADACHE. INTRODUCTION: MULTIPLE FACTORS, INCLUDING BOTH GENETIC AND ENVIRONMENTAL MECHANISMS, APPEAR TO PLAY A ROLE IN THE AETIOLOGY OF HEADACHE. AN INTERESTING AREA OF STUDY IS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS IN HEADACHE DEVELOPMENT AND THE TRANSFORMATION TO CHRONIC HEADACHE, AND THE POTENTIAL ROLE OF THESE FACTORS AS A THERAPEUTIC TARGET. METHODS: WE PERFORMED A LITERATURE REVIEW OF THE INVOLVEMENT OF DIFFERENT EPIGENETIC MECHANISMS IN HEADACHE, MAINLY USING THE MEDLINE/PUBMED DATABASE. TO THIS END, WE USED THE FOLLOWING ENGLISH SEARCH TERMS: HEADACHE, MIGRAINE, EPIGENETICS, DNA METHYLATION, HISTONES, NON-CODING RNA, AND MIRNA. RESULTS: A TOTAL OF 15 ENGLISH-LANGUAGE PUBLICATIONS RELATED TO THE ABOVE TERMS WERE OBTAINED. CONCLUSION: THERE IS LIMITED BUT CONSISTENT EVIDENCE OF THE RELATIONSHIP BETWEEN EPIGENETICS AND HEADACHE; IT IS THEREFORE ESSENTIAL TO CONTINUE RESEARCH OF EPIGENETIC CHANGES IN HEADACHE. THIS MAY HELP TO UNDERSTAND THE PATHOPHYSIOLOGY OF HEADACHE AND EVEN TO IDENTIFY CANDIDATE BIOMARKERS AND NEW, MORE EFFECTIVE, THERAPEUTIC TARGETS. 2021 5 6323 28 THE ROLE OF A POTENTIAL BIOMARKER IN PATIENTS WITH MIGRAINE: REVIEW AND NEW INSIGHTS. INTRODUCTION: THE SEARCH FOR AN IDEAL BIOMARKER FOR MIGRAINE HAS PERSISTED FOR A LONG TIME. THERE IS PLENTIFUL EVIDENCE OF POTENTIAL BIOMARKERS FOR MIGRAINE FOUND IN CEREBROSPINAL FLUID, BLOOD, AND SALIVA.AREAS COVERED: HEREIN, THE AUTHORS HIGHLIGHT AND DISCUSS THE MOST PROMISING CANDIDATES IN THE LITERATURE. AN ELECTRONIC SEARCH WAS PERFORMED FOR STUDIES PUBLISHED BETWEEN 2010 AND 2020 IN MEDLINE, PUBMED, AND EMBASE, RELATED TO POTENTIAL BIOMARKERS IN MIGRAINE PATIENTS, FOUND IN CEREBROSPINAL FLUID, SALIVA, AND SERUM, FOCUSING ON BIOMARKERS THAT CAN BE RELATED TO TREATMENT AND CLINICAL OUTCOMES.EXPERT OPINION: AN IDEAL BIOMARKER, OR A PANEL OF BIOMARKERS, COULD REVOLUTIONIZE THE WAY WE ADDRESS AND PROPOSE TREATMENTS FOR THIS DISEASE. ONCE SEVERE PRESENTATIONS AND PHENOTYPES HAVE BEEN IDENTIFIED USING A RELIABLE BIOMARKER, PATIENTS COULD BE TREATED AT EARLIER DISEASE STAGES WITH MORE SPECIFIC MEDICATIONS. THE MOST IMPORTANT BIOMARKERS WITH THE MOST SIGNIFICANT LEVELS OF EVIDENCE COMPRISED CALCITONIN GENE-RELATED PEPTIDE (CGRP), GLUTAMATE, NERVE GROWTH FACTOR, SOME INFLAMMATORY (CRP, TNF-ALPHA, INTERLEUKINS) AND OXIDATIVE STRESS MARKERS. CGRP WAS ASSOCIATED WITH EPISODIC, CHRONIC MIGRAINE AND RESPONSE TO TREATMENT. PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE IS AN EMERGING NEUROPEPTIDE INVOLVED IN MIGRAINE DIAGNOSTICS AND SEVERITY. NEW GENETIC AND EPIGENETIC BIOMARKERS WILL BE CANDIDATES FOR FUTURE RESEARCH. 2021 6 638 42 BIOMARKERS ASSOCIATED WITH MIGRAINE AND THEIR POTENTIAL ROLE IN MIGRAINE MANAGEMENT. OBJECTIVE: THE FOCUS OF THIS REVIEW IS TO REVIEW POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKERS ASSOCIATED WITH MIGRAINE. BACKGROUND: MIGRAINE HEADACHE IS A COMMON DISEASE THAT AFFECTS MILLIONS OF INDIVIDUALS WORLDWIDE. ALTHOUGH WELL-ACCEPTED DIAGNOSTIC CRITERIA EXIST FOR MIGRAINE, IT IS STILL A COMPLEX DISORDER THAT REMAINS BOTH UNDERDIAGNOSED AND MISDIAGNOSED. THE CAUSES OF MIGRAINE ARE LIKELY A MIX OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT, TOGETHER WITH THE INDIVIDUAL'S LIFE HISTORY, TRANSLATE INTO THE OBSERVED CLINICAL HETEROGENEITY. INHERENT CLINICAL HETEROGENEITY IS AN OBSTACLE IN DEVELOPING MORE EFFECTIVE TREATMENTS. THE LACK OF APPROPRIATE BIOMARKERS IS ALSO AN IMPEDIMENT TO DEVELOPING MORE EFFECTIVE THERAPEUTIC/PREVENTIVE APPROACHES. ULTIMATELY, BIOMARKERS MAY FACILITATE THE GOAL OF INDIVIDUALIZED MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER TYPES OF HEADACHE. METHODS: A COMPREHENSIVE REVIEW WAS CONDUCTED OF PUBMED CITATIONS CONTAINING THE KEY WORD "MARKER" OR "BIOMARKER" COMBINED WITH "MIGRAINE" OR "HEADACHE." OTHER KEY WORDS INCLUDED "SERUM," "SALIVA," "CEREBROSPINAL FLUID," "GENES," "BLOOD," AND "INFLAMMATION." THE ONLY RESTRICTION WAS ENGLISH-LANGUAGE PUBLICATION. THE ABSTRACTS OF ALL ARTICLES MEETING THESE CRITERIA WERE REVIEWED, AND FULL TEXT WAS RETRIEVED AND EXAMINED FOR RELEVANT REFERENCES. RESULTS: DATA FROM HUMAN STUDIES HAVE BEGUN TO IDENTIFY GENETIC MUTATIONS/POLYMORPHISMS AND ALTERED LEVELS OF SPECIFIC PROINFLAMMATORY AND NEUROMODULATORY MOLECULES THAT STRONGLY CORRELATE WITH MIGRAINE AS WELL AS SYMPTOM SEVERITY. RESULTS FROM A SMALLER NUMBER OF STUDIES HAVE IDENTIFIED PARAMETERS, SUCH AS THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP), WHICH ARE SIGNIFICANTLY ASSOCIATED WITH RESPONSE TO SPECIFIC TREATMENTS FOR ACUTE MIGRAINE ATTACKS AND PROPHYLAXIS. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MIGRAINE, AND UNDERSTANDING ENVIRONMENTALLY INDUCED GENETIC CHANGES ASSOCIATED WITH THIS DISEASE MAY EVENTUALLY GUIDE THE DEVELOPMENT OF THERAPIES CAPABLE OF REVERSING THESE PATHOPHYSIOLOGICAL CHANGES IN GENE FUNCTION. CONCLUSIONS: THE UNDERSTANDING OF THE ETIOLOGY OF MIGRAINE IS INCOMPLETE. ALTHOUGH THE IDENTIFICATION AND VALIDATION OF BIOMARKERS HAS GREATLY ADVANCED DIAGNOSTIC PRECISION AND MEASURES OF THERAPEUTIC EFFICACY IN OTHER DISEASES, THERE ARE NO CURRENTLY ACCEPTED BIOMARKERS FOR CHRONIC OR EPISODIC MIGRAINE. HOWEVER, THE CONTINUED INVESTIGATION AND IDENTIFICATION OF GENETIC, EPIGENETIC, AND MOLECULAR BIOMARKERS IS LIKELY TO FACILITATE THE GOAL OF INDIVIDUALIZING MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER HEADACHE DISORDERS. 2013 7 5038 24 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 8 2963 27 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 9 2611 19 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 10 4339 24 MIGRAINE: A GENETIC DISEASE? MIGRAINES CARRY A SUBSTANTIAL GENETIC LIABILITY, AND IN FAMILIES AFFECTED WITH THE TYPICAL MIGRAINES (MIGRAINE WITH, MA, AND WITHOUT AURA, MO) LINKAGE TO SOME CHROMOSOMAL LOCI HAS BEEN REPORTED. AS YET HOWEVER, NO GENES ARE KNOWN FOR MA/MO, WHILE THE THREE GENES DISCOVERED AS RESPONSIBLE FOR FAMILIAL HEMIPLEGIC MIGRAINE (FHM) ARE NOT INVOLVED IN THE TYPICAL MIGRAINES. ACCORDINGLY, WE PROPOSE TO CONSIDER FHM AS A SYNDROMIC MIGRAINE AND NOT AS A VARIETY OF MA. MOREOVER, WE SUGGEST THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE DETERMINATION OF THE TYPICAL MIGRAINES, AND THAT THE PRIMARY HEADACHES REPRESENT BEHAVIOURAL RESPONSES (SICKNESS BEHAVIOUR, FIGHT-OR-FLIGHT RESPONSES), HAVING ADAPTIVE ADVANTAGE AND HAVING BEEN EVOLUTIONARY CONSERVED, IN WHICH PAIN REPRESENTS A SIGNAL OF HOMEOSTATIC IMBALANCE. EPIGENETIC MECHANISMS AND THIS PROPOSED GENETIC BEHAVIOURAL MODEL COULD BE USEFULLY INCORPORATED INTO HEADACHE GENETIC RESEARCH. 2008 11 847 20 CHILDHOOD MALTREATMENT AND HEADACHE DISORDERS. CHILDHOOD MALTREATMENT IS SUBSTANTIATED IN 12 % OF CHILDREN, BUT NEARLY 50 % ADULTS RECALL HAVING BEEN NEGLECTED OR ABUSED AS CHILDREN. MALTREATMENT, ESPECIALLY EMOTIONAL ABUSE, IS ASSOCIATED WITH MIGRAINE. DYSREGULATION OF THE HPA AXIS, AUTONOMIC, IMMUNE, AND METABOLIC SYSTEMS APPEARS TO BE A CONSEQUENCE OF MALTREATMENT, AND IS ALSO REPORTED IN MIGRAINE. AREAS OF THE BRAIN STRUCTURALLY AND FUNCTIONALLY AFFECTED BY CHILDHOOD ABUSE AND BY MIGRAINE ARE ALSO SIMILAR, AND INCLUDE THE LIMBIC SYSTEM STRUCTURES, WHICH CONNECT TO PAIN REGIONS IN THE BRAINSTEM. PUTATIVE MECHANISMS BY WHICH EARLY LIFE STRESS INCREASES THE LIKELIHOOD OF DEVELOPING MIGRAINE INCLUDE GENE X ENVIRONMENT INTERACTIONS, IN ADDITION TO EPIGENETIC MODIFICATIONS VIA DNA METHYLATION. THESE MODIFICATIONS ARE STABLE AND MAY BE TRANSFERRED ACROSS GENERATIONS, BUT THEY MAY ALSO BE REVERSED BY SOME MEDICATIONS COMMONLY USED IN MIGRAINE, INCLUDING VALPROIC ACID AND TOPIRAMATE. 2016 12 1314 26 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 13 5387 30 REDOX MECHANISMS IN MIGRAINE: NOVEL THERAPEUTICS AND DIETARY INTERVENTIONS. SIGNIFICANCE: MIGRAINE REPRESENTS THE THIRD MOST PREVALENT AND THE SEVENTH MOST DISABLING HUMAN DISORDER. APPROXIMATELY 30% OF MIGRAINE PATIENTS EXPERIENCE TRANSIENT, FULLY REVERSIBLE, FOCAL NEUROLOGICAL SYMPTOMS (AURA) PRECEDING THE ATTACK. RECENT ADVANCES: AWARENESS OF THE HYPOTHESIS THAT MIGRAINE ACTUALLY EMBODIES A SPECTRUM OF ILLNESSES-RANGING FROM EPISODIC TO CHRONIC FORMS-IS PROGRESSIVELY INCREASING AND POSES NOVEL CHALLENGES FOR CLARIFYING THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF MIGRAINE AS WELL AS FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC INTERVENTIONS. SEVERAL THEORIES HAVE EVOLVED TO THE CURRENT CONCEPT THAT A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY PLAY A ROLE IN MIGRAINE PATHOGENESIS, ALTHOUGH THEIR RELATIVE IMPORTANCE IS STILL BEING DEBATED. CRITICAL ISSUES: ONE CRITICAL ISSUE THAT DESERVES A PARTICULAR ATTENTION IS THE ROLE OF OXIDATIVE STRESS IN MIGRAINE. INDEED, POTENTIALLY HARMFUL OXIDATIVE EVENTS OCCUR DURING THE MIGRAINE ATTACK AND LONG-LASTING OR FREQUENT MIGRAINE EPISODES MAY INCREASE BRAIN EXPOSURE TO OXIDATIVE EVENTS THAT CAN LEAD TO CHRONIC TRANSFORMATION. MOREOVER, A WIDE VARIETY OF DIETARY, ENVIRONMENTAL, PHYSIOLOGICAL, BEHAVIORAL, AND PHARMACOLOGICAL MIGRAINE TRIGGERS MAY ACT THROUGH OXIDATIVE STRESS, WITH CLEAR IMPLICATIONS FOR MIGRAINE TREATMENT AND PROPHYLAXIS. INTERESTINGLY, ALMOST ALL CURRENT PROPHYLACTIC MIGRAINE AGENTS EXERT ANTIOXIDANT EFFECTS. FUTURE DIRECTIONS: INCREASING AWARENESS OF THE ROLE OF OXIDATIVE STRESS AND/OR DECREASED ANTIOXIDANT DEFENSES IN MIGRAINE PATHOGENESIS AND PROGRESSION TO A CHRONIC CONDITION LAYS THE FOUNDATIONS FOR THE DESIGN OF NOVEL PROPHYLACTIC APPROACHES, WHICH, BY REDUCING BRAIN OXIDATIVE PHENOMENA, COULD FAVORABLY MODIFY THE CLINICAL COURSE OF MIGRAINE. ANTIOXID. REDOX SIGNAL. 28, 1144-1183. 2018 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 2252 23 EPIGENETIC MODULATION OF VISCERAL NOCICEPTION. EPIGENETICS IS A PROCESS THAT ALTERS GENE ACTIVITY OR PHENOTYPE WITHOUT ANY CHANGES IN THE UNDERLYING DNA SEQUENCE OR GENOTYPE. THESE BIOLOGICAL CHANGES MAY HAVE DELETERIOUS EFFECTS AND CAN LEAD TO VARIOUS HUMAN DISEASES. ONGOING RESEARCH IS CONTINUING TO ILLUMINATE THE ROLE OF EPIGENETICS IN A VARIETY OF PATHOPHYSIOLOGIC PROCESSES. SEVERAL CATEGORIES OF EPIGENETIC MECHANISMS HAVE BEEN STUDIED INCLUDING CHROMATIN REMODELING, DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MECHANISMS. THESE EPIGENETIC CHANGES CAN HAVE A LONG-TERM EFFECT ON GENE EXPRESSION WITHOUT ANY UNDERLYING CHANGES IN THE DNA SEQUENCES. THE UNDERLYING PATHOPHYSIOLOGY OF DISORDERS OF BRAIN-GUT INTERACTION AND STRESS-INDUCED VISCERAL PAIN ARE NOT FULLY UNDERSTOOD AND THE ROLE OF EPIGENETIC MECHANISMS IN THESE DISORDERS ARE STARTING TO BE BETTER UNDERSTOOD. CURRENT WORK IS UNDERWAY TO DETERMINE HOW EPIGENETICS PLAYS A ROLE IN THE NEUROBIOLOGY OF PATIENTS WITH CHRONIC VISCERAL PAIN AND HEIGHTENED VISCERAL NOCICEPTION. MORE RECENTLY, BOTH ANIMAL MODELS AND HUMAN STUDIES HAVE SHOWN HOW EPIGENETIC REGULATION MODULATES STRESS-INDUCED VISCERAL PAIN. WHILE MUCH MORE WORK IS NEEDED TO FULLY DELINEATE THE MECHANISTIC ROLE OF EPIGENETICS IN THE NEUROBIOLOGY OF CHRONIC VISCERAL NOCICEPTION, THE CURRENT STUDY BY LOUWIES ET AL., IN NEUROGASTROENTEROLOGY AND MOTILITY PROVIDES ADDITIONAL EVIDENCE SUPPORTING THE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN RODENTS. 2022 16 5928 18 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 17 2523 21 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 18 5926 23 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 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 2586 20 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018