1 191 122 ACETYL-L-CARNITINE: FROM A BIOLOGICAL CURIOSITY TO A DRUG FOR THE PERIPHERAL NERVOUS SYSTEM AND BEYOND. ACETYL-L-CARNITINE (ALC) IS A MOLECULE DERIVED FROM ACETYLATION OF CARNITINE IN THE MITOCHONDRIA. CARNITINE ACETYLATION ENABLES THE FUNCTION OF COA AND FACILITATES ELIMINATION OF OXIDATIVE PRODUCTS. BEYOND THIS METABOLIC ACTIVITY, ALC PROVIDES ACETYL GROUPS FOR ACETYLCHOLINE SYNTHESIS, EXERTS A CHOLINERGIC EFFECT AND OPTIMIZES THE BALANCE OF ENERGY PROCESSES. ACETYLCARNITINE SUPPLEMENTATION INDUCES NEUROPROTECTIVE, NEUROTROPHIC AND ANALGESIC EFFECTS IN THE PERIPHERAL NERVOUS SYSTEM. IN THE RECENT STUDIES, ALC, BY ACTING AS A DONOR OF ACETYL GROUPS TO NF-KB P65/RELA, ENHANCED THE TRANSCRIPTION OF THE GRM2 GENE ENCODING THE MGLU2 RECEPTORS, INDUCING LONG-TERM UPREGULATION OF THE MGLUR2, EVIDENCING THEREFORE THAT ITS LONG-TERM ANALGESIC EFFECTS ARE DEPENDENT ON EPIGENETIC MODIFICATIONS. SEVERAL STUDIES, INCLUDING DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP STUDIES AND FEW OPEN STUDIES SHOWED THE EFFECT OF ALC IN DISEASES CHARACTERIZED BY NEUROPATHIES AND NEUROPATHIC PAIN: THE STUDIES INCLUDED DIABETIC NEUROPATHY, HIV AND ANTIRETROVIRAL THERAPY-INDUCED NEUROPATHIES, NEUROPATHIES DUE TO COMPRESSION AND CHEMOTHERAPEUTIC AGENTS. DOUBLE-BLINDED STUDIES INVOLVED 1773 PATIENTS. STATISTICAL EVALUATIONS EVIDENCED REDUCTION OF PAIN, IMPROVEMENTS OF NERVE FUNCTION AND TROPHISM. IN CONCLUSION, ALC REPRESENTS A CONSISTENT THERAPEUTIC OPTION FOR PERIPHERAL NEUROPATHIES, AND ITS COMPLEX EFFECTS, NEUROTROPHIC AND ANALGESIC, BASED ON EPIGENETIC MECHANISM, OPEN NEW PATHWAYS IN THE STUDY OF PERIPHERAL NERVE DISEASE MANAGEMENT. 2013 2 189 38 ACETYL-L-CARNITINE IN CHRONIC PAIN: A NARRATIVE REVIEW. ACETYL-L-CARNITINE (ALC) IS AN ENDOGENOUS MOLECULE THAT NOT ONLY PLAYS A ROLE IN ENERGY METABOLISM, BUT ALSO HAS ANTIOXIDANT PROPERTIES, PROTECTS FROM OXIDATIVE STRESS, MODULATES BRAIN NEUROTRANSMITTERS SUCH AS ACETYLCHOLINE, SEROTONIN AND DOPAMINE, AND ACTS ON NEUROTROPHIC FACTORS SUCH AS NERVE GROWTH FACTOR (NGF) AND METABOTROPIC GLUTAMATE (MGLU) RECEPTORS BY MEANS OF EPIGENETIC MECHANISMS. IMPORTANTLY, IT INDUCES MGLU2 EXPRESSION AT NERVE TERMINALS, THUS GIVING RISE TO ANALGESIA AND PREVENTING SPINAL SENSITISATION. IT HAS ALSO BEEN FOUND TO HAVE EVEN LONG-TERM NEUROTROPHIC AND ANALGESIC ACTIVITY IN EXPERIMENTAL MODELS OF CHRONIC INFLAMMATORY AND NEUROPATHIC PAIN. THE AIM OF THIS NARRATIVE REVIEW IS TO SUMMARISE THE CURRENT EVIDENCE REGARDING THE USE OF ALC IN PATIENTS WITH CHRONIC PAIN, AND COGNITIVE AND MOOD DISORDERS, AND INVESTIGATE THE RATIONALE UNDERLYING ITS USE IN PATIENTS WITH FIBROMYALGIA SYNDROME, WHICH IS CHARACTERISED BY NOCIPLASTIC CHANGES THAT INCREASE THE SENSITIVITY OF THE NERVOUS SYSTEM TO PAIN. 2021 3 4619 32 NERVE TRAUMA-CAUSED DOWNREGULATION OF OPIOID RECEPTORS IN PRIMARY AFFERENT NEURONS: MOLECULAR MECHANISMS AND POTENTIAL MANAGEMENTS. NEUROPATHIC PAIN IS THE MOST COMMON CLINICAL DISORDER DESTROYING THE QUALITY OF PATIENT LIFE AND LEADING TO A MARKED ECONOMIC AND SOCIAL BURDEN. OPIOIDS ARE STILL LAST OPTION FOR PHARMACOLOGICAL TREATMENT OF THIS DISORDER, BUT THEIR ANTINOCICEPTIVE EFFECTS ARE LIMITED IN PART DUE TO THE DOWNREGULATION OF OPIOID RECEPTORS IN THE PRIMARY AFFERENT NEURONS AFTER PERIPHERAL NERVE TRAUMA. HOW THIS DOWNREGULATION OCCURS IS NOT COMPLETELY UNDERSTOOD, BUT RECENT STUDIES HAVE DEMONSTRATED THAT PERIPHERAL NERVE TRAUMA DRIVES THE ALTERATIONS IN EPIGENETIC MODIFICATIONS (INCLUDING DNA METHYLATION, HISTONE METHYLATION AND MCIRORNAS), EXPRESSION OF TRANSCRIPTION FACTORS, POST-TRANSCRIPTIONAL MODIFICATIONS (E.G., RNA METHYLATION) AND PROTEIN TRANSLATION INITIATION IN THE NEURONS OF NERVE TRAUMA-RELATED DORSAL ROOT GANGLION (DRG) AND THAT THESE ALTERNATIONS MAY BE ASSOCIATED WITH NERVE TRAUMA-CAUSED DOWNREGULATION OF DRG OPIOID RECEPTORS. THIS REVIEW PRESENTS HOW OPIOID RECEPTORS ARE DOWNREGULATED IN THE DRG AFTER PERIPHERAL NERVE TRAUMA, SPECIFICALLY FOCUSING ON DISTINCT MOLECULAR MECHANISMS UNDERLYING TRANSCRIPTIONAL AND TRANSLATIONAL PROCESSES. THIS REVIEW ALSO DISCUSSES HOW THIS DOWNREGULATION CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. A DEEPER UNDERSTANDING OF THESE MOLECULAR MECHANISMS LIKELY PROVIDES A NOVEL AVENUE FOR PREVENTION AND/OR TREATMENT OF NEUROPATHIC PAIN. 2021 4 2214 38 EPIGENETIC MODIFICATIONS ASSOCIATED TO NEUROINFLAMMATION AND NEUROPATHIC PAIN AFTER NEURAL TRAUMA. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS LIE BEHIND THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. NEUROPATHIC PAIN IS USUALLY A CHRONIC CONDITION CAUSED BY A LESION, OR PATHOLOGICAL CHANGE, WITHIN THE NERVOUS SYSTEM. NEUROPATHIC PAIN APPEARS FREQUENTLY AFTER NERVE AND SPINAL CORD INJURIES OR DISEASES, PRODUCING A DEBILITATION OF THE PATIENT AND A DECREASE OF THE QUALITY OF LIFE. AT THE CELLULAR LEVEL, NEUROPATHIC PAIN IS THE RESULT OF NEURONAL PLASTICITY SHAPED BY AN INCREASE IN THE SENSITIVITY AND EXCITABILITY OF SENSORY NEURONS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. ONE OF THE MECHANISMS THOUGHT TO CONTRIBUTE TO HYPEREXCITABILITY AND THEREFORE TO THE ONTOGENY OF NEUROPATHIC PAIN IS THE ALTERED EXPRESSION, TRAFFICKING, AND FUNCTIONING OF RECEPTORS AND ION CHANNELS EXPRESSED BY PRIMARY SENSORY NEURONS. BESIDES, NEURONAL AND GLIAL CELLS, SUCH AS MICROGLIA AND ASTROCYTES, TOGETHER WITH BLOOD BORNE MACROPHAGES, PLAY A CRITICAL ROLE IN THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN BY RELEASING POWERFUL NEUROMODULATORS SUCH AS PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, WHICH ENHANCE NEURONAL EXCITABILITY. ALTERED GENE EXPRESSION OF NEURONAL RECEPTORS, ION CHANNELS, AND PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, HAVE BEEN ASSOCIATED TO EPIGENETIC ADAPTATIONS OF THE INJURED TISSUE. WITHIN THIS REVIEW, WE DISCUSS THE INVOLVEMENT OF THESE EPIGENETIC CHANGES, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNAS, AND ALTERATION OF CHROMATIN MODIFIERS, THAT HAVE BEEN SHOWN TO TRIGGER MODIFICATION OF NOCICEPTION AFTER NEURAL LESIONS. IN PARTICULAR, THE FUNCTION ON THESE PROCESSES OF EZH2, JMJD3, MECP2, SEVERAL HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYL TRANSFERASES (HATS), G9A, DNMT, REST AND DIVERSE NON-CODING RNAS, ARE DESCRIBED. DESPITE THE EFFORT ON DEVELOPING NEW THERAPIES, CURRENT TREATMENTS HAVE ONLY PRODUCED LIMITED RELIEF OF THIS PAIN IN A PORTION OF PATIENTS. THUS, THE PRESENT REVIEW AIMS TO CONTRIBUTE TO FIND NOVEL TARGETS FOR CHRONIC NEUROPATHIC PAIN TREATMENT. 2018 5 3194 27 HDAC INHIBITORS ATTENUATE THE DEVELOPMENT OF HYPERSENSITIVITY IN MODELS OF NEUROPATHIC PAIN. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER THESE COMPOUNDS COULD ALSO AFFECT NEUROPATHIC PAIN. DIFFERENT CLASS I HDACIS WERE DELIVERED INTRATHECALLY INTO RAT SPINAL CORD IN MODELS OF TRAUMATIC NERVE INJURY AND ANTIRETROVIRAL DRUG-INDUCED PERIPHERAL NEUROPATHY (STAVUDINE, D4T). MECHANICAL AND THERMAL HYPERSENSITIVITY WAS ATTENUATED BY 40% TO 50% AS A RESULT OF HDACI TREATMENT, BUT ONLY IF STARTED BEFORE ANY INSULT. THE DRUGS GLOBALLY INCREASED HISTONE ACETYLATION IN THE SPINAL CORD, BUT APPEARED TO HAVE NO MEASURABLE EFFECTS IN RELEVANT DORSAL ROOT GANGLIA IN THIS TREATMENT PARADIGM, SUGGESTING THAT ANY POTENTIAL MECHANISM SHOULD BE SOUGHT IN THE CENTRAL NERVOUS SYSTEM. MICROARRAY ANALYSIS OF DORSAL CORD RNA REVEALED THE SIGNATURE OF THE SPECIFIC COMPOUND USED (MS-275) AND SUGGESTED THAT ITS MAIN EFFECT WAS MEDIATED THROUGH HDAC1. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE ACETYLATION IN THE EMERGENCE OF NEUROPATHIC PAIN. 2013 6 2176 25 EPIGENETIC MECHANISMS OF CHRONIC PAIN. NEUROPATHIC AND INFLAMMATORY PAIN PROMOTE A LARGE NUMBER OF PERSISTING ADAPTATIONS AT THE CELLULAR AND MOLECULAR LEVEL, ALLOWING EVEN TRANSIENT TISSUE OR NERVE DAMAGE TO ELICIT CHANGES IN CELLS THAT CONTRIBUTE TO THE DEVELOPMENT OF CHRONIC PAIN AND ASSOCIATED SYMPTOMS. THERE IS EVIDENCE THAT INJURY-INDUCED CHANGES IN CHROMATIN STRUCTURE DRIVE STABLE CHANGES IN GENE EXPRESSION AND NEURAL FUNCTION, WHICH MAY CAUSE SEVERAL SYMPTOMS, INCLUDING ALLODYNIA, HYPERALGESIA, ANXIETY, AND DEPRESSION. RECENT FINDINGS ON EPIGENETIC CHANGES IN THE SPINAL CORD AND BRAIN DURING CHRONIC PAIN MAY GUIDE FUNDAMENTAL ADVANCES IN NEW TREATMENTS. HERE, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETIC REGULATION IN THE NERVOUS SYSTEM AND THEN DISCUSS THE STILL-LIMITED LITERATURE THAT DIRECTLY IMPLICATES EPIGENETIC MODIFICATIONS IN CHRONIC PAIN SYNDROMES. 2015 7 2194 34 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015 8 2310 26 EPIGENETIC REGULATION OF CHRONIC PAIN. CHRONIC PAIN ARISING FROM PERIPHERAL INFLAMMATION AND TISSUE OR NERVE INJURY IS A COMMON CLINICAL SYMPTOM. ALTHOUGH INTENSIVE RESEARCH ON THE NEUROBIOLOGICAL MECHANISMS OF CHRONIC PAIN HAS BEEN CARRIED OUT DURING PREVIOUS DECADES, THIS DISORDER IS STILL POORLY MANAGED BY CURRENT DRUGS SUCH AS OPIOIDS AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. INFLAMMATION, TISSUE INJURY AND/OR NERVE INJURY-INDUCED CHANGES IN GENE EXPRESSION IN SENSORY NEURONS OF THE DORSAL ROOT GANGLION, SPINAL CORD DORSAL HORN AND PAIN-ASSOCIATED BRAIN REGIONS ARE THOUGHT TO PARTICIPATE IN CHRONIC PAIN GENESIS; HOWEVER, HOW THESE CHANGES OCCUR IS STILL ELUSIVE. EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION AND COVALENT HISTONE MODIFICATIONS CONTROL GENE EXPRESSION. RECENT STUDIES HAVE SHOWN THAT PERIPHERAL NOXIOUS STIMULATION CHANGES DNA METHYLATION AND HISTONE MODIFICATIONS AND THAT THESE CHANGES MAY BE RELATED TO THE INDUCTION OF PAIN HYPERSENSITIVITY UNDER CHRONIC PAIN CONDITIONS. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE AND PROGRESS IN EPIGENETIC RESEARCH IN CHRONIC PAIN AND DISCUSSES THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS AS THERAPEUTIC ANTINOCICEPTIVE TARGETS IN THIS DISORDER. 2015 9 3319 23 HISTONE ACETYLATION AND HISTONE DEACETYLATION IN NEUROPATHIC PAIN: AN UNRESOLVED PUZZLE? CHRONIC PAIN IS BROADLY CLASSIFIED INTO SOMATIC, VISCERAL OR NEUROPATHIC PAIN DEPENDING UPON THE LOCATION AND EXTENT OF PAIN PERCEPTION. EVIDENCES FROM DIFFERENT ANIMAL STUDIES SUGGEST THAT INFLAMMATORY OR NEUROPATHIC PAIN IS ASSOCIATED WITH ALTERED ACETYLATION AND DEACETYLATION OF HISTONE PROTEINS, WHICH RESULT IN ABNORMAL TRANSCRIPTION OF NOCICEPTIVE PROCESSING GENES. THERE HAVE BEEN A NUMBER OF STUDIES INDICATING THAT NERVE INJURY UP-REGULATES HISTONE DEACETYLASE ENZYMES, WHICH LEADS TO INCREASED HISTONE DEACETYLATION AND INDUCE CHRONIC PAIN. TREATMENT WITH HISTONE DEACETYLASE INHIBITORS RELIEVES PAIN BY NORMALIZING NERVE INJURY-INDUCED DOWN REGULATION OF METABOTROPIC GLUTAMATE RECEPTORS, GLUTAMATE TRANSPORTERS, GLUTAMIC ACID DECARBOXYLASE 65, NEURON RESTRICTIVE SILENCER FACTOR AND SERUM AND GLUCOCORTICOID INDUCIBLE KINASE 1. ON THE OTHER HAND, A FEW STUDIES REFER TO INCREASED EXPRESSION OF HISTONE ACETYLASE ENZYMES IN RESPONSE TO NERVE INJURY THAT PROMOTES HISTONE ACETYLATION LEADING TO PAIN INDUCTION. TREATMENT WITH HISTONE ACETYL TRANSFERASE INHIBITORS HAVE BEEN REPORTED TO RELIEVE CHRONIC PAIN BY BLOCKING THE UP-REGULATION OF CHEMOKINES AND CYCLOOXYGENASE-2, THE CRITICAL FACTORS ASSOCIATED WITH HISTONE ACETYLATION-INDUCED PAIN. THE PRESENT REVIEW DESCRIBES THE DUAL ROLE OF HISTONE ACETYLATION/DEACETYLATION IN DEVELOPMENT OR ATTENUATION OF NEUROPATHIC PAIN ALONG WITH THE UNDERLYING MECHANISMS. 2017 10 3675 21 INFLAMMATION AND HISTONE MODIFICATION IN CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS HAVE GREAT POTENTIAL IN THE FIELD OF PAIN. THE CHANGES AND ROLES OF EPIGENETICS OF THE SPINAL CORD AND DORSAL ROOT GANGLIA IN THE CHRONIC PAIN PROCESS MAY PROVIDE BROAD INSIGHTS FOR FUTURE PAIN MANAGEMENT. PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES RELEASED BY MICROGLIA AND ASTROCYTES, AS WELL AS BLOOD-DERIVED MACROPHAGES, PLAY CRITICAL ROLES IN INDUCING AND MAINTAINING CHRONIC PAIN, WHILE HISTONE MODIFICATIONS MAY PLAY AN IMPORTANT ROLE IN INFLAMMATORY METABOLISM. THIS REVIEW PROVIDES AN OVERVIEW OF NEUROINFLAMMATION AND CHRONIC PAIN, AND WE SYSTEMATICALLY DISCUSS THE REGULATION OF NEUROINFLAMMATION AND HISTONE MODIFICATIONS IN THE CONTEXT OF CHRONIC PAIN. SPECIFICALLY, WE ANALYZED THE ROLE OF EPIGENETICS IN ALLEVIATING OR EXACERBATING CHRONIC PAIN BY MODULATING MICROGLIA, ASTROCYTES, AND THE PROINFLAMMATORY MEDIATORS THEY RELEASE. THIS REVIEW AIMED TO CONTRIBUTE TO THE DISCOVERY OF NEW THERAPEUTIC TARGETS FOR CHRONIC PAIN. 2022 11 6139 32 THE ETIOLOGICAL CONTRIBUTION OF GABAERGIC PLASTICITY TO THE PATHOGENESIS OF NEUROPATHIC PAIN. NEUROPATHIC PAIN DEVELOPING AFTER PERIPHERAL OR CENTRAL NERVE INJURY IS THE RESULT OF PATHOLOGICAL CHANGES GENERATED THROUGH COMPLEX MECHANISMS. DISRUPTION IN THE HOMEOSTASIS OF EXCITATORY AND INHIBITORY NEURONS WITHIN THE CENTRAL NERVOUS SYSTEM IS A CRUCIAL FACTOR IN THE FORMATION OF HYPERALGESIA OR ALLODYNIA OCCURRING WITH NEUROPATHIC PAIN. THE CENTRAL GABAERGIC PATHWAY HAS RECEIVED ATTENTION FOR ITS EXTENSIVE DISTRIBUTION AND FUNCTION IN NEURAL CIRCUITS, INCLUDING THE GENERATION AND DEVELOPMENT OF NEUROPATHIC PAIN. GABAERGIC INHIBITORY CHANGES THAT OCCUR IN THE INTERNEURONS ALONG DESCENDING MODULATORY AND NOCICEPTIVE PATHWAYS IN THE CENTRAL NERVOUS SYSTEM ARE BELIEVED TO GENERATE NEURONAL PLASTICITY, SUCH AS SYNAPTIC PLASTICITY OR FUNCTIONAL PLASTICITY OF THE RELATED GENES OR PROTEINS, THAT IS THE FOUNDATION OF PERSISTENT NEUROPATHIC PAIN. THE PRIMARY GABAERGIC PLASTICITY OBSERVED IN NEUROPATHIC PAIN INCLUDES GABAERGIC SYNAPSE HOMO- AND HETEROSYNAPTIC PLASTICITY, DECREASED SYNTHESIS OF GABA, DOWN-EXPRESSION OF GLUTAMIC ACID DECARBOXYLASE AND GABA TRANSPORTER, ABNORMAL EXPRESSION OF NKCC1 OR KCC2, AND DISTURBED FUNCTION OF GABA RECEPTORS. IN THIS REVIEW, WE DESCRIBE POSSIBLE MECHANISMS ASSOCIATED WITH GABAERGIC PLASTICITY, SUCH AS CENTRAL SENSITIZATION AND GABAERGIC INTERNEURON APOPTOSIS, AND THE EPIGENETIC ETIOLOGIES OF GABAERGIC PLASTICITY IN NEUROPATHIC PAIN. MOREOVER, WE SUMMARIZE POTENTIAL THERAPEUTIC TARGETS OF GABAERGIC PLASTICITY THAT MAY ALLOW FOR SUCCESSFUL RELIEF OF HYPERALGESIA FROM NERVE INJURY. FINALLY, WE COMPARE THE EFFECTS OF THE GABAERGIC SYSTEM IN NEUROPATHIC PAIN TO OTHER TYPES OF CHRONIC PAIN TO UNDERSTAND THE CONTRIBUTION OF GABAERGIC PLASTICITY TO NEUROPATHIC PAIN. 2019 12 405 28 ANALYSIS OF EPIGENETIC MECHANISMS REGULATING OPIOID RECEPTOR GENE TRANSCRIPTION. OPIOID DRUGS ARE GENERALLY USED FOR MODERATE AND SEVERE PAIN REDUCTIONS WHICH ACT THROUGH OPIOID RECEPTORS. STUDIES ON TRANSCRIPTIONAL REGULATION OF OPIOID RECEPTORS ARE STILL INVALUABLE BECAUSE NOT ONLY TRANSCRIPTION IS THE FIRST STEP TO PRODUCE PROTEIN PRODUCTS IN CELLS, BUT THE RECEPTOR TRANSCRIPTION LEVELS ALSO AFFECT THE PAIN REDUCTION BY OPIOIDS, AS OBSERVED IN STUDIES OF HETEROZYGOUS OPIOID RECEPTOR KNOCKOUT MICE.THERE ARE GROWING EVIDENCES THAT EPIGENETIC REGULATION HAS PLAYED SIGNIFICANT ROLES IN TRANSCRIPTIONAL REGULATION OF GENES, INCLUDING OPIOID RECEPTORS. IN GENERAL, EPIGENETIC MECHANISMS INCLUDE THREE MAIN REGULATORY FACTORS: DNA METHYLATION, CHROMATIN MODIFICATION, AND NONCODING RNAS (SUCH AS MICRORNA). FROM PREVIOUS STUDIES OF OURS AND OTHERS ON OPIOID RECEPTORS, THOSE EPIGENETIC FACTORS WERE CLEARLY INVOLVED IN REGULATING OPIOID RECEPTOR EXPRESSION IN VIVO AND IN VITRO. IN THIS CHAPTER, AMONG THOSE THREE TECHNIQUES WE DESCRIBE MORE DETAILS OF DNA METHYLATION METHODS BECAUSE OF EMERGING CONCEPTS OF DNA METHYLATION WITH THE RECENT DISCOVERY OF 5-HYDROXYMETHYLCYTOSINE CONVERTING ENZYME, TET1. ANOTHER ANALYTICAL METHOD OF THE EPIGENETIC FACTORS, CHROMATIN MODIFICATION, WILL BE DESCRIBED BRIEFLY AND INFORMATION OF ANALYZING NONCODING RNAS IS BRIEFLY MENTIONED IN SUBHEADING 1. 2015 13 5007 25 PERIPHERAL NERVE INJURY IS ASSOCIATED WITH CHRONIC, REVERSIBLE CHANGES IN GLOBAL DNA METHYLATION IN THE MOUSE PREFRONTAL CORTEX. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ARE ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS INCLUDING LOW BACK PAIN AND FIBROMYALGIA. THE MAGNITUDE OF THESE CHANGES CORRELATES WITH THE DURATION AND/OR THE INTENSITY OF CHRONIC PAIN. MOST STUDIES REPORT CHANGES IN COMMON AREAS INVOLVED IN PAIN MODULATION, INCLUDING THE PREFRONTAL CORTEX (PFC), AND PAIN-RELATED PATHOLOGICAL CHANGES IN THE PFC CAN BE REVERSED WITH EFFECTIVE TREATMENT. WHILE THE MECHANISMS UNDERLYING THESE CHANGES ARE UNKNOWN, THEY MUST BE DYNAMICALLY REGULATED. EPIGENETIC MODULATION OF GENE EXPRESSION IN RESPONSE TO EXPERIENCE AND ENVIRONMENT IS REVERSIBLE AND DYNAMIC. EPIGENETIC MODULATION BY DNA METHYLATION IS ASSOCIATED WITH ABNORMAL BEHAVIOR AND PATHOLOGICAL GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM. DNA METHYLATION MIGHT ALSO BE INVOLVED IN MEDIATING THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN IN THE BRAIN. WE THEREFORE TESTED A) WHETHER ALTERATIONS IN DNA METHYLATION ARE FOUND IN THE BRAIN LONG AFTER CHRONIC NEUROPATHIC PAIN IS INDUCED IN THE PERIPHERY USING THE SPARED NERVE INJURY MODAL AND B) WHETHER THESE INJURY-ASSOCIATED CHANGES ARE REVERSIBLE BY INTERVENTIONS THAT REVERSE THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN. SIX MONTHS FOLLOWING PERIPHERAL NERVE INJURY, ABNORMAL SENSORY THRESHOLDS AND INCREASED ANXIETY WERE ACCOMPANIED BY DECREASED GLOBAL METHYLATION IN THE PFC AND THE AMYGDALA BUT NOT IN THE VISUAL CORTEX OR THE THALAMUS. ENVIRONMENTAL ENRICHMENT ATTENUATED NERVE INJURY-INDUCED HYPERSENSITIVITY AND REVERSED THE CHANGES IN GLOBAL PFC METHYLATION. FURTHERMORE, GLOBAL PFC METHYLATION CORRELATED WITH MECHANICAL AND THERMAL SENSITIVITY IN NEUROPATHIC MICE. IN SUMMARY, INDUCTION OF CHRONIC PAIN BY PERIPHERAL NERVE INJURY IS ASSOCIATED WITH EPIGENETIC CHANGES IN THE BRAIN. THESE CHANGES ARE DETECTED LONG AFTER THE ORIGINAL INJURY, AT A LONG DISTANCE FROM THE SITE OF INJURY AND ARE REVERSIBLE WITH ENVIRONMENTAL MANIPULATION. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION THAT ARE ASSOCIATED WITH CHRONIC PAIN CONDITIONS MAY THEREFORE BE MEDIATED BY EPIGENETIC MECHANISMS. 2013 14 2199 27 EPIGENETIC MODIFICATION OF DRG NEURONAL GENE EXPRESSION SUBSEQUENT TO NERVE INJURY: ETIOLOGICAL CONTRIBUTION TO COMPLEX REGIONAL PAIN SYNDROMES (PART II). CUMULATING EVIDENCE INDICATED THAT NERVE INJURY-ASSOCIATED CELLULAR AND MOLECULAR CHANGES PLAY AN ESSENTIAL ROLE IN CONTRIBUTING TO THE DEVELOPMENT OF PATHOLOGICAL PAIN, AND MORE RECENT FINDINGS IMPLICATED THE CRITICAL ROLE OF EPIGENETIC MECHANISMS IN PAIN-RELATED SENSITIZATION IN THE DRG SUBSEQUENT TO NERVE INJURY. IN THIS PART OF THE DYAD REVIEW (PART II), WE REVIEWED AND PAID SPECIAL ATTENTION ON THE ETIOLOGICAL CONTRIBUTION OF DGR GENE EXPRESSION MODULATED BY EPIGENETIC MECHANISMS OF CRPS. AS ESSENTIAL EFFECTORS TO DIFFERENT MOLECULAR ACTIVATION, WE FIRST DISCUSSED THE ACTIVATION OF VARIOUS SIGNALING PATHWAYS THAT SUBSEQUENTLY FROM NERVE INJURY, AND IN FURTHER ILLUSTRATED THE FUNDAMENTAL AND FUNCTIONAL UNDERPINNINGS OF NERVE INJURY-INDUCED PAIN, IN WHICH WE ARGUED FOR THE POTENTIAL EPIGENETIC MECHANISMS IN RESPONSE TO SENSITIZING STIMULI OR INJURY. THEREFORE, UNDERSTANDING THE SPECIFIC MEDIATING FACTORS THAT INFLUENCE INDIVIDUAL EPIGENETIC DIFFERENCES CONTRIBUTING TO PAIN SENSITIVITY AND RESPONSIVENESS TO ANALGESICS POSSESSES CRUCIAL CLINICAL IMPLICATIONS. 2014 15 789 29 CELLULAR AND MOLECULAR MECHANISMS DRIVING NEUROPATHIC PAIN: RECENT ADVANCEMENTS AND CHALLENGES. CURRENT PHARMACOTHERAPEUTICS FOR NEUROPATHIC PAIN OFFER ONLY SYMPTOMATIC RELIEF WITHOUT TREATING THE UNDERLYING PATHOPHYSIOLOGY. ADDITIONALLY, THEY ARE ASSOCIATED WITH VARIOUS DOSE-LIMITING SIDE EFFECTS. PAIN RESEARCH IN THE PAST FEW DECADES HAS REVOLVED AROUND THE ROLE OF OXIDATIVE-NITROSATIVE STRESS, PROTEIN KINASES, GLIAL CELL ACTIVATION, AND INFLAMMATORY SIGNALING CASCADES BUT HAS FAILED TO PRODUCE SPECIFIC AND EFFECTIVE THERAPIES. AREAS COVERED: THIS REVIEW FOCUSES ON RECENT ADVANCES IN CELLULAR AND MOLECULAR MECHANISMS OF NEUROPATHIC PAIN THAT MAY BE TRANSLATED INTO FUTURE THERAPIES. WE DISCUSS EMERGING TARGETS SUCH AS WNT SIGNALING MECHANISMS, THE TETRAHYDROBIOPTERIN PATHWAY, MRG RECEPTORS, ENDOGENOUS LIPID MEDIATORS, MICRO-RNAS AND THEIR ROLES IN PAIN REGULATION. RECENT EVIDENCE IS ALSO PRESENTED REGARDING GENETIC AND EPIGENETIC MECHANISMS OF PAIN MODULATION. EXPERT OPINION: DURING CHRONIC NEUROPATHIC PAIN, MALADAPTATION OCCURS IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, INCLUDING A SHIFT IN MICROGLIAL PHENOTYPE FROM A SURVEILLANCE STATE TO AN ACTIVATED STATE. MICROGLIAL ACTIVATION LEADS TO AN ALTERED EXPRESSION OF CELL SURFACE PROTEINS, GROWTH FACTORS, AND INTRACELLULAR SIGNALING MOLECULES THAT CONTRIBUTE TO DEVELOPMENT OF A NEUROINFLAMMATORY CASCADE AND CHRONIC PAIN SENSITIZATION. SPECIFIC TARGETING OF THESE CELLULAR AND MOLECULAR MECHANISMS MAY PROVIDE THE KEY TO DEVELOPMENT OF EFFECTIVE NEUROPATHIC PAIN THERAPIES THAT HAVE MINIMAL SIDE EFFECTS. 2018 16 6138 32 THE ETIOLOGICAL CHANGES OF ACETYLATION IN PERIPHERAL NERVE INJURY-INDUCED NEUROPATHIC HYPERSENSITIVITY. NEUROPATHIC PAIN IS A COMMON CHRONIC PAIN CONDITION WITH MECHANISMS FAR CLEARLY BEEN ELUCIDATED. MOUNTING PRECLINICAL AND CLINICAL STUDIES HAVE SHOWN NEUROPATHIC PAIN IS HIGHLY ASSOCIATED WITH HISTONE ACETYLATION MODIFICATION, WHICH FOLLOWS EXPRESSION REGULATION OF VARIOUS PAIN-RELATED MOLECULES SUCH AS MGLUR1/5, GLUTAMATE ASPARTATE TRANSPORTER, GLUTAMATE TRANSPORTER-1, GAD65, NA(V)1.8, KV4.3, MU-OPIOID RECEPTOR, BRAIN-DERIVED NEUROTROPHIC FACTOR, AND CERTAIN CHEMOKINES. AS TWO TYPES OF PIVOTAL ENZYMES INVOLVED IN HISTONE ACETYLATION, HISTONE DEACETYLASES INDUCE HISTONE DEACETYLATION TO SILENCE GENE EXPRESSION; IN CONTRAST, HISTONE ACETYL TRANSFERASES FACILITATE HISTONE ACETYLATION TO POTENTIATE GENE TRANSCRIPTION. ACCORDINGLY, UPREGULATION OR BLOCKADE OF ACETYLATION MAY BE A PROMISING INTERVENTION DIRECTION FOR NEUROPATHIC PAIN TREATMENT. IN FACT, NUMEROUS ANIMAL STUDIES HAVE SUGGESTED VARIOUS HISTONE DEACETYLASE INHIBITORS, SIRT (CLASS III HISTONE DEACETYLASES) ACTIVATORS, AND HISTONE ACETYL TRANSFERASES INHIBITORS ARE EFFECTIVE IN NEUROPATHIC PAIN TREATMENT VIA TARGETING SPECIFIC EPIGENETIC SITES. IN THIS REVIEW, WE SUMMARIZE THE CHARACTERISTICS OF THE MOLECULES AND MECHANISMS OF NEUROPATHY-RELATED ACETYLATION, AS WELL AS THE ACETYLATION UPREGULATION AND BLOCKADE FOR NEUROPATHIC PAIN THERAPY. FINALLY, WE WILL DISCUSS THE CURRENT DRUG ADVANCES FOCUSING ON NEUROPATHY-RELATED ACETYLATION ALONG WITH THE UNDERLYING TREATMENT MECHANISMS. 2018 17 5926 31 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 18 1509 20 DNA METHYLATION AND NON-CODING RNAS DURING TISSUE-INJURY ASSOCIATED PAIN. WHILE ABOUT HALF OF THE POPULATION EXPERIENCE PERSISTENT PAIN ASSOCIATED WITH TISSUE DAMAGES DURING THEIR LIFETIME, CURRENT SYMPTOM-BASED APPROACHES OFTEN FAIL TO REDUCE SUCH PAIN TO A SATISFACTORY LEVEL. TO PROVIDE BETTER PATIENT CARE, MECHANISM-BASED ANALGESIC APPROACHES MUST BE DEVELOPED, WHICH NECESSITATES A COMPREHENSIVE UNDERSTANDING OF THE NOCICEPTIVE MECHANISM LEADING TO TISSUE INJURY-ASSOCIATED PERSISTENT PAIN. EPIGENETIC EVENTS LEADING THE ALTERED TRANSCRIPTION IN THE NERVOUS SYSTEM ARE PIVOTAL IN THE MAINTENANCE OF PAIN IN TISSUE INJURY. HOWEVER, THE MECHANISMS THROUGH WHICH THOSE EVENTS CONTRIBUTE TO THE PERSISTENCE OF PAIN ARE NOT FULLY UNDERSTOOD. THIS REVIEW PROVIDES A SUMMARY AND CRITICAL EVALUATION OF TWO EPIGENETIC MECHANISMS, DNA METHYLATION AND NON-CODING RNA EXPRESSION, ON TRANSCRIPTIONAL MODULATION IN NOCICEPTIVE PATHWAYS DURING THE DEVELOPMENT OF TISSUE INJURY-ASSOCIATED PAIN. WE ASSESS THE PRE-CLINICAL DATA AND THEIR TRANSLATIONAL IMPLICATION AND EVALUATE THE POTENTIAL OF CONTROLLING DNA METHYLATION AND NON-CODING RNA EXPRESSION AS NOVEL ANALGESIC APPROACHES AND/OR BIOMARKERS OF PERSISTENT PAIN. 2022 19 4604 28 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 20 2551 26 EPIGENETICS IN PAIN AND ANALGESIA: AN IMMINENT RESEARCH FIELD. HERITABLE PHENOTYPES RESULTING FROM ENVIRONMENT-CAUSED CHANGES IN A CHROMOSOME WITHOUT ALTERATIONS IN THE DNA SEQUENCE ARE INCREASINGLY RECOGNIZED AS A BASIS OF PERSONALIZED THERAPY. EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF THE DNA (METHYLATION) OR OF THE DNA-PACKAGING HISTONES (E.G., DEACETYLATION OR PHOSPHORYLATION). IN ADDITION, REGULATORY NON-CODING RNA MOLECULES (MICRO-RNAS) EXERT EPIGENETIC ACTIONS. THIS LEADS TO DISRUPTION OR OTHERWISE MODIFIED EXPRESSION OF GENES. ENVIRONMENTAL INFLUENCES SUCH AS NUTRITIONAL FACTORS, EXPOSURE TO CHEMICALS OR DRUGS, BUT ALSO SOCIAL FACTORS APPEAR TO EXERT EPIGENETIC ACTIONS. HISTONE MODIFICATIONS AND DNA METHYLATION ARE ASSOCIATED WITH THE SUBJECT'S AGE. EPIGENETIC MECHANISMS CAN SILENCE THE EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. TO THE EPIGENETIC CONTROL OF NOCICEPTION ADDS ITS CONTROL OF THE PHARMACODYNAMICS OR PHARMACOKINETICS OF ANALGESICS BY EPIGENETIC CONTROL OF DRUG TARGETS AND ANALGESICS METABOLIZING ENZYMES. ALTHOUGH EPIGENETICS-BASED STRATEGIES FOR PAIN THERAPY ARE NOT YET AVAILABLE, EXPERIMENTS IN RODENTS SUGGEST THAT RNA INTERFERENCE MAY BECOME A NEW THERAPY APPROACH FOR NEUROPATHIC AND OTHER PAIN. ANOTHER EPIGENETIC APPROACH TO ANALGESIC TREATMENT EMPLOYS INHIBITORS OF HISTONE DEACETYLASE THAT ACT ON THE EPIGENOME BY INDIRECTLY REMODELING THE SPATIAL CONFORMATION OF THE CHROMATIN. FINALLY, EPIGENETIC TECHNIQUES SUCH AS RNA INTERFERENCE HAVE BEEN EMPLOYED IN PAIN RESEARCH TO PROOF THE CONTRIBUTION OF CERTAIN PROTEINS TO NOCICEPTION. THUS, THE NEW FIELD OF EPIGENETICS BECOMES INCREASINGLY USED IN RESEARCH AND MANAGEMENT OF PAIN AND WILL COMPLEMENT GENETICS. THIS ARTICLE INTRODUCES EPIGENETICS TO PAIN AND SUMMARIZES THE CURRENT AND FUTURE UTILITY. 2011