1 4645 113 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 2 2176 26 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 3 4619 29 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 2993 28 GENETIC PAIN LOSS DISORDERS. GENETIC PAIN LOSS INCLUDES CONGENITAL INSENSITIVITY TO PAIN (CIP), HEREDITARY SENSORY NEUROPATHIES AND, IF AUTONOMIC NERVES ARE INVOLVED, HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY (HSAN). THIS HETEROGENEOUS GROUP OF DISORDERS HIGHLIGHTS THE ESSENTIAL ROLE OF NOCICEPTION IN PROTECTING AGAINST TISSUE DAMAGE. PATIENTS WITH GENETIC PAIN LOSS HAVE RECURRENT INJURIES, BURNS AND POORLY HEALING WOUNDS AS DISEASE HALLMARKS. CIP AND HSAN ARE CAUSED BY PATHOGENIC GENETIC VARIANTS IN >20 GENES THAT LEAD TO DEVELOPMENTAL DEFECTS, NEURODEGENERATION OR ALTERED NEURONAL EXCITABILITY OF PERIPHERAL DAMAGE-SENSING NEURONS. THESE GENETIC VARIANTS LEAD TO HYPERACTIVITY OF SODIUM CHANNELS, DISTURBED HAEM METABOLISM, ALTERED CLATHRIN-MEDIATED TRANSPORT AND IMPAIRED GENE REGULATORY MECHANISMS AFFECTING EPIGENETIC MARKS, LONG NON-CODING RNAS AND REPETITIVE ELEMENTS. THERAPIES FOR PAIN LOSS DISORDERS ARE MAINLY SYMPTOMATIC BUT THE FIRST TARGETED THERAPIES ARE BEING TESTED. CONVERSELY, CHRONIC PAIN REMAINS ONE OF THE GREATEST UNRESOLVED MEDICAL CHALLENGES, AND THE GENES AND MECHANISMS ASSOCIATED WITH PAIN LOSS OFFER NEW TARGETS FOR ANALGESICS. GIVEN THE PROGRESS THAT HAS BEEN MADE, THE COMING YEARS ARE PROMISING BOTH IN TERMS OF TARGETED TREATMENTS FOR PAIN LOSS DISORDERS AND THE DEVELOPMENT OF INNOVATIVE PAIN MEDICINES BASED ON KNOWLEDGE OF THESE GENETIC DISEASES. 2022 5 2310 29 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 6 2199 24 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 7 2214 42 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 8 78 37 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 9 6139 30 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 10 2179 26 EPIGENETIC MECHANISMS OF NEURAL PLASTICITY IN CHRONIC NEUROPATHIC PAIN. NEUROPATHIC PAIN IS A CHALLENGING CLINICAL PROBLEM AND REMAINS DIFFICULT TO TREAT. ALTERED GENE EXPRESSION IN PERIPHERAL SENSORY NERVES AND NEURONS DUE TO NERVE INJURY IS WELL DOCUMENTED AND CONTRIBUTES CRITICALLY TO THE SYNAPTIC PLASTICITY IN THE SPINAL CORD AND THE INITIATION AND MAINTENANCE OF CHRONIC PAIN. HOWEVER, OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS REGULATING THE TRANSCRIPTION OF PRO-NOCICEPTIVE (E.G., NMDA RECEPTORS AND ALPHA2DELTA-1) AND ANTINOCICEPTIVE (E.G., POTASSIUM CHANNELS AND OPIOID AND CANNABINOID RECEPTORS) GENES ARE STILL LIMITED. IN THIS REVIEW, WE SUMMARIZE RECENT STUDIES DETERMINING THE ROLES OF HISTONE MODIFICATIONS (INCLUDING METHYLATION, ACETYLATION, AND UBIQUITINATION), DNA METHYLATION, AND NONCODING RNAS IN NEUROPATHIC PAIN DEVELOPMENT. WE REVIEW THE EPIGENETIC WRITER, READER, AND ERASER PROTEINS THAT PARTICIPATE IN THE TRANSCRIPTIONAL CONTROL OF THE EXPRESSION OF KEY ION CHANNELS AND NEUROTRANSMITTER RECEPTORS IN THE DORSAL ROOT GANGLION AFTER TRAUMATIC NERVE INJURY, WHICH IS COMMONLY USED AS A PRECLINICAL MODEL OF NEUROPATHIC PAIN. A BETTER UNDERSTANDING OF EPIGENETIC REPROGRAMMING INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN COULD LEAD TO THE DEVELOPMENT OF NEW TREATMENTS FOR NEUROPATHIC PAIN. 2022 11 789 35 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 12 6895 24 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 13 6226 16 THE LINK BETWEEN EPIGENETICS, PAIN SENSITIVITY AND CHRONIC PAIN. INCREASING EVIDENCE SUGGESTS AN ASSOCIATION BETWEEN GENE EXPRESSION AND CLINICAL PAIN. EPIGENETIC MODIFICATIONS ARE THE MAIN MODULATORS OF GENE EXPRESSION OR PROTEIN TRANSLATION IN RESPONSE TO ENVIRONMENTAL STIMULI AND PATHOPHYSIOLOGICAL CONDITIONS. PRECLINICAL AND CLINICAL STUDIES INDICATE THAT EPIGENETIC MODIFICATIONS COULD ALSO IMPACT THE DEVELOPMENT OF PAIN, THE TRANSITION FROM ACUTE TO CHRONIC PAIN, AND THE MAINTENANCE HEREOF. 2022 14 189 28 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 15 6828 25 [GLOBAL UNDERSTANDING OF PAIN]. CLINICALLY, IT IS WELL-KNOWN THAT CHRONIC PAIN INDUCES DEPRESSION, ANXIETY, AND REDUCED QUALITY OF LIFE. NEUROPATHIC PAIN, WHICH IS CHARACTERIZED BY SPONTANEOUS BURNING PAIN, HYPERALGESIA AND ALLODYNIA, IS THE MOST DIFFICULT PAIN TO MANAGE IN THE PAIN CLINIC. HOWEVER, THE COMPLICATED PATHOPHYSIOLOGY OF NEUROPATHIC PAIN IS NOT YET UNDERSTOOD. A BETTER UNDERSTANDING OF ITS PATHOPHYSIOLOGY HAS GIVEN US MORE INSIGHT INTO ITS VARIOUS MECHANISMS AND POSSIBLE TREATMENT OPTIONS. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF PAIN, WITH A FOCUS ON TRANSCRIPTIONAL RESEARCH, EPIGENETIC RESEARCH AND POST-TRANSCRIPTIONAL RESEARCH. FOR A GLOBAL UNDERSTANDING OF THE PAIN, IT IS NECESSARY TO ANALYZE THE CORRELATION BETWEEN THESE TEMPORAL PARAMETERS AND PHENOMICS. 2012 16 191 28 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 17 3675 22 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 18 4036 24 MACROPHAGE EPIGENETIC MEMORIES OF EARLY LIFE INJURY DRIVE NEONATAL NOCICEPTIVE PRIMING. THE DEVELOPING PERIPHERAL NERVOUS AND IMMUNE SYSTEMS ARE FUNCTIONALLY DISTINCT FROM ADULTS. THESE SYSTEMS ARE VULNERABLE TO EFFECTS OF EARLY LIFE INJURY WHICH CAN INFLUENCE OUTCOMES RELATED TO NOCICEPTION FOLLOWING SUBSEQUENT INJURY LATER IN LIFE (I.E. "NEONATAL NOCICEPTIVE PRIMING"). THE UNDERPINNINGS OF THIS PHENOMENON ARE LARGELY UNKNOWN, ALTHOUGH MACROPHAGES CAN BE EPIGENETICALLY TRAINED BY INJURY. WE FOUND THAT MACROPHAGES ARE BOTH NECESSARY AND PARTIALLY SUFFICIENT TO DRIVE NEONATAL NOCICEPTIVE PRIMING POSSIBLY DUE TO A LONG-LASTING EPIGENETIC REMODELING OF PERIPHERAL MACROPHAGES. THE P75 NEUROTROPHIC FACTOR RECEPTOR (NTR) WAS OBSERVED TO BE AN IMPORTANT EFFECTOR IN REGULATING NEONATAL NOCICEPTIVE PRIMING. P75NTR MODULATES THE INFLAMMATORY PROFILE AND RESPONSES OF RODENT AND HUMAN MACROPHAGES. THIS "PAIN MEMORY" WAS ABLE TO BE TRANSFERRED TO A NAIVE HOST TO ALTER SEX-SPECIFIC PAIN-RELATED BEHAVIORS. THIS STUDY REVEALS A NOVEL MECHANISM BY WHICH ACUTE POST-SURGICAL PAIN MAY TRANSITION TO CHRONIC PAIN IN CHILDREN. 2023 19 6846 31 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 20 2194 26 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