1 4418 118 MOLECULAR AND EPIGENETIC ASPECTS OF OPIOID RECEPTORS IN DRUG ADDICTION AND PAIN MANAGEMENT IN SPORT. OPIOIDS ARE SUBSTANCES DERIVED FROM OPIUM (NATURAL OPIOIDS). IN ITS RAW STATE, OPIUM IS A GUMMY LATEX EXTRACTED FROM PAPAVER SOMNIFERUM. THE USE OF OPIOIDS AND THEIR NEGATIVE HEALTH CONSEQUENCES AMONG PEOPLE WHO USE DRUGS HAVE BEEN STUDIED. TODAY, OPIOIDS ARE STILL THE MOST COMMONLY USED AND EFFECTIVE ANALGESIC TREATMENTS FOR SEVERE PAIN, BUT THEIR USE AND ABUSE CAUSES DETRIMENTAL SIDE EFFECTS FOR HEALTH, INCLUDING ADDICTION, THUS IMPACTING THE USER'S QUALITY OF LIFE AND CAUSING OVERDOSE. THE MESOCORTICOLIMBIC DOPAMINERGIC CIRCUITRY REPRESENTS THE BRAIN CIRCUIT MEDIATING BOTH NATURAL REWARDS AND THE REWARDING ASPECTS OF NEARLY ALL DRUGS OF ABUSE, INCLUDING OPIOIDS. HENCE, UNDERSTANDING HOW OPIOIDS AFFECT THE FUNCTION OF DOPAMINERGIC CIRCUITRY MAY BE USEFUL FOR BETTER KNOWLEDGE OF THE PROCESS AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES IN ADDICTION. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE MAIN FEATURES OF OPIOIDS AND OPIOID RECEPTORS AND FOCUS ON THE MOLECULAR AND UPCOMING EPIGENETIC MECHANISMS LEADING TO OPIOID ADDICTION. SINCE SYNTHETIC OPIOIDS CAN BE EFFECTIVE FOR PAIN MANAGEMENT, THEIR ABILITY TO INDUCE ADDICTION IN ATHLETES, WITH THE RISK OF INCURRING DOPING, IS ALSO DISCUSSED. 2023 2 2841 39 FREQUENCY OF THE DOPAMINE RECEPTOR D3 (RS6280) VS. OPIOID RECEPTOR MICRO1 (RS1799971) POLYMORPHIC RISK ALLELES IN PATIENTS WITH OPIOID USE DISORDER: A PREPONDERANCE OF DOPAMINERGIC MECHANISMS? WHILE OPIOIDS ARE A POWERFUL CLASS OF DRUGS THAT INHIBIT TRANSMISSION OF PAIN SIGNALS, THEIR USE IS TARNISHED BY THE CURRENT EPIDEMIC OF OPIOID USE DISORDER (OUD) AND OVERDOSE DEATHS. NOTWITHSTANDING PUBLISHED REPORTS, THERE REMAIN GAPS IN OUR KNOWLEDGE OF OPIOID RECEPTOR MECHANISMS AND THEIR ROLE IN OPIOID SEEKING BEHAVIOR. THUS, NOVEL INSIGHTS INTO MOLECULAR, NEUROGENETIC AND NEUROPHARMACOLOGICAL BASES OF OUD ARE NEEDED. WE PROPOSE THAT AN ADDICTIVE ENDOPHENOTYPE MAY NOT BE ENTIRELY SPECIFIC TO THE DRUG OF CHOICE BUT RATHER MAY BE GENERALIZABLE TO ALTERED BRAIN REWARD CIRCUITS IMPACTING NET MESOCORTICOLIMBIC DOPAMINE RELEASE. WE SUGGEST THAT GENETIC OR EPIGENETIC ALTERATIONS ACROSS DOPAMINERGIC REWARD SYSTEMS LEAD TO UNCONTROLLABLE SELF-ADMINISTRATION OF OPIOIDS AND OTHER DRUGS. FOR INSTANCE, DIMINISHED AVAILABILITY VIA KNOCKOUT OF DOPAMINE D3 RECEPTOR (DRD3) INCREASES VULNERABILITY TO OPIOIDS. BUILDING UPON THIS CONCEPT VIA THE USE OF A SOPHISTICATED POLYMORPHIC RISK ANALYSIS IN A HUMAN COHORT OF CHRONIC OPIOID USERS, WE FOUND EVIDENCE FOR A HIGHER FREQUENCY OF POLYMORPHIC DRD3 RISK ALLELE (RS6280) THAN OPIOID RECEPTOR MICRO1 (RS1799971). IN CONCLUSION, WHILE OPIOIDERGIC MECHANISMS ARE INVOLVED IN OUD, DOPAMINE-RELATED RECEPTORS MAY HAVE PRIMARY INFLUENCE ON OPIOID-SEEKING BEHAVIOR IN AFRICAN AMERICANS. THESE FINDINGS SUGGEST OUD-TARGETED NOVEL AND IMPROVED NEUROPHARMACOLOGICAL THERAPIES MAY REQUIRE FOCUS ON DRD3-MEDIATED REGULATION OF DOPAMINERGIC HOMEOSTASIS. 2022 3 3899 25 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 4 2000 21 EPIGENETIC AND NON-CODING REGULATION OF ALCOHOL ABUSE AND ADDICTION. ALCOHOL USE DISORDER IS A CHRONIC DEBILITATED CONDITION ADVERSELY AFFECTING THE LIVES OF MILLIONS OF INDIVIDUALS THROUGHOUT THE MODERN WORLD. INDIVIDUALS SUFFERING FROM AN ALCOHOL USE DISORDER DIAGNOSIS FREQUENTLY HAVE SERIOUS COOCCURRING CONDITIONS, WHICH OFTEN FURTHER EXACERBATES PROBLEMATIC DRINKING BEHAVIOR. COMPREHENDING THE BIOCHEMICAL PROCESSES UNDERLYING THE PROGRESSION AND PERPETUATION OF DISEASE IS ESSENTIAL FOR MITIGATING MALADAPTIVE BEHAVIOR IN ORDER TO RESTORE BOTH PHYSIOLOGICAL AND PSYCHOLOGICAL HEALTH. THE RANGE OF CELLULAR AND BIOLOGICAL SYSTEMS CONTRIBUTING TO, AND AFFECTED BY, ALCOHOL USE DISORDER AND OTHER COMORBID DISORDERS NECESSITATES A FUNDAMENTAL GRASP OF INTRICATE FUNCTIONAL RELATIONSHIPS THAT GOVERN MOLECULAR BIOLOGY. EPIGENETIC FACTORS ARE RECOGNIZED AS ESSENTIAL MEDIATORS OF CELLULAR BEHAVIOR, ORCHESTRATING A SYMPHONY OF GENE EXPRESSION CHANGES WITHIN MULTICELLULAR ENVIRONMENTS THAT ARE ULTIMATELY RESPONSIBLE FOR DIRECTING HUMAN BEHAVIOR. UNDERSTANDING THE EPIGENETIC AND TRANSCRIPTIONAL REGULATORY MECHANISMS INVOLVED IN THE PATHOGENESIS OF DISEASE IS IMPORTANT FOR IMPROVING AVAILABLE PHARMACOTHERAPIES AND REDUCING THE INCIDENCE OF ALCOHOL ABUSE AND COOCCURRING CONDITIONS. 2021 5 4631 28 NEUROGENETICS OF ACUTE AND CHRONIC OPIATE/OPIOID ABSTINENCE: TREATING SYMPTOMS AND THE CAUSE. THIS REVIEW BEGINS WITH A COMPREHENSIVE HISTORY OF OPIOID DEPENDENCE AND TREATMENT IN THE UNITED STATES. THE FOCUS IS AN EVIDENCE-BASED TREATMENT MODEL FOR OPIOID/OPIATE DEPENDENT INDIVIDUALS. THE ROLE OF REWARD GENETIC POLYMORPHISMS AND THE EPIGENETIC MODIFICATIONS THAT LEAD TO VULNERABILITY TO USE AND MISUSE OF OPIATES/OPIOID TO TREAT PAIN ARE REVIEWED. THE NEUROCHEMICAL MECHANISMS OF ACUTE OPIATE WITHDRAWAL AND OPIATE/OPIOID REWARD MECHANISMS ARE EXPLORED WITH A GOAL OF IDENTIFYING SPECIFIC TREATMENT TARGETS. ALTERATIONS IN FUNCTIONAL BRAIN CONNECTIVITY BASED ON NEUROBIOLOGICAL MECHANISMS IN HEROIN DEPENDENCE AND ABSTINENCE ARE ALSO REVIEWED. A NEW CLINICAL MODEL AN ALTERNATIVE TO MERELY BLOCKING ACUTE WITHDRAWAL SYMPTOMS AS IDENTIFIED IN THE DSM -5 IS PROPOSED. GENETIC DIAGNOSIS AT THE ONSET OF DETOXIFICATION, TO DETERMINE RISK STRATIFICATION, AND IDENTIFY POLYMORPHIC GENE TARGETS FOR PHARMACEUTICAL AND NUTRACEUTICAL INTERVENTIONS, FOLLOWED BY THE SIMULTANEOUS INITIATION OF MEDICATION ASSISTED THERAPY (MAT), TO ENABLE PSYCHOLOGICAL EXTINCTION, AND STEADY PRO-DOPAMINERGIC THERAPY WITH THE GOAL OF DEVELOPING "DOPAMINE HOMEOSTASIS" IS RECOMMENDED. THE OBJECTIVE OF THESE INTERVENTIONS IS TO PREVENT FUTURE RELAPSE BY TREATING ALL "REWARD DEFICIENCY SYNDROME" (RDS) BEHAVIORS AND EVENTUALLY MAKE AN ADDICTION-FREE LIFE POSSIBLE. 2017 6 4599 24 NATURE AND NURTURE OF HUMAN PAIN. HUMANS ARE VERY DIFFERENT WHEN IT COMES TO PAIN. SOME GET PAINFUL PIERCINGS AND TATTOOS; OTHERS CAN NOT STAND EVEN A FLU SHOT. INTERINDIVIDUAL VARIABILITY IS ONE OF THE MAIN CHARACTERISTICS OF HUMAN PAIN ON EVERY LEVEL INCLUDING THE PROCESSING OF NOCICEPTIVE IMPULSES AT THE PERIPHERY, MODIFICATION OF PAIN SIGNAL IN THE CENTRAL NERVOUS SYSTEM, PERCEPTION OF PAIN, AND RESPONSE TO ANALGESIC STRATEGIES. AS FOR MANY OTHER COMPLEX BEHAVIORS, THE SOURCES OF THIS VARIABILITY COME FROM BOTH NURTURE (ENVIRONMENT) AND NATURE (GENES). HERE, I WILL DISCUSS HOW THESE FACTORS CONTRIBUTE TO HUMAN PAIN SEPARATELY AND VIA INTERPLAY AND HOW EPIGENETIC MECHANISMS ADD TO THE COMPLEXITY OF THEIR EFFECTS. 2013 7 5374 35 RECENT ADVANCES IN UNDERSTANDING/MANAGEMENT OF PREMENSTRUAL DYSPHORIC DISORDER/PREMENSTRUAL SYNDROME. PREMENSTRUAL SYNDROME (PMS) AND PREMENSTRUAL DYSPHORIC DISORDER (PMDD) ARE COMMON DISORDERS OF THE LUTEAL PHASE OF THE MENSTRUAL CYCLE AND ARE CHARACTERIZED BY MODERATE TO SEVERE PHYSICAL, AFFECTIVE, OR BEHAVIORAL SYMPTOMS THAT IMPAIR DAILY ACTIVITIES AND QUALITY OF LIFE. PMS AND PMDD HAVE RECENTLY RAISED GREAT INTEREST IN THE RESEARCH COMMUNITY FOR THEIR CONSIDERABLE GLOBAL PREVALENCE. THE ETIOLOGY OF PMS/PMDD IS COMPLEX. OVARIAN REPRODUCTIVE STEROIDS (ESTRADIOL AND PROGESTERONE) ARE CONSIDERED PATHOGENETIC EFFECTORS, BUT THE KEY FEATURE SEEMS TO BE AN ALTERED SENSITIVITY OF THE GABAERGIC CENTRAL INHIBITORY SYSTEM TO ALLOPREGNANOLONE, A NEUROSTEROID DERIVED FROM PROGESTERONE PRODUCED AFTER OVULATION. ALSO, A REDUCED AVAILABILITY OF SEROTONIN SEEMS TO BE INVOLVED. NEW INSIGHTS POINT TO A ROLE FOR GENETIC AND EPIGENETIC MODIFICATIONS OF HORMONAL AND NEUROTRANSMITTER PATHWAYS, AND INFLAMMATION IS THE POTENTIAL LINK BETWEEN PERIPHERAL AND NEUROLOGICAL INTEGRATED RESPONSES TO STRESSORS. THUS, NEW THERAPEUTIC APPROACHES TO PMS/PMDD INCLUDE INHIBITION OF PROGESTERONE RECEPTORS IN THE BRAIN (I.E., WITH ULIPRISTAL ACETATE), REDUCED CONVERSION OF PROGESTERONE TO ITS METABOLITE ALLOPREGNANOLONE WITH DUTASTERIDE, AND POSSIBLE MODULATION OF THE ACTION OF ALLOPREGNANOLONE ON THE BRAIN GABAERGIC SYSTEM WITH SEPRANOLONE. FURTHER RESEARCH IS NEEDED TO BETTER UNDERSTAND THE INTERACTION BETWEEN PERIPHERAL INFLAMMATORY MOLECULES (CYTOKINES, INTERLEUKINS, C-REACTIVE PROTEIN, AND REACTIVE OXYGEN SPECIES) AND THE BRAIN NEUROTRANSMITTER SYSTEMS IN WOMEN WITH PMS/PMDD. IF CONFIRMED, NEUROINFLAMMATION COULD LEAD BOTH TO DEVELOP TARGETED ANTI-INFLAMMATORY THERAPIES AND TO DEFINE PREVENTION STRATEGIES FOR THE ASSOCIATED CHRONIC INFLAMMATORY RISK IN PMS/PMDD. FINALLY, THE OBSERVED ASSOCIATION BETWEEN PREMENSTRUAL DISORDERS AND PSYCHOLOGICAL DISEASES MAY GUIDE PROMPT AND ADEQUATE INTERVENTIONS TO ACHIEVE A BETTER QUALITY OF LIFE. 2022 8 4834 28 ON THE INTERPLAY BETWEEN THE MEDICINE OF HILDEGARD OF BINGEN AND MODERN MEDICINE: THE ROLE OF ESTROGEN RECEPTOR AS AN EXAMPLE OF BIODYNAMIC INTERFACE FOR STUDYING THE CHRONIC DISEASE'S COMPLEXITY. INTRODUCTION: HILDEGARD OF BINGEN (1098-1179) INTERPRETED THE ORIGINS OF CHRONIC DISEASE HIGHLIGHTING AND ANTICIPATING, ALTHOUGH ONLY IN A LIMITED FASHION, THE IMPORTANCE THAT COMPLEX INTERACTIONS AMONG NUMEROUS GENETIC, INTERNAL MILIEU AND EXTERNAL ENVIRONMENTAL FACTORS HAVE IN DETERMINING THE DISEASE PHENOTYPE. TODAY, WE RECOGNIZE THOSE FACTORS, CAPABLE OF MEDIATING THE TRANSMISSION OF MESSAGES BETWEEN HUMAN BODY AND ENVIRONMENT AND VICE VERSA, AS BIODYNAMIC INTERFACES. AIM: WE ANALYZED, IN THE LIGHT OF MODERN SCIENTIFIC EVIDENCE, HILDEGARD OF BINGEN'S MEDICAL APPROACH AND HER ORIGINAL HUMORAL THEORY IN ORDER TO IDENTIFY POSSIBLE INSIGHTS INCLUDED IN HER MEDICINE THAT COULD BE REFERRED TO IN THE CONTEXT OF MODERN EVIDENCE-BASED MEDICINE. IN PARTICULAR, THE ABBESS'S HUMORAL THEORY SUGGESTS THE IDENTIFICATION OF BIODYNAMIC INTERFACES WITH SEX HORMONES AND THEIR RECEPTORS. FINDINGS: WE FOUND THAT THE HILDEGARDIAN HOLISTIC VISION OF THE ORGANISM-ENVIRONMENT RELATIONSHIP CAN ACTUALLY REPRESENT A VISIONARY APPROACH TO MODERN ENDOCRINOLOGY AND THAT SEX HORMONES, IN PARTICULAR ESTROGENS, COULD REPRESENT AN EXAMPLE OF A BIODYNAMIC INTERFACE. ESTROGEN RECEPTORS ARE FOUND IN REGIONS OF THE BRAIN INVOLVED IN EMOTIONAL AND COGNITIVE REGULATION, CONTROLLING THE MOLECULAR MECHANISM OF BRAIN FUNCTION. ESTROGEN RECEPTORS ARE INVOLVED IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IN THE EPIGENETIC REGULATION OF RESPONSES TO PHYSIOLOGICAL, SOCIAL, AND HORMONAL STIMULI. FURTHERMORE, ESTROGEN AFFECTS GENE METHYLATION ON ITS OWN AND RELATED RECEPTOR PROMOTERS IN DISCRETE REGIONS OF THE DEVELOPING BRAIN. THIS SCENARIO WAS STRIKINGLY PERCEIVED BY THE ABBESS IN THE XIITH CENTURY, AND DEPICTED AS A COMPLEX INTERPLAY AMONG DIFFERENT HUMORS AND FLEGMATA THAT SHE RECOGNIZED TO BE SEX SPECIFIC AND ENVIRONMENTALLY REGULATED. VIEWPOINT: CONSIDERING THE FUNCTION PLAYED BY HORMONES, ANALYZED THROUGH THE LAST SCIENTIFIC EVIDENCE, AND SCIENTIFIC LITERATURE ON BIODYNAMIC INTERFACES, WE COULD SUGGEST HILDEGARDIAN INSIGHTS AND THEORIES AS THE FIRST ATTEMPT TO DESCRIBE THE MODERN HOLISTIC, SEX-BASED MEDICINE. CONCLUSION: HILDEGARD ANTICIPATED A CONCEPT OF PATHOGENESIS THAT SEES A CENTRAL ROLE FOR ENDOCRINOLOGY IN SEX-SPECIFIC DISEASE. FURTHERMORE, ESTROGENS AND ESTROGEN RECEPTORS COULD REPRESENT A GOOD EXAMPLE OF MOLECULAR INTERFACES CAPABLE OF MODULATING THE INTERACTION BETWEEN THE ORGANISM INTERNAL MILIEU AND THE ENVIRONMENTAL FACTORS. 2022 9 1732 22 DYSTONIA AND LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON'S DISEASE: IS THERE A CONNECTION? DYSTONIA AND LEVODOPA-INDUCED DYSKINESIA (LID) ARE BOTH HYPERKINETIC MOVEMENT DISORDERS. DYSTONIA ARISES MOST OFTEN SPONTANEOUSLY, ALTHOUGH IT MAY BE SEEN AFTER STROKE, INJURY, OR AS A RESULT OF GENETIC CAUSES. LID IS ASSOCIATED WITH PARKINSON'S DISEASE (PD), EMERGING AS A CONSEQUENCE OF CHRONIC THERAPY WITH LEVODOPA, AND MAY BE EITHER DYSTONIC OR CHOREIFORM. LID AND DYSTONIA SHARE IMPORTANT PHENOMENOLOGICAL PROPERTIES AND MECHANISMS. BOTH LID AND DYSTONIA ARE GENERATED BY AN INTEGRATED CIRCUIT INVOLVING THE CORTEX, BASAL GANGLIA, THALAMUS AND CEREBELLUM. THEY ALSO SHARE DYSREGULATION OF STRIATAL CHOLINERGIC SIGNALING AND ABNORMALITIES OF STRIATAL SYNAPTIC PLASTICITY. THE LONG DURATION NATURE OF BOTH LID AND DYSTONIA SUGGESTS THAT THERE MAY BE UNDERLYING EPIGENETIC DYSREGULATION AS A PROXIMATE CAUSE. WHILE BOTH MAY IMPROVE AFTER INTERVENTIONS SUCH AS DEEP BRAIN STIMULATION (DBS), NEITHER CURRENTLY HAS A SATISFACTORY MEDICAL THERAPY, AND MANY PEOPLE ARE DISABLED BY THE SYMPTOMS OF DYSTONIA AND LID. FURTHER STUDY OF THE FUNDAMENTAL MECHANISMS CONNECTING THESE TWO DISORDERS MAY LEAD TO NOVEL APPROACHES TO TREATMENT OR PREVENTION. 2019 10 4469 26 MOLECULAR NEUROLOGICAL CORRELATES OF ENDORPHINERGIC/DOPAMINERGIC MECHANISMS IN REWARD CIRCUITRY LINKED TO ENDORPHINERGIC DEFICIENCY SYNDROME (EDS). THE CONSENSUS OF THE CURRENT LITERATURE STRONGLY SUPPORTS THE CONCEPT THAT BRAIN NEUROTRANSMITTERS, AND SECOND MESSENGERS INVOLVED IN THE NET RELEASE OF DOPAMINE IN THE MESOLIMBIC REGION, ESPECIALLY THE NUCLEUS ACCUMBENS (NAC), IS DIRECTLY LINKED TO MOTIVATION, ANTI-STRESS, INCENTIVE SALIENCE (WANTING), AND WELL-BEING. THE ROLE OF DOPAMINE IN TERMS OF ALCOHOL WITHDRAWAL SYMPTOMOLOGY, COCAINE CRAVING BEHAVIOR, DOPAMINE -CONDENSATION PRODUCTS (TIQS), AND MORE RECENTLY, THE GENETIC ASPECTS OF DRUG-SEEKING AND PRO-DOPAMINE REGULATION, PROVIDE COMPELLING EVIDENCE OF THE RELEVANT MOLECULAR NEUROLOGICAL CORRELATES OF DOPAMINERGIC /ENDORPHINERGIC MECHANISMS IN REWARD CIRCUITRY DUE TO GENETIC POLYMORPHISMS AND EPIGENETIC INSULTS. IN THE FACE OF AN AMERICANS OPIOID EPIDEMIC, THE CLINICAL CONSENSUS IS TO TREAT OPIOID USE DISORDER (OUD) WITH LIFE-LONG OPIOID SUBSTITUTION THERAPY. HOWEVER, THE AUTHORS SUGGEST A PARADIGM SHIFT INVOLVING NOVEL MODALITIES LIKE TARGETING THE ENDORPHINERGIC SYSTEM LINKED TO DOPAMINE RELEASE AT THE NAC, IN TERMS OF THE INDUCTION OF REQUIRED "DOPAMINE HOMEOSTASIS." UTILIZING THE KNOWN GENETIC - ENVIRONMENTAL INTERACTION THEOREM P = G +E, THE AUTHORS PROVIDE A CLEAR RATIONALE FOR THE ADOPTION OF GENETIC RISK TESTING COUPLED WITH ENDORPHINERGIC/DOPAMINE REGULATION TO ADDRESS DYSFUNCTION ACROSS THE BRAIN REWARD CIRCUITRY. THE GOAL OF ALTERING RESTING-STATE, FUNCTIONAL CONNECTIVITY MAY REQUIRE A GENTLE "NEUROTRANSMITTER FIX" VIS ENKEPHALINASE INHIBITION TO OVERCOME OR COMBAT - SELF-INDUCTION OF ACUTE DOPAMINE RELEASE VIA PSYCHOACTIVE SUBSTANCE MISUSE RESULTING IN CHRONIC DOPAMINE DOWN-REGULATION. AS SUBSETS OF REWARD DEFICIENCY, WE ARE POISED TO PROVIDE NOVEL, GENETICALLY GUIDED THERAPY FOR ENDORPHINERGIC, OPIOIDERGIC, AND DOPAMINERGIC DEFICIENCIES AND RELATED SYNDROMES, UTILIZING "PRECISION ADDICTION MANAGEMENT. 2020 11 636 38 BIOLOGICAL SUBSTRATES OF ADDICTION. THIS REVIEW IS AN INTRODUCTION TO ADDICTION, THE REWARD CIRCUITRY, AND LABORATORY ADDICTION MODELS. ADDICTION IS A CHRONIC DISEASE HALLMARKED BY A STATE OF COMPULSIVE DRUG SEEKING THAT PERSISTS DESPITE NEGATIVE CONSEQUENCES. MOST OF THE ADVANCES IN ADDICTION RESEARCH HAVE CENTERED ON THE CANONICAL AND CONTEMPORARY DRUGS OF ABUSE; HOWEVER, ADDICTIONS TO OTHER ACTIVITIES AND STIMULI ALSO EXIST. SUBSTANCES OF ABUSE HAVE THE POTENTIAL TO INDUCE LONG-LASTING CHANGES IN THE BRAIN AT THE BEHAVIORAL, CIRCUIT, AND SYNAPTIC LEVELS. ADDICTION-RELATED BEHAVIORAL CHANGES INVOLVE INITIATION, ESCALATION, AND OBSESSION TO DRUG SEEKING AND MUCH OF THE CURRENT RESEARCH IS FOCUSED ON MAPPING THESE MANIFESTATIONS TO SPECIFIC NEURAL PATHWAYS. DRUG ABUSE IS WELL KNOWN TO RECRUIT COMPONENTS OF THE MESOLIMBIC DOPAMINE SYSTEM, INCLUDING THE NUCLEUS ACCUMBENS AND VENTRAL TEGMENTAL AREA. IN ADDITION, ALTERED FUNCTION OF A WIDE VARIETY OF BRAIN REGIONS IS TIGHTLY ASSOCIATED WITH SPECIFIC MANIFESTATIONS OF DRUG ABUSE. THESE REGIONS PERIPHERAL TO THE MESOLIMBIC PATHWAY LIKELY PLAY A ROLE IN SPECIFIC OBSERVED COMORBIDITIES AND ENDOPHENOTYPES THAT CAN FACILITATE, OR BE CAUSED BY, SUBSTANCE ABUSE. ALTERATIONS IN SYNAPTIC STRUCTURE, FUNCTION, AND CONNECTIVITY, AS WELL AS EPIGENETIC AND GENETIC MECHANISMS ARE THOUGHT TO UNDERLIE THE PATHOLOGIES OF ADDICTION. IN PRECLINICAL MODELS, THESE PERSISTENT CHANGES ARE STUDIED AT THE LEVELS OF MOLECULAR PHARMACOLOGY AND BIOCHEMISTRY, EX VIVO AND IN VIVO ELECTROPHYSIOLOGY, RADIOGRAPHY, AND BEHAVIOR. COORDINATING RESEARCH EFFORTS ACROSS THESE DISCIPLINES AND EXAMINING CELL TYPE- AND CIRCUIT-SPECIFIC PHENOMENA ARE CRUCIAL COMPONENTS FOR TRANSLATING PRECLINICAL FINDINGS TO VIABLE MEDICAL INTERVENTIONS THAT EFFECTIVELY TREAT ADDICTION AND RELATED DISORDERS. WIRES COGN SCI 2014, 5:151-171. DOI: 10.1002/WCS.1273 CONFLICT OF INTEREST: THE AUTHORS HAVE DECLARED NO CONFLICTS OF INTEREST FOR THIS ARTICLE. FOR FURTHER RESOURCES RELATED TO THIS ARTICLE, PLEASE VISIT THE WIRES WEBSITE. 2014 12 677 25 BRAIN CIRCUITS AT RISK IN PSYCHIATRIC DISEASES AND PHARMACOLOGICAL PATHWAYS. THE MULTIPLE BRAIN CIRCUITS INVOLVED IN PSYCHIATRIC DISEASES MAY APPEAR DAUNTING, BUT WE PREFER TO CONCENTRATE ON A SELECT FEW, WITH A PARTICULAR SENSITIVITY TO STRESS AND NEURODEVELOPMENTAL ISSUES, WITH A CLEAR PHARMACOTHERAPY. THIS REVIEW IS STRUCTURED AROUND 1. THE KEY CIRCUITS, THEIR ROLE IN HEALTH AND DISEASE, AND THE NEUROTRANSMITTERS MAINTAINING THEM, 2. THE INFLUENCE OF UPBRINGING, STRESS, CHRONOBIOLOGY, INFLAMMATION AND INFECTION, 3. THE GENETIC AND EPIGENETIC INFLUENCE ON THESE CIRCUITS, PARTICULARLY REGARDING COPY NUMBER VARIANTS AND NEURONAL PLASTICITY, 4. THE USE AND ABUSE OF PHARMACOLOGICAL AGENTS WITH THE PARTICULAR RISKS OF STRESS AND CHRONOBIOLOGY AT CRITICAL PERIODS. A MAJOR EMPHASIS IS PLACED ON THE LINKS BETWEEN HIPPOCAMPUS, PREFRONTAL CORTEX AND AMYGDALA/PERIAQUEDUCTAL GREY WHICH CONTROL SPECIFIC ASPECTS OF COGNITION, MOOD, PAIN AND EVEN VIOLENCE. SOME OF THE RESEARCH FINDINGS WERE FROM THE INNOVATIVE MEDICINE INITIATIVE (IMI) NEWMEDS, A 22MEURO ACADEMIC/INDUSTRIAL CONSORTIUM ON THE BRAIN CIRCUITS CRITICAL FOR PSYCHIATRIC DISEASE. 2021 13 6433 20 THE VINDICATION OF LAMARCK? EPIGENETICS AT THE INTERSECTION OF LAW AND MENTAL HEALTH. RESEARCH ON EPIGENETIC MECHANISMS IS GAINING TRACTION, YET IS POORLY UNDERSTOOD BY CRIMINOLOGISTS AND BEHAVIORAL SCIENTISTS. THE CURRENT OBJECTIVE IS TO REVIEW RELEVANT STUDIES OF INTEREST TO BEHAVIORAL SCIENTISTS WHO STUDY CRIME, AND TO TRANSLATE ADMITTEDLY CHALLENGING SCIENTIFIC INFORMATION INTO TEXT THAT IS DIGESTIBLE TO THE AVERAGE CRIMINOLOGIST. USING SYSTEMATIC SEARCH PROCEDURES THE AUTHORS IDENTIFIED AND REVIEWED 41 STUDIES OF EPIGENETIC MECHANISMS IN PSYCHIATRIC AND BEHAVIORAL PHENOTYPES AMONG HUMANS. FINDINGS REVEALED SIGNIFICANT EPIGENETIC EFFECTS IN AN ASSORTMENT OF GENES THAT ARE IMPLICATED IN THE ETIOLOGY OF DEPRESSION, SUICIDALITY, CALLOUS-UNEMOTIONAL TRAITS, AND CHRONIC AND INTERGENERATIONAL AGGRESSIVE BEHAVIOR. SEVERAL POLYMORPHISMS THAT MEDIATE THE HPA AXIS, NEUROTRANSMISSION, IMMUNE RESPONSE, BRAIN DEVELOPMENT, SEROTONIN SYNTHESIS, AND OTHER PROCESSES WERE FOUND. ALTHOUGH PRESCRIPTIVE KNOWLEDGE BASED ON EPIGENETIC FINDINGS TO DATE IS PREMATURE, EPIGENETICS IS A NEW AND EXCITING SCIENTIFIC FRONTIER NOT TOO DIFFERENT IN SPIRIT FROM LAMARCK'S OBSERVATIONS CENTURIES AGO. 2015 14 2568 24 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022 15 1676 35 DRUG ADDICTION: FROM BENCH TO BEDSIDE. DRUG ADDICTION IS RESPONSIBLE FOR MILLIONS OF DEATHS PER YEAR AROUND THE WORLD. STILL, ITS MANAGEMENT AS A CHRONIC DISEASE IS SHADOWED BY MISCONCEPTIONS FROM THE GENERAL PUBLIC. INDEED, DRUG CONSUMERS ARE OFTEN LABELLED AS "WEAK", "IMMORAL" OR "DEPRAVED". CONSEQUENTLY, DRUG ADDICTION IS OFTEN PERCEIVED AS AN INDIVIDUAL PROBLEM AND NOT SOCIETAL. IN TECHNICAL TERMS, DRUG ADDICTION IS DEFINED AS A CHRONIC, RELAPSING DISEASE RESULTING FROM SUSTAINED EFFECTS OF DRUGS ON THE BRAIN. THROUGH A BETTER CHARACTERISATION OF THE CEREBRAL CIRCUITS INVOLVED, AND THE LONG-TERM MODIFICATIONS OF THE BRAIN INDUCED BY ADDICTIVE DRUGS ADMINISTRATIONS, FIRST, WE MIGHT BE ABLE TO CHANGE THE WAY THE GENERAL PUBLIC SEE THE PATIENT WHO IS SUFFERING FROM DRUG ADDICTION, AND SECOND, WE MIGHT BE ABLE TO FIND NEW TREATMENTS TO NORMALISE THE ALTERED BRAIN HOMEOSTASIS. IN THIS REVIEW, WE SYNTHETISE THE CONTRIBUTION OF FUNDAMENTAL RESEARCH TO THE UNDERSTANDING DRUG ADDICTION AND ITS CONTRIBUTION TO POTENTIAL NOVEL THERAPEUTICS. MOSTLY BASED ON DRUG-INDUCED MODIFICATIONS OF SYNAPTIC PLASTICITY AND EPIGENETIC MECHANISMS (AND THEIR BEHAVIOURAL CORRELATES) AND AFTER DEMONSTRATION OF THEIR REVERSIBILITY, WE TRIED TO HIGHLIGHT PROMISING THERAPEUTICS. WE ALSO UNDERLINE THE SPECIFIC TEMPORAL DYNAMICS AND PSYCHOSOCIAL ASPECTS OF THIS COMPLEX PSYCHIATRIC DISEASE ADDING PARAMETERS TO BE CONSIDERED IN CLINICAL TRIALS AND PAVING THE WAY TO TEST NEW THERAPEUTIC VENUES. 2021 16 3002 24 GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS FOR TREATMENT OF MAJOR DEPRESSION: THE 5-HT1A RECEPTOR GENE AS A PARADIGM. MAJOR DEPRESSION AND ANXIETY ARE HIGHLY PREVALENT AND INVOLVE CHRONIC DYSREGULATION OF SEROTONIN, BUT THEY REMAIN POORLY UNDERSTOOD. HERE, WE REVIEW NOVEL TRANSCRIPTIONAL (GENETIC, EPIGENETIC) AND POSTTRANSCRIPTIONAL (MICRORNA, ALTERNATIVE SPLICING) MECHANISMS IMPLICATED IN MENTAL ILLNESS, FOCUSING ON A KEY SEROTONIN-RELATED REGULATOR, THE SEROTONIN 1A (5-HT1A) RECEPTOR. FUNCTIONAL SINGLE-NUCLEOTIDE POLYMORPHISMS AND STRESS-INDUCED DNA METHYLATION OF THE 5-HT1A PROMOTER CONVERGE TO DIFFERENTIALLY ALTER PRE- AND POSTSYNAPTIC 5-HT1A RECEPTOR EXPRESSION ASSOCIATED WITH MAJOR DEPRESSION AND REDUCED THERAPEUTIC RESPONSE TO SEROTONERGIC ANTIDEPRESSANTS. MAJOR DEPRESSION IS ALSO ASSOCIATED WITH ALTERED LEVELS OF SPLICE FACTORS AND MICRORNA, POSTTRANSCRIPTIONAL MECHANISMS THAT REGULATE RNA STABILITY. THE HUMAN 5-HT1A 3'-UNTRANSLATED REGION IS ALTERNATIVELY SPLICED, REMOVING MICRORNA SITES AND INCREASING 5-HT1A EXPRESSION, WHICH IS REDUCED IN MAJOR DEPRESSION AND MAY BE GENOTYPE-DEPENDENT. THUS, THE 5-HT1A RECEPTOR GENE ILLUSTRATES THE CONVERGENCE OF GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS IN GENE EXPRESSION, NEURODEVELOPMENT AND NEUROPLASTICITY, AND MAJOR DEPRESSION. UNDERSTANDING GENE REGULATORY MECHANISMS COULD ENHANCE THE DETECTION, CATEGORIZATION AND PERSONALIZED TREATMENT OF MAJOR DEPRESSION. 2019 17 257 30 ADVANCES IN ONCOANAESTHESIA AND CANCER PAIN. INTRODUCTION: THE GROWING INTEREST ON HOW PERI-?OPERATIVE INTERVENTIONS, ESPECIALLY REGIONAL ANESTHESIA, DURING CANCER SURGERY CAN ALTER ONCOLOGICAL OUTCOME INCREASING DISEASE FREE SURVIVAL IS PROBABLY RESPONSIBLE FOR THE BIRTH OF THE NEW SUBSPECIALTY CALLED ONCO-ANESTHESIA. A PARADIGM SHIFT IN THE CONCEPT OF ANESTHETIC MANAGEMENT HAS OCCURRED RECENTLY OWING TO THE INNUMERABLE DIVERSE REVELATIONS FROM THE ONGOING RESEARCH IN THIS FIELD. DISCUSSION: LONG LASTING BUT REVERSIBLE EPIGENETIC CHANGES CAN OCCUR DUE TO SURGICAL STRESS AND PERIOPERATIVE ANESTHETIC MEDICATIONS. THE EXACT RELATIONSHIP BETWEEN THESE FACTORS AND TUMOR BIOLOGY IS BEING STUDIED FURTHER. A POPULAR TOPIC UNDER RESEARCH NOW IS THE INFLUENCE OF REGIONAL ANESTHESIA ON CANCER RECURRENCE. COMBINING NERVE BLOCKS WITH TOTAL INTRAVENOUS ANESTHESIA (TIVA) BRINGS DOWN THE REQUIREMENT OF OPIOIDS AND VOLATILE ANESTHETIC AGENTS IMPLICATED IN CANCER RECURRENCE. THE STUDY OF MECHANISM OF PAIN AT THE MOLECULAR LEVEL HAS LED TO THE DISCOVERY OF NOVEL MODES OF PREVENTION OF CHRONIC POST-SURGICAL PAIN. NEWER COMBINATION AGGRESSIVE TREATMENT THERAPIES -INTRAOPERATIVE CHEMOTHERAPY AND RADIOTHERAPY, ISOLATED LIMB PERFUSION, PHOTODYNAMIC THERAPY AND ROBOTIC SURGERY REQUIRE SPECIALIZED ANESTHETIC MANAGEMENT. THE COVID PANDEMIC INTRODUCED NEW GUIDELINES FOR SAFE MANAGEMENT OF ONCOSURGICAL PATIENTS .USE OF GENOMIC MAPPING TO PERSONALIZE PAIN MANAGEMENT WILL BE THE BREAKTHROUGH OF THE DECADE. CONCLUSION: THE DISCOVERY THAT ANESTHETIC STRATEGY COULD HAVE SIGNIFICANT ONCOLOGICAL SEQUEL IS A QUANTUM LEAP FORWARD. AVOIDING SOME ANESTHETIC MEDICATIONS MAY DECREASE CANCER RECURRENCE. COMPREHENSIVE CANCER CARE AND TRANSLATIONAL RESEARCH WILL PAVE THE WAY TO UNCOVER SAFE ANESTHETIC PRACTICES. 2021 18 856 21 CHROMATIN ACCESSIBILITY MAPPING OF THE STRIATUM IDENTIFIES TYROSINE KINASE FYN AS A THERAPEUTIC TARGET FOR HEROIN USE DISORDER. THE CURRENT OPIOID EPIDEMIC NECESSITATES A BETTER UNDERSTANDING OF HUMAN ADDICTION NEUROBIOLOGY TO DEVELOP EFFICACIOUS TREATMENT APPROACHES. HERE, WE PERFORM GENOME-WIDE ASSESSMENT OF CHROMATIN ACCESSIBILITY OF THE HUMAN STRIATUM IN HEROIN USERS AND MATCHED CONTROLS. OUR STUDY REVEALS DISTINCT NEURONAL AND NON-NEURONAL EPIGENETIC SIGNATURES, AND IDENTIFIES A LOCUS IN THE PROXIMITY OF THE GENE ENCODING TYROSINE KINASE FYN AS THE MOST AFFECTED REGION IN NEURONS. FYN EXPRESSION, KINASE ACTIVITY AND THE PHOSPHORYLATION OF ITS TARGET TAU ARE INCREASED BY HEROIN USE IN THE POST-MORTEM HUMAN STRIATUM, AS WELL AS IN RATS TRAINED TO SELF-ADMINISTER HEROIN AND PRIMARY STRIATAL NEURONS TREATED WITH CHRONIC MORPHINE IN VITRO. PHARMACOLOGICAL OR GENETIC MANIPULATION OF FYN ACTIVITY SIGNIFICANTLY ATTENUATES HEROIN SELF-ADMINISTRATION AND RESPONDING FOR DRUG-PAIRED CUES IN RODENTS. OUR FINDINGS SUGGEST THAT STRIATAL FYN IS AN IMPORTANT DRIVER OF HEROIN-RELATED NEURODEGENERATIVE-LIKE PATHOLOGY AND DRUG-TAKING BEHAVIOR, MAKING FYN A PROMISING THERAPEUTIC TARGET FOR HEROIN USE DISORDER. 2020 19 6130 26 THE EPIGENETIC REGULATION OF THE OPIOID SYSTEM: NEW INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. THE MOST WELL-KNOWN PHYSIOLOGICAL EFFECT ASSOCIATED WITH OPIOD SYSTEM IS THEIR EFFICACY IN PAIN REDUCTION OR ANALGESIA, ALTHOUGH THEIR EFFECT ON A VARIETY OF OTHER PHYSIOLOGICAL AND PHYSIOPHOLOGICAL FUNCTIONS HAS BECOME APPARENT IN RECENT YEARS. THIS REVIEW IS AN ATTEMPT TO CLARIFY IN MORE DETAIL THE EPIGENETIC REGULATION OF OPIOID SYSTEM TO UNDERSTAND WITH MORE PRECISION THEIR TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION IN MULTIPLE PYISIOLOGICAL AND PHARMACOLOGICAL CONTEXTS. THE OPIOID RECEPTORS SHOW AN EPIGENETIC REGULATION AND OPIOID PEPTIDE PRECURSORS BY METHYLATION, CHROMATIN REMODELING AND MICRORNA. ALTHOUGH THE OPIOID RECEPTOR PROMOTERS HAVE SIMILARITY BETWEEN THEM, THEY USE DIFFERENT EPIGENETIC REGULATION FORMS AND THEY EXHIBIT DIFFERENT PATTERN OF EXPRESSION DURING THE CELL DIFFERENTIATION. DNA METHYLATION IS ALSO CONFIRMED IN OPIOID PEPTIDE PRECURSORS, BEING IMPORTANT FOR GENE EXPRESSION AND TISSUE SPECIFICITY. UNDERSTANDING THE EPIGENETIC BASIS OF THOSE PHYSIOLOGICAL AND PHYSIOPATHOLOGICAL PROCESESS IS ESSENTIAL FOR THE DEVELOPMENT OF INDIVIDUALIZED PROMPT PREVENTION AND TREATMENT STRATEGIES. 2015 20 78 23 A NEW MECHANISTIC APPROACH FOR THE TREATMENT OF CHRONIC NEUROPATHIC PAIN WITH NITROUS OXIDE INTEGRATED FROM A SYSTEMS BIOLOGY NARRATIVE REVIEW. THE LIMITATIONS OF THE CURRENTLY AVAILABLE TREATMENTS FOR CHRONIC NEUROPATHIC PAIN HIGHLIGHT THE NEED FOR SAFER AND MORE EFFECTIVE ALTERNATIVES. THE AUTHORS CARRIED OUT A FOCUSED REVIEW USING A SYSTEMS BIOLOGY APPROACH TO INTEGRATE THE COMPLEX MECHANISMS OF NOCICEPTION AND NEUROPATHIC PAIN, AND TO DECIPHER THE EFFECTS OF NITROUS OXIDE (N(2)O) ON THOSE PATHWAYS, BEYOND THE KNOWN EFFECT OF N(2)O ON N-METHYL-D-ASPARTATE RECEPTORS. THIS REVIEW IDENTIFIED A NUMBER OF POTENTIAL MECHANISMS BY WHICH N(2)O COULD IMPACT THE PROCESSES INVOLVED IN PERIPHERAL AND CENTRAL SENSITIZATION. IN THE ASCENDING PATHWAY, THE EFFECTS OF N(2)O INCLUDE ACTIVATING TWIK-RELATED K(+) CHANNEL 1 POTASSIUM CHANNELS ON FIRST-ORDER NEURONS, BLOCKING VOLTAGE-DEPENDENT CALCIUM CHANNELS TO ATTENUATE NEURONAL EXCITABILITY, ATTENUATING POSTSYNAPTIC GLUTAMATERGIC RECEPTOR ACTIVATION, AND POSSIBLY BLOCKING VOLTAGE-DEPENDENT SODIUM CHANNELS. IN THE DESCENDING PATHWAY, N(2)O INDUCES THE RELEASE OF ENDOGENOUS OPIOID LIGANDS AND STIMULATES NOREPINEPHRINE RELEASE. IN ADDITION, N(2)O MAY MEDIATE EPIGENETIC CHANGES BY INHIBITING METHIONINE SYNTHASE, A KEY ENZYME INVOLVED IN DNA AND RNA METHYLATION. THIS COULD EXPLAIN WHY THIS SHORT-ACTING ANALGESIC HAS SHOWN LONG-LASTING ANTI-PAIN SENSITIZATION EFFECTS IN ANIMAL MODELS OF CHRONIC PAIN. THESE NEW HYPOTHESES SUPPORT THE RATIONALE FOR INVESTIGATING N(2)O, EITHER ALONE OR IN COMBINATION WITH OTHER ANALGESICS, FOR THE MANAGEMENT OF CHRONIC NEUROPATHIC PAIN. 2021