1 5835 124 STRESS-INDUCED VISCERAL PAIN: TOWARD ANIMAL MODELS OF IRRITABLE-BOWEL SYNDROME AND ASSOCIATED COMORBIDITIES. VISCERAL PAIN IS A GLOBAL TERM USED TO DESCRIBE PAIN ORIGINATING FROM THE INTERNAL ORGANS, WHICH IS DISTINCT FROM SOMATIC PAIN. IT IS A HALLMARK OF FUNCTIONAL GASTROINTESTINAL DISORDERS SUCH AS IRRITABLE-BOWEL SYNDROME (IBS). CURRENTLY, THE TREATMENT STRATEGIES TARGETING VISCERAL PAIN ARE UNSATISFACTORY, WITH DEVELOPMENT OF NOVEL THERAPEUTICS HINDERED BY A LACK OF DETAILED KNOWLEDGE OF THE UNDERLYING MECHANISMS. STRESS HAS LONG BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF VISCERAL PAIN IN BOTH PRECLINICAL AND CLINICAL STUDIES. HERE, WE DISCUSS THE COMPLEX ETIOLOGY OF VISCERAL PAIN REVIEWING OUR CURRENT UNDERSTANDING IN THE CONTEXT OF THE ROLE OF STRESS, GENDER, GUT MICROBIOTA ALTERATIONS, AND IMMUNE FUNCTIONING. FURTHERMORE, WE REVIEW THE ROLE OF GLUTAMATE, GABA, AND EPIGENETIC MECHANISMS AS POSSIBLE THERAPEUTIC STRATEGIES FOR THE TREATMENT OF VISCERAL PAIN FOR WHICH THERE IS AN UNMET MEDICAL NEED. MOREOVER, WE DISCUSS THE MOST WIDELY DESCRIBED RODENT MODELS USED TO MODEL VISCERAL PAIN IN THE PRECLINICAL SETTING. THE THEORY BEHIND, AND APPLICATION OF, ANIMAL MODELS IS KEY FOR BOTH THE UNDERSTANDING OF UNDERLYING MECHANISMS AND DESIGN OF FUTURE THERAPEUTIC INTERVENTIONS. TAKEN TOGETHER, IT IS APPARENT THAT STRESS-INDUCED VISCERAL PAIN AND ITS PSYCHIATRIC COMORBIDITIES, AS TYPIFIED BY IBS, HAS A MULTIFACETED ETIOLOGY. MOREOVER, TREATMENT STRATEGIES STILL LAG FAR BEHIND WHEN COMPARED TO OTHER PAIN MODALITIES. THE DEVELOPMENT OF NOVEL, EFFECTIVE, AND SPECIFIC THERAPEUTICS FOR THE TREATMENT OF VISCERAL PAIN HAS NEVER BEEN MORE PERTINENT. 2015 2 5926 41 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 3 2167 41 EPIGENETIC MECHANISMS IN IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A BRAIN-GUT AXIS DISORDER CHARACTERIZED BY ABDOMINAL PAIN AND ALTERED BOWEL HABITS. IBS IS A MULTIFACTORIAL, STRESS-SENSITIVE DISORDER WITH EVIDENCE FOR FAMILIAL CLUSTERING ATTRIBUTED TO GENETIC OR SHARED ENVIRONMENTAL FACTORS. HOWEVER, THERE ARE WEAK GENETIC ASSOCIATIONS REPORTED WITH IBS AND A LACK OF EVIDENCE TO SUGGEST THAT MAJOR GENETIC FACTOR(S) CONTRIBUTE TO IBS PATHOPHYSIOLOGY. STUDIES ON ANIMAL MODELS OF STRESS, INCLUDING EARLY LIFE STRESS, SUGGEST A ROLE FOR ENVIRONMENTAL FACTORS, SPECIFICALLY, STRESS ASSOCIATED WITH DYSREGULATION OF CORTICOTROPIN RELEASING FACTOR AND HYPOTHALAMUS-PITUITARY-ADRENAL (HPA) AXIS PATHWAYS IN THE PATHOPHYSIOLOGY OF IBS. RECENT EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS, WHICH CONSTITUTE MOLECULAR CHANGES NOT DRIVEN BY A CHANGE IN GENE SEQUENCE, CAN MEDIATE ENVIRONMENTAL EFFECTS ON CENTRAL AND PERIPHERAL FUNCTION. EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION CHANGES, HISTONE MODIFICATIONS, AND DIFFERENTIAL EXPRESSION OF NON-CODING RNAS (MICRORNA [MIRNA] AND LONG NON-CODING RNA) HAVE BEEN ASSOCIATED WITH SEVERAL DISEASES. THE OBJECTIVE OF THIS REVIEW IS TO ELUCIDATE THE MOLECULAR FACTORS IN THE PATHOPHYSIOLOGY OF IBS WITH AN EMPHASIS ON EPIGENETIC MECHANISMS. EMERGING EVIDENCE FOR EPIGENETIC CHANGES IN IBS INCLUDES CHANGES IN DNA METHYLATION IN ANIMAL MODELS OF IBS AND PATIENTS WITH IBS, AND VARIOUS MIRNAS THAT HAVE BEEN ASSOCIATED WITH IBS AND ENDOPHENOTYPES, SUCH AS INCREASED VISCERAL SENSITIVITY AND INTESTINAL PERMEABILITY. DNA METHYLATION, IN PARTICULAR, IS AN EMERGING FIELD IN THE REALM OF COMPLEX DISEASES AND A PROMISING MECHANISM WHICH CAN PROVIDE IMPORTANT INSIGHTS INTO IBS PATHOGENESIS AND IDENTIFY POTENTIAL TARGETS FOR TREATMENT. 2020 4 5927 34 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC VISCERAL PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. BACKGROUND: CHRONIC VISCERAL PAIN IS PERSISTENT PAIN EMANATING FROM THORACIC, PELVIC, OR ABDOMINAL ORIGIN THAT IS POORLY LOCALIZED WITH REGARD TO THE SPECIFIC ORGAN AFFECTED. THE PREVALENCE CAN RANGE UP TO 25% IN THE ADULT POPULATION AS CHRONIC VISCERAL PAIN IS A COMMON FEATURE OF MANY VISCERAL DISORDERS, WHICH MAY OR MAY NOT BE ACCOMPANIED BY DISTINCT STRUCTURAL OR HISTOLOGICAL ABNORMALITIES WITHIN THE VISCERAL ORGANS. MOUNTING EVIDENCE SUGGESTS THAT CHANGES IN EPIGENETIC MECHANISMS ARE INVOLVED IN THE TOP-DOWN OR BOTTOM-UP SENSITIZATION OF PAIN PATHWAYS AND THE DEVELOPMENT OF CHRONIC PAIN. EPIGENETIC CHANGES CAN LEAD TO LONG-TERM ALTERATIONS IN GENE EXPRESSION PROFILES OF NEURONS AND CONSEQUENTLY ALTER FUNCTIONALITY OF PERIPHERAL NEURONS, DORSAL ROOT GANGLIA, SPINAL CORD, AND BRAIN NEURONS. HOWEVER, EPIGENETIC MODIFICATIONS ARE DYNAMIC, AND THUS, DETRIMENTAL CHANGES MAY BE REVERSIBLE. HENCE, EXTERNAL FACTORS/THERAPEUTIC INTERVENTIONS MAY BE CAPABLE OF MODULATING THE EPIGENOME AND RESTORE NORMAL GENE EXPRESSION FOR EXTENDED PERIODS OF TIME. PURPOSE: THE GOAL OF THIS REVIEW IS TO HIGHLIGHT THE LATEST DISCOVERIES MADE TOWARD UNDERSTANDING THE EPIGENETIC MECHANISMS THAT ARE INVOLVED IN THE DEVELOPMENT OR MAINTENANCE OF CHRONIC VISCERAL PAIN. FURTHERMORE, THIS REVIEW WILL PROVIDE EVIDENCE SUPPORTING THAT TARGETING THESE EPIGENETIC MECHANISMS MAY REPRESENT A NOVEL APPROACH TO TREAT CHRONIC VISCERAL PAIN. 2019 5 2963 29 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 6 2252 29 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 7 1204 33 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 8 6260 27 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 4518 32 MULTI-OMICS FOR BIOMARKER APPROACHES IN THE DIAGNOSTIC EVALUATION AND MANAGEMENT OF ABDOMINAL PAIN AND IRRITABLE BOWEL SYNDROME: WHAT LIES AHEAD. RELIABLE BIOMARKERS FOR COMMON DISORDERS OF GUT-BRAIN INTERACTION CHARACTERIZED BY ABDOMINAL PAIN, INCLUDING IRRITABLE BOWEL SYNDROME (IBS), ARE CRITICALLY NEEDED TO ENHANCE CARE AND DEVELOP INDIVIDUALIZED THERAPIES. THE DYNAMIC AND HETEROGENEOUS NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS THAT UNDERLIE VISCERAL HYPERSENSITIVITY HAVE CHALLENGED SUCCESSFUL BIOMARKER DEVELOPMENT. CONSEQUENTLY, EFFECTIVE THERAPIES FOR PAIN IN IBS ARE LACKING. HOWEVER, RECENT ADVANCES IN MODERN OMICS TECHNOLOGIES OFFER NEW OPPORTUNITIES TO ACQUIRE DEEP BIOLOGICAL INSIGHTS INTO MECHANISMS OF PAIN AND NOCICEPTION. NEWER METHODS FOR LARGE-SCALE DATA INTEGRATION OF COMPLEMENTARY OMICS APPROACHES HAVE FURTHER EXPANDED OUR ABILITY TO BUILD A HOLISTIC UNDERSTANDING OF COMPLEX BIOLOGICAL NETWORKS AND THEIR CO-CONTRIBUTIONS TO ABDOMINAL PAIN. HERE, WE REVIEW THE MECHANISMS OF VISCERAL HYPERSENSITIVITY, FOCUSING ON IBS. WE DISCUSS CANDIDATE BIOMARKERS FOR PAIN IN IBS IDENTIFIED THROUGH SINGLE OMICS STUDIES AND SUMMARIZE EMERGING MULTI-OMICS APPROACHES FOR DEVELOPING NOVEL BIOMARKERS THAT MAY TRANSFORM CLINICAL CARE FOR PATIENTS WITH IBS AND ABDOMINAL PAIN. 2023 10 2611 26 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 11 1329 38 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 12 6124 30 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 13 6807 22 [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 14 4144 33 MECHANISMS OF STRESS-INDUCED VISCERAL PAIN. EVIDENCE SUGGESTS THAT LONG-TERM STRESS FACILITATES VISCERAL PAIN THROUGH SENSITIZATION OF PAIN PATHWAYS AND PROMOTES CHRONIC VISCERAL PAIN DISORDERS SUCH AS THE IRRITABLE BOWEL SYNDROME (IBS). THIS REVIEW WILL DESCRIBE THE IMPORTANCE OF STRESS IN EXACERBATING IBS-INDUCED ABDOMINAL PAIN. ADDITIONALLY, WE WILL BRIEFLY REVIEW OUR UNDERSTANDING OF THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BY BOTH CHRONIC ADULT STRESS AND FOLLOWING EARLY LIFE STRESS IN THE PATHOGENESIS OF IBS. THE REVIEW WILL FOCUS ON THE GLUCOCORTICOID RECEPTOR AND CORTICOTROPIN-RELEASING HORMONE-MEDIATED MECHANISMS IN THE AMYGDALA INVOLVED IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY. ONE POTENTIAL MECHANISM UNDERLYING PERSISTENT EFFECTS OF STRESS ON VISCERAL SENSITIVITY COULD BE EPIGENETIC MODULATION OF GENE EXPRESSION. WHILE THERE ARE RELATIVELY FEW STUDIES EXAMINING EPIGENETICALLY MEDIATED MECHANISMS INVOLVED IN STRESS-INDUCED VISCERAL NOCICEPTION, ALTERATIONS IN DNA METHYLATION AND HISTONE ACETYLATION PATTERNS WITHIN THE BRAIN, HAVE BEEN LINKED TO ALTERATIONS IN NOCICEPTIVE SIGNALING VIA INCREASED EXPRESSION OF PRO-NOCICEPTIVE NEUROTRANSMITTERS. THIS REVIEW WILL DISCUSS THE LATEST STUDIES INVESTIGATING THE LONG-TERM EFFECTS OF STRESS ON VISCERAL SENSITIVITY. ADDITIONALLY, WE WILL CRITICALLY REVIEW THE IMPORTANCE OF EXPERIMENTAL MODELS OF ADULT STRESS AND EARLY LIFE STRESS IN ENHANCING OUR UNDERSTANDING OF THE BASIC MOLECULAR MECHANISMS OF NOCICEPTIVE PROCESSING. 2018 15 1686 34 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 16 5369 24 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 17 6414 35 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 18 5778 30 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 19 4914 26 PAIN VULNERABILITY: A NEUROBIOLOGICAL PERSPECTIVE. THERE ARE MANY KNOWN RISK FACTORS FOR CHRONIC PAIN CONDITIONS, YET THE BIOLOGICAL UNDERPINNINGS THAT LINK THESE FACTORS TO ABNORMAL PROCESSING OF PAINFUL SIGNALS ARE ONLY JUST BEGINNING TO BE EXPLORED. THIS REVIEW WILL DISCUSS THE POTENTIAL MECHANISMS THAT HAVE BEEN PROPOSED TO UNDERLIE VULNERABILITY AND RESILIENCE TOWARD DEVELOPING CHRONIC PAIN. PARTICULAR FOCUS WILL BE GIVEN TO GENETIC AND EPIGENETIC PROCESSES, PRIMING EFFECTS ON A CELLULAR LEVEL, AND ALTERATIONS IN BRAIN NETWORKS CONCERNED WITH REWARD, MOTIVATION/LEARNING AND DESCENDING MODULATORY CONTROL. ALTHOUGH RESEARCH IN THIS AREA IS STILL IN ITS INFANCY, A BETTER UNDERSTANDING OF HOW PAIN VULNERABILITY EMERGES HAS THE POTENTIAL TO HELP IDENTIFY INDIVIDUALS AT RISK AND MAY OPEN UP NEW THERAPEUTIC AVENUES. 2014 20 1291 32 DECODING THE ROLE OF EPIGENETICS AND GENOMICS IN PAIN MANAGEMENT. PERSISTENT PAIN IS A COSTLY EPIDEMIC, AFFECTING >50 MILLION AMERICANS WITH ESTIMATED EXPENDITURES OF >$200 BILLION ANNUALLY FOR DIRECT CARE AND LOST PRODUCTIVITY. RECENT ADVANCES IN EPIGENETIC/GENOMIC UNDERSTANDING OF PAIN AND ANALGESIC RESPONSE MAY LEAD TO IMPROVEMENTS IN PAIN MANAGEMENT AND HELP CURTAIL COSTS BY PROVIDING MORE PRECISE DETECTION OF THE PAIN MECHANISMS INVOLVED AND THEREBY MORE PERSONALIZED AND EFFECTIVE TREATMENTS. HOWEVER, THE TRANSLATION OF EPIGENETIC AND GENOMIC STRATEGIES FOR PAIN MANAGEMENT INTO CLINICAL PRACTICE WILL DEPEND ON UNDERSTANDING THEIR POTENTIAL APPLICATIONS. THE PURPOSE OF THIS ARTICLE IS TO EXAMINE CURRENT KNOWLEDGE ABOUT EPIGENETIC AND GENOMIC MECHANISMS OF PERSISTENT PAIN AND POTENTIAL OPPORTUNITIES FOR IMPROVING PAIN MANAGEMENT. THE INITIAL DISCUSSION FOCUSES ON PRESENT UNDERSTANDING OF NOCICEPTIVE PATHWAYS AND ALTERATIONS THAT LEAD TO PATHOLOGIC PAIN. THE DISCUSSION THEN MOVES TO A REVIEW OF EPIGENETIC MECHANISMS THAT HAVE BEEN IDENTIFIED IN THE TRANSITION TO AND MAINTENANCE OF PERSISTENT PAIN AS WELL AS IN THE INDIVIDUAL'S RESPONSE TO ANALGESICS. POTENTIAL APPLICATIONS OF EPIGENETICS/GENOMICS TO IDENTIFY PEOPLE AT RISK AND POSSIBLY PREVENT PERSISTENT PAIN AND GUIDE DIAGNOSIS AND THE SELECTION OF THERAPEUTIC MODALITIES ARE PRESENTED. 2013