1 4608 143 NEONATAL ANESTHESIA AND DYSREGULATION OF THE EPIGENOMEDAGGER. EACH YEAR, MILLIONS OF INFANTS AND CHILDREN ARE ANESTHETIZED FOR MEDICAL AND SURGICAL PROCEDURES. YET, A SUBSTANTIAL BODY OF PRECLINICAL EVIDENCE SUGGESTS THAT ANESTHETICS ARE NEUROTOXINS THAT CAUSE RAPID AND WIDESPREAD APOPTOTIC CELL DEATH IN THE BRAINS OF INFANT RODENTS AND NONHUMAN PRIMATES. THESE ANIMALS HAVE PERSISTENT IMPAIRMENTS IN COGNITION AND BEHAVIOR MANY WEEKS OR MONTHS AFTER ANESTHESIA EXPOSURE, LEADING US TO HYPOTHESIZE THAT ANESTHETICS DO MORE THAN SIMPLY KILL BRAIN CELLS. INDEED, ANESTHETICS CAUSE CHRONIC NEUROPATHOLOGY IN NEURONS THAT SURVIVE THE INSULT, WHICH THEN INTERFERES WITH MAJOR ASPECTS OF BRAIN DEVELOPMENT, SYNAPTIC PLASTICITY, AND NEURONAL FUNCTION. UNDERSTANDING THE PHENOMENON OF ANESTHESIA-INDUCED DEVELOPMENTAL NEUROTOXICITY IS OF CRITICAL PUBLIC HEALTH IMPORTANCE BECAUSE CLINICAL STUDIES NOW REPORT THAT ANESTHESIA IN HUMAN INFANCY IS ASSOCIATED WITH COGNITIVE AND BEHAVIORAL DEFICITS. IN OUR SEARCH FOR MECHANISTIC EXPLANATIONS FOR WHY A YOUNG AND PLIABLE BRAIN CANNOT FULLY RECOVER FROM A RELATIVELY BRIEF PERIOD OF ANESTHESIA, WE HAVE ACCUMULATED EVIDENCE THAT NEONATAL ANESTHESIA CAN DYSREGULATE EPIGENETIC TAGS THAT INFLUENCE GENE TRANSCRIPTION SUCH AS HISTONE ACETYLATION AND DNA METHYLATION. IN THIS REVIEW, WE BRIEFLY SUMMARIZE THE PHENOMENON OF ANESTHESIA-INDUCED DEVELOPMENTAL NEUROTOXICITY. WE THEN DISCUSS CHRONIC NEUROPATHOLOGY CAUSED BY NEONATAL ANESTHESIA, INCLUDING DISTURBANCES IN COGNITION, SOCIO-AFFECTIVE BEHAVIOR, NEURONAL MORPHOLOGY, AND SYNAPTIC PLASTICITY. FINALLY, WE PRESENT EVIDENCE OF ANESTHESIA-INDUCED GENETIC AND EPIGENETIC DYSREGULATION WITHIN THE DEVELOPING BRAIN THAT MAY BE TRANSMITTED INTERGENERATIONALLY TO ANESTHESIA-NAIVE OFFSPRING. 2021 2 257 24 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 3 4532 27 MULTIMODAL ANALGESIA FOR PERIOPERATIVE MANAGEMENT OF PATIENTS PRESENTING FOR SPINAL SURGERY. MULTIMODAL, NON-OPIOID BASED ANALGESIA HAS BECOME THE CORNERSTONE OF ERAS PROTOCOLS FOR EFFECTIVE ANALGESIA AFTER SPINAL SURGERY. OPIOID SIDE EFFECTS, DEPENDENCE AND LEGISLATION RESTRICTING LONG TERM OPIOID USE HAS LED TO A RESURGENCE IN INTEREST IN OPIOID SPARING TECHNIQUES. THE INCREASING ARRAY OF MULTIMODAL OPIOID SPARING ANALGESICS AVAILABLE FOR SPINAL SURGERY TARGETING NOVEL RECEPTORS, TRANSMITTERS, AND ALTERING EPIGENETICS CAN HELP PROVIDE AN OPTIMAL PERIOPERATIVE EXPERIENCE WITH LESS OPIOID SIDE EFFECTS AND LONG-TERM DEPENDENCE. EPIGENETIC MECHANISMS OF PAIN MAY ENHANCE OR SUPPRESS GENE EXPRESSION, WITHOUT ALTERING THE GENOME ITSELF. SUCH MECHANISMS ARE COMPLEX, DYNAMIC AND RESPONSIVE TO ENVIRONMENT. ALTERATIONS THAT OCCUR CAN AFFECT THE PATHOPHYSIOLOGY OF PAIN MANAGEMENT AT A DNA LEVEL, MODIFYING PERCEIVED PAIN RELIEF. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETICS OF PAIN, SYSTEMIC LOCAL ANESTHETICS AND NEURAXIAL TECHNIQUES THAT CONTINUE TO REMAIN USEFUL FOR SPINAL SURGERY, NEUROPATHIC AGENTS, AS WELL AS OTHER COMMON AND LESS COMMON TARGET RECEPTORS FOR A TRULY MULTIMODAL APPROACH TO PERIOPERATIVE PAIN MANAGEMENT. 2019 4 2924 34 GENERAL ANESTHETIC NEUROTOXICITY IN THE YOUNG: MECHANISM AND PREVENTION. GENERAL ANESTHESIA (GA) IS USUALLY CONSIDERED TO SAFELY INDUCE A REVERSIBLE UNCONSCIOUS STATE ALLOWING SURGERY TO BE PERFORMED WITHOUT PAIN. A GROWING NUMBER OF STUDIES, IN PARTICULAR PRE-CLINICAL STUDIES, HOWEVER, DEMONSTRATE THAT GENERAL ANESTHETICS CAN CAUSE NEURONAL DEATH AND EVEN LONG-TERM NEUROLOGICAL DEFICITS. HEREIN, WE REPORT OUR LITERATURE REVIEW AND META-ANALYSIS DATA OF THE NEUROLOGICAL OUTCOMES AFTER ANESTHESIA IN THE YOUNG. WE ALSO REVIEW AVAILABLE MECHANISTIC AND EPIGENETIC DATA OF GA EXPOSURE RELATED TO COGNITIVE IMPAIRMENT PER SE AND THE POTENTIAL PREVENTIVE STRATEGIES INCLUDING NATURAL HERBAL COMPOUNDS TO ATTENUATE THOSE SIDE EFFECTS. IN SUMMARY, ANESTHETIC-INDUCED NEUROTOXICITY MAY BE TREATABLE AND NATURAL HERBAL COMPOUNDS AND OTHER MEDICATIONS MAY HAVE GREAT POTENTIAL FOR SUCH USE BUT WARRANTS FURTHER STUDY BEFORE CLINICAL APPLICATIONS CAN BE INITIATED. 2019 5 6838 31 [INTRODUCTION OF TRANSLATIONAL RESEARCH IN OMICS SCIENCE TO CLINICAL ANESTHESIA]. MUCH PROGRESS HAS BEEN MADE IN OMICS RESEARCH FOLLOWING COMPLETION OF THE HUMAN GENOME PROJECT. THIS COMPREHENSIVE ANALYSIS PRODUCED A NEW DISCIPLINE (I.E., BIOINFORMATICS), AND ITS FINDINGS CONTRIBUTED TO THE CLINICAL PRACTICE OF ANESTHESIOLOGY. GENOMES OF PATIENTS SHOW GENETIC VARIATIONS AND MAY PREDICT THE SENSITIVITY TO ANESTHETICS AND ANALGESICS, INCIDENCE OF ADVERSE EFFECTS, AND INTENSITY OF POSTSURGICAL PAIN. CHANGES IN THE TRANSCRIPTOMES OF PATIENTS MAY ALSO REFLECT ANESTHESIA-RELATED EXPRESSION PROFILES OF VARIOUS TYPES OF NEURONS IN THE BRAIN, AND INFORMATION ON SUCH CHANGES MAY CONTRIBUTE TO MOLECULAR TARGETED THERAPY IN ANESTHETIZED PATIENTS. IN ADDITION, NOVEL EPIGENOME RESEARCH MAY EXPLAIN WHY ENVIRONMENTS CHANGE THE PHENOTYPES OF CLINICAL ANESTHESIA. WE CURRENTLY HYPOTHESIZE THAT FEMALE GENDER IS ASSOCIATED WITH DNA METHYLATION IN PAIN-RELATED AND VOMITING-RELATED GENE PROMOTER REGIONS AT THE GENOME-WIDE LEVEL AND THAT EPIGENETIC MECHANISMS ARE INVOLVED IN GENDER DIFFERENCES IN ANESTHESIA PRACTICE. 2013 6 6805 28 [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 7 3880 20 KETAMINE: REPURPOSING AND REDEFINING A MULTIFACETED DRUG. THIS SHORT REVIEW WILL HIGHLIGHT RECENT CLINICAL AND BASIC RESEARCH THAT SUPPORTS THE THERAPEUTIC UTILITY OF KETAMINE AS A RAPID-ACTING, LIFE-SAVING ANTIDEPRESSANT AND A VERSATILE ANALGESIC. AFTER 50 YEARS OF USE AS A DISSOCIATIVE ANESTHETIC AND MISUSE AS A STREET DRUG, KETAMINE HAS RE-EMERGED AS A USEFUL OFF-LABEL AGENT FOR AMELIORATING VARIOUS TYPES OF PAIN AND RESISTANT DEPRESSION. IN ADDITION TO ITS ABILITY TO INHIBIT N-METHYL-D-ASPARTATE (NMDA) RECEPTORS, THE DIVERSE ACTIONS OF KETAMINE MIGHT INVOLVE EPIGENETIC MECHANISMS SUCH AS MICRORNA REGULATION. THUS, KETAMINE IS TRANSITIONING FROM BEING THE PHARMACOLOGIST'S NIGHTMARE TO ONE OF THE MOST INTERESTING DEVELOPMENTS IN THE PHARMACOLOGY OF DEPRESSION AND PAIN. 2014 8 6185 25 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 1692 31 DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA AT DELIVERY, DNA METHYLATION IN UMBILICAL CORD BLOOD AND THEIR ASSOCIATION WITH OFFSPRING ASTHMA IN NON-HISPANIC BLACK WOMEN. EPIDURAL ANESTHESIA IS AN EFFECTIVE PAIN RELIEF MODALITY, WIDELY USED FOR LABOR ANALGESIA. CHILDHOOD ASTHMA IS ONE OF THE COMMONEST CHRONIC MEDICAL ILLNESSES IN THE USA WHICH PLACES A SIGNIFICANT BURDEN ON THE HEALTH-CARE SYSTEM. WE RECENTLY DEMONSTRATED A NEGATIVE ASSOCIATION BETWEEN THE DURATION OF EPIDURAL ANESTHESIA AND THE DEVELOPMENT OF CHILDHOOD ASTHMA; HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS STILL REMAIN UNCLEAR. IN THIS STUDY OF 127 MOTHER-CHILD PAIRS COMPRISED OF 75 NON-HISPANIC BLACK (NHB) AND 52 NON-HISPANIC WHITE (NHW) FROM THE NEWBORN EPIGENETIC STUDY, WE TESTED THE HYPOTHESIS THAT UMBILICAL CORD BLOOD DNA METHYLATION MEDIATES THE ASSOCIATION BETWEEN THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA AT DELIVERY AND THE DEVELOPMENT OF CHILDHOOD ASTHMA AND WHETHER THIS DIFFERED BY RACE/ETHNICITY. IN THE MOTHER-CHILD PAIRS OF NHB ANCESTRY, THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA WAS ASSOCIATED WITH A MARGINALLY LOWER RISK OF ASTHMA (ODDS RATIO = 0.88, 95% CONFIDENCE INTERVAL = 0.76-1.01) FOR EACH 1-H INCREASE IN EXPOSURE TO EPIDURAL ANESTHESIA. OF THE 20 CPGS IN THE NHB POPULATION SHOWING THE STRONGEST MEDIATION EFFECT, 50% DEMONSTRATED AN AVERAGE MEDIATION PROPORTION OF 52%, WITH DIRECTIONAL CONSISTENCY OF DIRECT AND INDIRECT EFFECTS. THESE TOP 20 CPGS MAPPED TO 21 GENES ENRICHED FOR PATHWAYS ENGAGED IN ANTIGEN PROCESSING, ANTIGEN PRESENTATION, PROTEIN UBIQUITINATION AND REGULATORY NETWORKS RELATED TO THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I COMPLEX AND NUCLEAR FACTOR KAPPA-B (NFKB) COMPLEX. OUR FINDINGS SUGGEST THAT DNA METHYLATION IN IMMUNE-RELATED PATHWAYS CONTRIBUTES TO THE EFFECTS OF THE DURATION OF EXPOSURE TO EPIDURAL ANESTHESIA ON CHILDHOOD ASTHMA RISK IN NHB OFFSPRING. 2023 10 4418 28 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 11 4850 31 OPIOIDS AND OPIOID RECEPTORS; UNDERSTANDING PHARMACOLOGICAL MECHANISMS AS A KEY TO THERAPEUTIC ADVANCES AND MITIGATION OF THE MISUSE CRISIS. OPIOIDS ARE A MAINSTAY IN ACUTE PAIN MANAGEMENT AND PRODUCE THEIR EFFECTS AND SIDE EFFECTS (E.G., TOLERANCE, OPIOID-USE DISORDER AND IMMUNE SUPPRESSION) BY INTERACTION WITH OPIOID RECEPTORS. I WILL DISCUSS OPIOID PHARMACOLOGY IN SOME CONTROVERSIAL AREAS OF ENQUIRY OF ANAESTHETIC RELEVANCE. THE MAIN OPIOID TARGET IS THE MICRO (MU,MOP) RECEPTOR BUT OTHER MEMBERS OF THE OPIOID RECEPTOR FAMILY, DELTA (DELTA; DOP) AND KAPPA (KAPPA; KOP) OPIOID RECEPTORS ALSO PRODUCE ANALGESIC ACTIONS. THESE ARE NALOXONE-SENSITIVE. THERE IS IMPORTANT CLINICAL DEVELOPMENT RELATING TO THE NOCICEPTIN/ORPHANIN FQ (NOP) RECEPTOR, AN OPIOID RECEPTOR THAT IS NOT NALOXONE-SENSITIVE. BETTER UNDERSTANDING OF THE DRIVERS FOR OPIOID EFFECTS AND SIDE EFFECTS MAY FACILITATE SEPARATION OF SIDE EFFECTS AND PRODUCTION OF SAFER DRUGS. OPIOIDS BIND TO THE RECEPTOR ORTHOSTERIC SITE TO PRODUCE THEIR EFFECTS AND CAN ENGAGE MONOMER OR HOMO-, HETERODIMER RECEPTORS. SOME LIGANDS CAN DRIVE ONE INTRACELLULAR PATHWAY OVER ANOTHER. THIS IS THE BASIS OF BIASED AGONISM (OR FUNCTIONAL SELECTIVITY). OPIOID ACTIONS AT THE ORTHOSTERIC SITE CAN BE MODULATED ALLOSTERICALLY AND POSITIVE ALLOSTERIC MODULATORS THAT ENHANCE OPIOID ACTION ARE IN DEVELOPMENT. AS WELL AS TARGETING LIGAND-RECEPTOR INTERACTION AND TRANSDUCTION, MODULATING RECEPTOR EXPRESSION AND HENCE FUNCTION IS ALSO TRACTABLE. THERE IS EVIDENCE FOR EPIGENETIC ASSOCIATIONS WITH DIFFERENT TYPES OF PAIN AND ALSO SUBSTANCE MISUSE. AS LONG AS THE OPIOID NARRATIVE IS DEFINED BY THE 'OPIOID CRISIS' THE DRIVE TO REMOVE THEM COULD GATHER PACE. THIS WILL DENY USE WHERE THEY ARE EFFECTIVE, AND ACCESS TO MORPHINE FOR PAIN RELIEF IN LOW INCOME COUNTRIES. 2023 12 5447 33 REPOSITIONING LIDOCAINE AS AN ANTICANCER DRUG: THE ROLE BEYOND ANESTHESIA. WHILE CANCER TREATMENT HAS IMPROVED DRAMATICALLY, IT HAS ALSO ENCOUNTERED MANY CRITICAL CHALLENGES, SUCH AS DISEASE RECURRENCE, METASTASIS, AND DRUG RESISTANCE, MAKING NEW DRUGS WITH NOVEL MECHANISMS AN URGENT CLINICAL NEED. THE TERM "DRUG REPOSITIONING," ALSO KNOWN AS OLD DRUGS FOR NEW USES, HAS EMERGED AS ONE PRACTICAL STRATEGY TO DEVELOP NEW ANTICANCER DRUGS. ANESTHETICS HAVE BEEN WIDELY USED IN SURGICAL PROCEDURES TO REDUCE THE EXCRUCIATING PAIN. LIDOCAINE, ONE OF THE MOST-USED LOCAL ANESTHETICS IN CLINICAL SETTINGS, HAS BEEN FOUND TO SHOW MULTI-ACTIVITIES, INCLUDING POTENTIAL IN CANCER TREATMENT. GROWING EVIDENCE SHOWS THAT LIDOCAINE MAY NOT ONLY WORK AS A CHEMOSENSITIZER THAT SENSITIZES OTHER CONVENTIONAL CHEMOTHERAPEUTICS TO CERTAIN RESISTANT CANCER CELLS, BUT ALSO COULD SUPPRESS CANCER CELLS GROWTH BY SINGLE USE AT DIFFERENT DOSES OR CONCENTRATIONS. LIDOCAINE COULD SUPPRESS CANCER CELL GROWTH IN VITRO AND IN VIVO VIA MULTIPLE MECHANISMS, SUCH AS REGULATING EPIGENETIC CHANGES AND PROMOTING PRO-APOPTOSIS PATHWAYS, AS WELL AS REGULATING ABC TRANSPORTERS, METASTASIS, AND ANGIOGENESIS, ETC., PROVIDING VALUABLE INFORMATION FOR ITS FURTHER APPLICATION IN CANCER TREATMENT AND FOR NEW DRUG DISCOVERY. IN ADDITION, LIDOCAINE IS NOW UNDER CLINICAL TRIALS TO TREAT CERTAIN TYPES OF CANCER. IN THE CURRENT REVIEW, WE SUMMARIZE THE RESEARCH AND ANALYZE THE UNDERLYING MECHANISMS, AND ADDRESS KEY ISSUES IN THIS AREA. 2020 13 4645 23 NEUROPATHIC PAIN: FROM MECHANISMS TO TREATMENT. NEUROPATHIC PAIN CAUSED BY A LESION OR DISEASE OF THE SOMATOSENSORY NERVOUS SYSTEM IS A COMMON CHRONIC PAIN CONDITION WITH MAJOR IMPACT ON QUALITY OF LIFE. EXAMPLES INCLUDE TRIGEMINAL NEURALGIA, PAINFUL POLYNEUROPATHY, POSTHERPETIC NEURALGIA, AND CENTRAL POSTSTROKE PAIN. MOST PATIENTS COMPLAIN OF AN ONGOING OR INTERMITTENT SPONTANEOUS PAIN OF, FOR EXAMPLE, BURNING, PRICKING, SQUEEZING QUALITY, WHICH MAY BE ACCOMPANIED BY EVOKED PAIN, PARTICULAR TO LIGHT TOUCH AND COLD. ECTOPIC ACTIVITY IN, FOR EXAMPLE, NERVE-END NEUROMA, COMPRESSED NERVES OR NERVE ROOTS, DORSAL ROOT GANGLIA, AND THE THALAMUS MAY IN DIFFERENT CONDITIONS UNDERLIE THE SPONTANEOUS PAIN. EVOKED PAIN MAY SPREAD TO NEIGHBORING AREAS, AND THE UNDERLYING PATHOPHYSIOLOGY INVOLVES PERIPHERAL AND CENTRAL SENSITIZATION. MALADAPTIVE STRUCTURAL CHANGES AND A NUMBER OF CELL-CELL INTERACTIONS AND MOLECULAR SIGNALING UNDERLIE THE SENSITIZATION OF NOCICEPTIVE PATHWAYS. THESE INCLUDE ALTERATION IN ION CHANNELS, ACTIVATION OF IMMUNE CELLS, GLIAL-DERIVED MEDIATORS, AND EPIGENETIC REGULATION. THE MAJOR CLASSES OF THERAPEUTICS INCLUDE DRUGS ACTING ON ALPHA(2)DELTA SUBUNITS OF CALCIUM CHANNELS, SODIUM CHANNELS, AND DESCENDING MODULATORY INHIBITORY PATHWAYS. 2021 14 2571 35 EPIGENETICS OF CHRONIC PAIN AFTER THORACIC SURGERY. PURPOSE OF REVIEW: CHRONIC PAIN AFTER SURGERY IS A MAJOR PUBLIC HEALTH PROBLEM AND A MAJOR CONCERN FOR PERIOPERATIVE PHYSICIANS. THORACIC SURGERY PRESENTS A UNIQUE CHALLENGE, AS THORACOTOMY IS AMONG THE HIGHEST RISK SURGERIES TO DEVELOP PERSISTENT POSTSURGICAL PAIN. THE PURPOSE OF THIS REVIEW IS TO DISCUSS THE RELEVANCE OF RESEARCH IN PAIN EPIGENETICS TO PATIENTS WITH PERSISTENT PAIN AFTER THORACIC SURGERY. RECENT FINDINGS: RECENT ADVANCES HAVE LINKED CHRONIC PAIN STATES TO GENETIC AND EPIGENETIC CHANGES. PROGRESS IN OUR UNDERSTANDING OF CHRONIC PAIN HAS HIGHLIGHTED THE IMPORTANCE OF IMMUNE MODULATION OF PAIN. IT IS POSSIBLE THAT EPIGENETIC CHANGES DRIVING CHRONIC PAIN OCCUR IN THE PERIOPERATIVE SETTING VIA HISTONE MODIFICATION AND DNA METHYLATION. SUMMARY: THE TRANSITION FROM ACUTE TO CHRONIC PAIN AFTER THORACIC SURGERY MAY BE MEDIATED BY EPIGENETICS. HERE, WE DISCUSS EPIGENETIC MODIFICATIONS THAT HAVE BEEN DISCOVERED IN ANIMAL MODELS OF CHRONIC PAIN THAT MAY PREDISPOSE PATIENTS TO PERSISTENT NEUROPATHIC PAIN AFTER THORACIC SURGERY. 2014 15 6617 35 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS. 2020 16 3571 29 IMPACT OF LOCAL ANESTHETICS ON EPIGENETICS IN CANCER. DEFECTIVE SILENCING OF TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC ALTERATIONS CONTRIBUTES TO ONCOGENESIS BY PERTURBING CELL CYCLE REGULATION, DNA REPAIR OR CELL DEATH MECHANISMS. REVERSAL OF SUCH EPIGENETIC CHANGES INCLUDING DNA HYPERMETHYLATION PROVIDES A PROMISING ANTICANCER STRATEGY. UNTIL NOW, THE NUCLEOSIDE DERIVATIVES 5-AZACYTIDINE AND DECITABINE ARE THE SOLE DNA METHYLTRANSFERASE (DNMT) INHIBITORS APPROVED BY THE FDA FOR THE TREATMENT OF SPECIFIC HEMATOLOGICAL CANCERS. NEVERTHELESS, DUE TO THEIR NUCLEOSIDE STRUCTURE, THESE INHIBITORS DIRECTLY INCORPORATE INTO DNA, WHICH LEADS TO SEVERE SIDE EFFECTS AND COMPROMISES GENOMIC STABILITY. MUCH EMPHASIS HAS BEEN PLACED ON THE DEVELOPMENT OF LESS TOXIC EPIGENETIC MODIFIERS. RECENTLY, SEVERAL PRECLINICAL STUDIES DEMONSTRATED THE POTENT EPIGENETIC EFFECTS OF LOCAL ANESTHETICS, WHICH ARE ROUTINELY USED DURING PRIMARY TUMOR RESECTION TO RELIEF SURGICAL PAIN. THESE NON-NUCLEOSIDE MOLECULES INHIBIT DNMT ACTIVITY, AFFECT THE EXPRESSION OF MICRO-RNAS AND REPRESS HISTONE ACETYLATION, THUS EXERTING CYTOTOXIC EFFECTS ON MALIGNANT CELLS. THE IN-DEPTH MECHANISTIC COMPREHENSION OF THESE EPIGENETIC EFFECTS MIGHT PROMOTE THE USE OF LOCAL ANESTHETICS AS ANTICANCER DRUGS. 2022 17 3010 33 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 18 78 27 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 19 2841 32 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 20 5876 31 SYNAPTIC PLASTICITY AND PAIN AVERSION. NEGATIVE AFFECTIVE EMOTIONS ARE DEFINED AS THE CONCEPTUAL FEATURE OF PAIN. A NUMBER OF CLINICAL AND ANIMAL STUDIES HAVE INDICATED THAT THE LIMBIC SYSTEM INCLUDING THE ANTERIOR CINGULATE CORTEX (ACC) AND AMYGDALA PLAYS A CRITICAL ROLE IN THE PROCESSING OF AFFECTIVE COMPONENTS OF PAIN. GLUTAMATERGIC TRANSMISSION PLAYS AN IMPORTANT ROLE IN THE PROCESSING OF AFFECTIVE ASPECTS OF PAIN. LONG-TERM CHANGES ON GLUTAMATERGIC SYNAPSES CONTRIBUTE TO THE EXPRESSION OF AVERSION BEHAVIOR INDUCED BY PAIN. IN THIS ARTICLE, THE NEUROCIRCUITS INVOLVED IN THE PROCESSING OF AFFECTIVE ASPECTS OF PAIN, THE GLUTAMATERGIC SYNAPTIC PLASTICITY IN THESE BRAIN REGIONS, AND THE EPIGENETIC MECHANISMS UNDERLYING PAIN-RELATED SYNAPTIC PLASTICITY WILL BE REVIEWED AND DISCUSSED. NEW DISCOVERIES REGARDING THE INTERACTION BETWEEN THE SYNAPTIC PLASTICITY AND AFFECTIVE COMPONENTS OF PAIN MAY ADVANCE OUR UNDERSTANDING ON THE PAIN MECHANISM, AND LEAD TO NEW STRATEGIES FOR PAIN TREATMENT. 2011