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1.
Science ; 369(6505): 842-846, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32792398

RESUMO

How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron-specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3-bound c-Fos and importin α3-deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.


Assuntos
Dor Crônica/fisiopatologia , Neuralgia/fisiopatologia , Células Receptoras Sensoriais/fisiologia , alfa Carioferinas/fisiologia , Transporte Ativo do Núcleo Celular , Animais , Benzofenonas/farmacologia , Dor Crônica/genética , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Isoxazóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/genética , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator de Transcrição AP-1/metabolismo , alfa Carioferinas/genética
2.
Nat Commun ; 11(1): 2501, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427844

RESUMO

Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons.


Assuntos
Dor Crônica/enzimologia , Dor Crônica/psicologia , Núcleos da Linha Média do Tálamo/enzimologia , Neurônios/enzimologia , Óxido Nítrico Sintase Tipo I/metabolismo , Córtex Pré-Frontal/enzimologia , Animais , Ansiedade , Comportamento Animal , Dor Crônica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleos da Linha Média do Tálamo/citologia , Neurônios/citologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Córtex Pré-Frontal/citologia
3.
PLoS One ; 15(5): e0232721, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379790

RESUMO

BACKGROUND: Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. METHODS: Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. RESULTS: Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. CONCLUSIONS: S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.


Assuntos
Anemia Falciforme/genética , Dor Crônica/genética , Polimorfismo de Nucleotídeo Único , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Adulto , Afro-Americanos/genética , Anemia Falciforme/complicações , Dor Crônica/complicações , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
4.
Medicine (Baltimore) ; 99(8): e19325, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080151

RESUMO

Elucidation of epigenetic mechanisms correlating with neuropathic pain in humans is crucial for the prevention and treatment of this treatment-resistant pain state. In the present study, associations between neuropathic pain characteristics and DNA methylation of the transient receptor potential ankyrin 1 (TRPA1) gene were evaluated in chronic pain patients and preoperative patients. Pain and psychological states were prospectively assessed in patients who suffered chronic pain or were scheduled for thoracic surgery. Neuropathic characteristics were assessed using the Douleur Neuropathique 4 (DN4) questionnaire. DNA methylation levels of the CpG islands in the TRPA1 gene were examined using whole blood. Forty-eight adult patients were enrolled in this study. Increases in DNA methylation rates at CpG -51 showed positive correlations with increases in the DN4 score both in preoperative and chronic pain patients. Combined methylation rates at CpG -51 in these patients also significantly increased together with increase in DN4 scores. Neuropathic pain characteristics are likely associated with methylation rates at the promoter region of the TRPA1 gene in human peripheral blood.


Assuntos
Metilação de DNA , Neuralgia/genética , Canal de Cátion TRPA1/genética , Idoso , Dor Crônica/genética , Ilhas de CpG , Depressão/psicologia , Feminino , Humanos , Masculino , Neuralgia/psicologia , Medição da Dor , Regiões Promotoras Genéticas , Estudos Prospectivos
5.
Anaesthesia ; 75 Suppl 1: e111-e120, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31903573

RESUMO

Chronic postoperative pain is common and can have a negative impact on quality of life. Recent studies show that genetic risk factors are likely to play a role, although only gene-targeted analysis has been used to date. This is the first genome-wide association study to identify single-nucleotide polymorphisms associated with the development of chronic postoperative pain based on two independent cohorts. In a discovery cohort, 330 women scheduled for hysterectomy were genotyped. A case-control association analysis compared patients without chronic postoperative pain and the 34 who had severe chronic postoperative pain 3 months after surgery. No single-nucleotide polymorphisms reached genome-wide significance, but several showed suggestive associations with chronic postoperative pain (p < 1 × 10-5 ). Single-nucleotide polymorphisms with significance p < 1 × 10-5 were followed up in a replication cohort consisting of 203 men and women scheduled for orthopaedic or abdominal surgery. Ten of these patients developed severe chronic postoperative pain. A single-nucleotide polymorphism in NAV3 was significantly replicated with chronic postoperative pain in the replication cohort (p = 0.009). Meta-analysis revealed that two loci (IQGAP1 and CRTC3) were significantly associated with chronic postoperative pain at 3 months (IQGAP1 p = 3.93 × 10-6 ß = 2.3863, CRTC3 p = 2.26 × 10-6 , ß = 2.4209). The present genome-wide association study provides initial evidence for genetic risk factors of chronic postoperative pain and supports follow-up studies.


Assuntos
Dor Crônica/genética , Estudo de Associação Genômica Ampla/métodos , Dor Pós-Operatória/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
6.
PLoS One ; 15(1): e0228134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990932

RESUMO

Chronic lameness affects bovine welfare and has a negative economic impact in dairy industry. Moreover, due to the translational gap between traditional pain models and new drugs development for treating chronic pain states, naturally occurring painful diseases could be a potential translational tool for chronic pain research. We therefore employed liquid chromatography tandem mass spectrometry (LC-MS/MS) to stablish the proteomic profile of the spinal cord samples from lumbar segments (L2-L4) of chronic lame dairy cows. Data were validated and quantified through software tool (Scaffold® v 4.0) using output data from two search engines (SEQUEST® and X-Tandem®). Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis was performed to detect proteins interactions. LC-MS/MS identified a total amount of 177 proteins; of which 129 proteins were able to be quantified. Lame cows showed a strong upregulation of interacting proteins with chaperone and stress functions such as Hsp70 (p < 0.006), Hsc70 (p < 0.0079), Hsp90 (p < 0.015), STIP (p > 0.0018) and Grp78 (p <0.0068), and interacting proteins associated to glycolytic pathway such as; γ-enolase (p < 0.0095), α-enolase (p < 0.013) and hexokinase-1 (p < 0.028). It was not possible to establish a clear network of interaction in several upregulated proteins in lame cows. Non-interacting proteins were mainly associated to redox process and cytoskeletal organization. The most relevant down regulated protein in lame cows was myelin basic protein (MBP) (p < 0.02). Chronic inflammatory lameness in cows is associated to increased expression of stress proteins with chaperone, metabolism, redox and structural functions. A state of endoplasmic reticulum stress and unfolded protein response (UPR) might explain the changes in protein expression in lame cows; however, further studies need to be performed in order to confirm these findings.


Assuntos
Doenças dos Bovinos/genética , Dor Crônica/veterinária , Regulação da Expressão Gênica , Coxeadura Animal/genética , Proteína Básica da Mielina/genética , Proteínas do Tecido Nervoso/genética , Animais , Bovinos , Doenças dos Bovinos/metabolismo , Doenças dos Bovinos/fisiopatologia , Dor Crônica/genética , Dor Crônica/metabolismo , Dor Crônica/fisiopatologia , Indústria de Laticínios , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Lactação/fisiologia , Coxeadura Animal/metabolismo , Coxeadura Animal/fisiopatologia , Anotação de Sequência Molecular , Proteína Básica da Mielina/metabolismo , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/metabolismo , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Proteômica/métodos , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/fisiopatologia
7.
Anesth Analg ; 130(1): 240-247, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30829673

RESUMO

BACKGROUND: Tissue injuries such as surgery and trauma are usually accompanied by simultaneous development of acute pain, which typically resolves along with tissue healing. However, in many cases, acute pain does not resolve despite proper tissue repair; rather, it transitions to chronic pain. In this study, we examined whether proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondria biogenesis, is implicated in pain chronification after burn injury in mice. METHODS: We used PGC-1α and littermates PGC-1α mice of both sex. Burn injury was induced on these mice. Hindpaw mechanical withdrawal thresholds and thermal withdrawal latency were examined. RESULTS: Hindpaw mechanical withdrawal thresholds and thermal withdrawal latencies were comparable at baseline between PGC-1α and PGC-1α mice. After burn injury, both PGC-1α and PGC-1α mice exhibited an initial dramatic decrease of withdrawal parameters at days 3 and 5 after injury. While PGC-1α mice fully recovered their withdrawal parameters to preinjury levels by days 11-14, PGC-1α mice failed to recover those parameters during the same time frame, regardless of sex. Moreover, we found that PGC-1α mice resolved tissue inflammation in a similar fashion to PGC-1α mice using a chemiluminescence-based reactive oxygen species imaging technique. CONCLUSIONS: Taken together, our data suggest that PGC-1α haploinsufficiency promotes pain chronification after burn injury.


Assuntos
Dor Aguda/metabolismo , Comportamento Animal , Encéfalo/metabolismo , Queimaduras/metabolismo , Dor Crônica/metabolismo , Limiar da Dor , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/deficiência , Dor Aguda/genética , Dor Aguda/fisiopatologia , Dor Aguda/psicologia , Trifosfato de Adenosina/metabolismo , Animais , Encéfalo/fisiopatologia , Queimaduras/genética , Queimaduras/fisiopatologia , Queimaduras/psicologia , Dor Crônica/genética , Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Haploinsuficiência , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Tempo de Reação , Cicatrização
8.
Yakugaku Zasshi ; 139(11): 1403-1415, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685737

RESUMO

For my Ph.D. research topic, I isolated endogenous morphine-like analgesic dipeptide, kyotorphin, which mediates Met-enkephalin release, and discovered kyotorphin synthetase, a putative receptor and antagonist. Furthermore, I succeeded in purifying µ-opioid receptor and functional reconstitution with purified G proteins. After receiving my full professor position at Nagasaki University in 1996, I worked on two topics of research, molecular mechanisms of chronic pain through lysophosphatidic acid (LPA) and identification and characterization of neuroprotective protein, prothymosin α. In a series of studies, we have shown that LPA signaling defines the molecular mechanisms of neuropathic pain and fibromyalgia in terms of development and maintenance. Above all, the discovery of feed-forward system in LPA production and pain memory may contribute to better understanding of chronic pain and future analgesic drug discovery. Regarding prothymosin α, we first discovered it as neuronal necrosis-inhibitory molecule through two independent mechanisms, such as toll-like receptor and F0/F1 ATPase, both which protect neurons through indirect mechanisms. Prothymosin α is released by non-classical and non-vesicular mechanisms on various stresses, such as ischemia, starvation, and heat-shock. Thus it may be called a new type of neuroprotective damage-associated molecular patterns (DAMPs)/Alarmins. Heterozygotic mice showed a defect in memory-learning and neurogenesis as well as anxiogenic behaviors. Small peptide, P6Q derived from prothymosin α retains neuroprotective actions, which include blockade of cerebral hemorrhage caused by late treatment with tissue plasminogen activator in the stroke model in mice.


Assuntos
Dor Crônica/etiologia , Dor Crônica/genética , Fármacos Neuroprotetores , Precursores de Proteínas , Receptores de Ácidos Lisofosfatídicos/fisiologia , Transdução de Sinais/fisiologia , Timosina/análogos & derivados , Animais , Endorfinas , Humanos , Camundongos , Precursores de Proteínas/metabolismo , ATPases Translocadoras de Prótons , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores Opioides , Acidente Vascular Cerebral , Timosina/metabolismo , Receptores Toll-Like
9.
Philos Trans R Soc Lond B Biol Sci ; 374(1785): 20190283, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31544613

RESUMO

Animal behaviours are affected not only by inherited genes but also by environmental experiences. For example, in both rats and humans, stressful early-life events such as being reared by an inattentive mother can leave a lasting trace and affect later stress response in adult life. This is owing to a chemical trace left on the chromatin attributed to so-called epigenetic mechanisms. Such an epigenetic trace often has consequences, sometimes long-lasting, on the functioning of our genes, thereby allowing individuals to rapidly adapt to a new environment. One gene under such epigenetic control is FKBP5, the gene that encodes the protein FKPB51, a crucial regulator of the stress axis and a significant driver of chronic pain states. In this article, we will discuss the possibility that exposure to stress could drive the susceptibly to chronic pain via epigenetic modifications of genes within the stress axis such as FKBP5. The possibility that such modifications, and therefore, the susceptibility to chronic pain, could be transmitted across generations in mammals and whether such mechanisms may be evolutionarily conserved across phyla will also be debated. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.


Assuntos
Dor Crônica/genética , Epigênese Genética , Estresse Psicológico/genética , Proteínas de Ligação a Tacrolimo/genética , Animais , Humanos , Camundongos , Ratos , Estresse Psicológico/fisiopatologia , Proteínas de Ligação a Tacrolimo/metabolismo
10.
Br J Anaesth ; 123(6): 853-864, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31558312

RESUMO

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.


Assuntos
Dopamina/metabolismo , Variação Genética/genética , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Dor Crônica/genética , Dor Crônica/metabolismo , Dopamina/genética , Humanos , Transmissão Sináptica/genética
11.
Proc Natl Acad Sci U S A ; 116(34): 17045-17050, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31391309

RESUMO

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that is linked to immune modulation and tissue regeneration. Here, we show that TNFR2 essentially promotes long-term pain resolution independently of sex. Genetic deletion of TNFR2 resulted in impaired neuronal regeneration and chronic nonresolving pain after chronic constriction injury (CCI). Further, pharmacological activation of TNFR2 using the TNFR2 agonist EHD2-sc-mTNFR2 in mice with chronic neuropathic pain promoted long-lasting pain recovery. TNFR2 agonist treatment reduced neuronal injury, alleviated peripheral and central inflammation, and promoted repolarization of central nervous system (CNS)-infiltrating myeloid cells into an antiinflammatory/reparative phenotype. Depletion of regulatory T cells (Tregs) delayed spontaneous pain recovery and abolished the therapeutic effect of EHD2-sc-mTNFR2 This study therefore reveals a function of TNFR2 in neuropathic pain recovery and demonstrates that both TNFR2 signaling and Tregs are essential for pain recovery after CCI. Therefore, therapeutic strategies based on the concept of enhancing TNFR2 signaling could be developed into a nonopioid therapy for the treatment of chronic neuropathic pain.


Assuntos
Dor Crônica/imunologia , Neuralgia/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Dor Crônica/genética , Dor Crônica/patologia , Dor Crônica/terapia , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Depleção Linfocítica , Masculino , Camundongos , Camundongos Knockout , Neuralgia/genética , Neuralgia/patologia , Neuralgia/terapia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Transdução de Sinais/genética , Linfócitos T Reguladores/patologia
12.
Medicine (Baltimore) ; 98(34): e16706, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441843

RESUMO

OBJECTIVE: Postoperative chronic pain is characterized by high incidence, long duration, and complex pathogenesis. The purpose of this study was to investigate the correlation between the single nucleotide polymorphisms of the CCL2 gene rs4586 (g.5974T>C), CALCA rs3781719 (-692T>C), CX3CL1 rs614230 (2342C>T), and the risk of postoperative chronic pain in Chinese Han women. METHODS: We analyzed the CCL2 gene rs4586, CALCA rs3781719, CX3CL1 rs614230 single nucleotide polymorphism (SNPs) of 350 Chinese Han women with chronic postsurgical pain (CPSP) 6 months after cesarean section and 350 healthy women without chronic pain (HC). The levels of CCL2, CALCA, and CX3CL1 in serum were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The CCL2 rs4586 T allele and the CX3CL1 gene rs614230C allele were protective factors for CPSP risk (adjusted OR = 0.766, 95% CI: 0.675-0.865 and OR = 0.336, 95% CI: 0.644-0.835). The CALCA gene rs3781719C allele was a risk factor for CPSP (adjusted OR = 1.273, 95% CI: 1.125-1.424). CCL2 rs4586, CX3CL1 gene rs614230, and CALCA gene rs3781719 locus gene polymorphisms were associated with serum CCL2, CX3CL1, and CALCA protein levels. CONCLUSION: Our results support that CCL2 gene rs4586, CALCA rs3781719, CX3CL1 rs614230 gene polymorphism are associated with the occurrence of chronic pain after cesarean section in Chinese Han women.


Assuntos
Cesárea/efeitos adversos , Dor Crônica/etiologia , Dor Crônica/genética , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Peptídeo Relacionado com Gene de Calcitonina/genética , Estudos de Casos e Controles , Quimiocina CCL2/genética , Quimiocina CX3CL1/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Pain Pract ; 19(8): 836-847, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31269327

RESUMO

OBJECTIVES: Chronic pain is one of the most common reasons individuals seek medical attention. It is a major issue because of the wide interindividual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics. METHODS: The study included 231 opioid-naïve patients from the Spine Unit; age 63 ± 14 years, 64% female, body mass index 29 ± 6 kg/m2 , visual analog scale pain intensity score 73 ± 16 mm. Clinical data were collected at baseline, 3 months after opioid titration, and after 2 to 4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities, and drug prescription (opioid dose, rotations, and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by reverse-transcription polymerase chain reaction genotyping. RESULTS: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low back pain disability, anxiety, and depression significantly decreased, while quality of life improved. CONCLUSION: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in patients with CLBP. We encourage clinical trials for their clinical application in chronic pain management.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor Crônica/genética , Estudos de Associação Genética/métodos , Dor Lombar/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Dor Crônica/diagnóstico , Dor Crônica/tratamento farmacológico , Feminino , Seguimentos , Humanos , Dor Lombar/diagnóstico , Dor Lombar/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Estudos Prospectivos , Qualidade de Vida , Receptores Opioides mu/genética
14.
J Neuroinflammation ; 16(1): 132, 2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31255170

RESUMO

BACKGROUND: Liver X receptors (LXRs), including LXRα and LXRß, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXRß expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated. METHODS: The deficit of LXR isoform and analgesic effect of LXR activation by GW3965 were evaluated using the mouse model of CIP induced by hindpaw injection of complete Freund's adjuvant (CFA). The mechanisms involved in GW-mediated analgesic effects were analyzed with immunohistochemical methods, ELISA, co-immunoprecipitation (Co-IP), Western blot, and electrophysiological recording. The epigenetic regulation of LXRß expression was investigated by chromatin immunoprecipitation, quantitative real-time PCR, and sequencing. RESULTS: We revealed that CFA insult led to LXRß reduction in ACC, which was associated with upregulated expression of histone deacetylase 5 (HDAC5), and knockdown of LXRß by shRNA led to thermal hyperalgesia. Co-IP showed that LXRß interacted with NF-κB p65 physically. LXRß activation by GW3965 exerted analgesic effects by inhibiting the nuclear translocation of NF-κB, reducing the phosphorylation of mitogen-activated protein kinases (MAPKs) in ACC, and decreasing the promoted input-output and enhanced mEPSC frequency in ACC neurons after CFA exposure. In vitro experiments confirmed that HDAC5 triggered histone deacetylation on the promoter region of Lxrß, resulting in downregulation of Lxrß transcription. CONCLUSION: These findings highlight an epigenetic mechanism underlying LXRß deficits linked to CIP, and LXRß activation may represent a potential novel target for the treatment of CIP with an alteration in inflammation responses and synaptic transmission in ACC.


Assuntos
Dor Crônica/metabolismo , Epigênese Genética/fisiologia , Adjuvante de Freund/toxicidade , Giro do Cíngulo/metabolismo , Histona Desacetilases/biossíntese , Receptores X do Fígado/metabolismo , Animais , Sequência de Bases , Dor Crônica/induzido quimicamente , Dor Crônica/genética , Epigênese Genética/efeitos dos fármacos , Giro do Cíngulo/efeitos dos fármacos , Histona Desacetilases/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Receptores X do Fígado/antagonistas & inibidores , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
PLoS Genet ; 15(6): e1008164, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194737

RESUMO

Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype 'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.


Assuntos
Dor Crônica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Adulto , Idoso , Asma/genética , Asma/fisiopatologia , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Dor Crônica/fisiopatologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurogênese/genética , Plasticidade Neuronal/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Reino Unido
16.
Indian J Med Res ; 149(1): 47-50, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31115374

RESUMO

Background & objectives: : Fibromyalgia syndrome (FMS) is one of the most common chronic pain conditions of unknown aetiology. Mitochondrial dysfunction has been reported in FMS with some studies reporting the presence of mitochondrial mutation namely A3243G, which also causes mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. This pilot study was conducted to assess this mutation and also detect large deletions in mitochondrial DNA (mtDNA) in patients with FMS. Methods: : Thirty female patients with FMS participated and 30 matched controls were included. Genomic DNA was subjected to polymerase chain reaction (PCR) amplification using specific primers followed by restriction digestion with Apa I enzyme to detect the specific A3243G mtDNA mutation. Long-range PCR was done in two sets to detect the large deletions in the mtDNA. Biochemical parameters including thyroid-stimulating hormone and vitamin D levels were also looked at. Results: : None of the patients were found to carry the common mutation or large deletions. Low vitamin D level was a common finding. Hypothyroidism was found in a few patients. Interpretation & conclusions: : Although the common mutation or large mtDNA deletions were not detected in blood mtDNA in the FMS patients, mutations in the muscle and sequence variation in mtDNA remained a possibility. Future studies in both blood and muscle tissue including mtDNA sequencing are warranted in such patients to determine if a subset of FMS patients have mitochondrial myopathy.


Assuntos
Dor Crônica/genética , DNA Mitocondrial/genética , Fibromialgia/genética , Mitocôndrias/genética , Adulto , Idoso , Dor Crônica/sangue , Dor Crônica/fisiopatologia , DNA Mitocondrial/sangue , Feminino , Fibromialgia/sangue , Fibromialgia/fisiopatologia , Humanos , Pessoa de Meia-Idade , Mitocôndrias/patologia , Mutação/genética , Fenótipo , Projetos Piloto , Deleção de Sequência/genética , Vitamina D/sangue , Vitamina D/genética
17.
Rheumatology (Oxford) ; 58(9): 1649-1654, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30938446

RESUMO

OBJECTIVES: A positive family history (PFH) of spondyloarthritis, in particular a PFH of AS or acute anterior uveitis, is associated with HLA-B27 carriership in chronic back pain patients. As it is unknown, the study aimed to investigate if a PFH contributes to diagnosing axial spondyloarthritis (axSpA) once HLA-B27 status is known. METHODS: In axSpA-suspected patients from the Assessment of SpondyloArthritis international Society (ASAS), DEvenir des Spondyloarthropathies Indifférenciéés Récentes (DESIR) and SPondyloArthritis Caught Early (SPACE) cohorts, logistic regression analyses were performed with HLA-B27 status and PFH according to the ASAS definition (ASAS-PFH) as determinants and clinical axSpA diagnosis as outcome at baseline. Analyses were repeated with a PFH of AS or acute anterior uveitis. RESULTS: In total, 1818 patients suspected of axSpA were analysed (ASAS n = 594, DESIR n = 647, and SPACE n = 577). In patients from the ASAS, DESIR and SPACE cohorts, respectively 23%, 39% and 38% had an ASAS-PFH, 52%, 58% and 43% were HLA-B27 positive, and 62%, 47% and 54% were diagnosed with axSpA. HLA-B27 was independently associated with an axSpA diagnosis in each cohort but an ASAS-PFH was not [ASAS cohort: HLA-B27 odds ratio (OR): 6.9 (95% CI: 4.7, 10.2), ASAS-PFH OR: 0.9 (95% CI: 0.6, 1.4); DESIR: HLA-B27 OR: 2.1 (95% CI: 1.5, 2.9), ASAS-PFH OR: 1.0 (95% CI 0.7, 1.3); SPACE: HLA-B27 OR: 10.4 (95% CI: 6.9, 15.7), ASAS-PFH OR: 1.0 (95% CI: 0.7, 1.5)]. Similar negative results were found for PFH of AS and acute anterior uveitis. CONCLUSION: In three independent cohorts with different ethnical backgrounds, ASAS, DESIR and SPACE, a PFH was not associated independently of HLA-B27 with a diagnosis of axSpA. This indicates that in the vast majority of patients presenting with back pain, a PFH does not contribute to the likelihood of an axSpA diagnosis if HLA-B27 status is known.


Assuntos
Antígeno HLA-B27/análise , Anamnese/métodos , Espondiloartropatias/diagnóstico , Espondiloartropatias/genética , Adolescente , Adulto , Dor nas Costas/etiologia , Dor nas Costas/genética , Dor Crônica/etiologia , Dor Crônica/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Espondiloartropatias/complicações , Espondilite Anquilosante/complicações , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/genética , Uveíte Anterior/diagnóstico , Uveíte Anterior/genética , Adulto Jovem
18.
Sci Signal ; 12(575)2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940767

RESUMO

Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein ß-arrestin2 to the nucleus. The nuclear translocation of ß-arrestin2 in turn prevented its recruitment to the µ-opioid receptor (MOR), the subsequent internalization of agonist-bound MOR, and the suppression of MOR activity that occurs upon receptor desensitization. Using the complete Freund's adjuvant (CFA) inflammatory pain model to examine the role of TRPV1 in regulating endogenous opioid analgesia in mice, we found that naloxone methiodide (Nal-M), a peripherally restricted, nonselective, and competitive opioid receptor antagonist, slowed the recovery from CFA-induced hypersensitivity in wild-type, but not TRPV1-deficient, mice. Furthermore, we showed that inflammation prolonged morphine-induced antinociception in a mouse model of opioid receptor desensitization, a process that depended on TRPV1. Together, our data reveal a TRPV1-mediated signaling pathway that serves as an endogenous pain-resolution mechanism by promoting the nuclear translocation of ß-arrestin2 to minimize MOR desensitization. This previously uncharacterized mechanism may underlie the peripheral opioid control of inflammatory pain. Dysregulation of the TRPV1-ß-arrestin2 axis may thus contribute to the transition from acute to chronic pain.


Assuntos
Dor Aguda/metabolismo , Analgésicos Opioides/farmacologia , Dor Crônica/metabolismo , Naloxona/análogos & derivados , Antagonistas de Entorpecentes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Dor Aguda/induzido quimicamente , Dor Aguda/tratamento farmacológico , Dor Aguda/genética , Analgesia , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Modelos Animais de Doenças , Adjuvante de Freund/efeitos adversos , Adjuvante de Freund/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Naloxona/farmacologia , Compostos de Amônio Quaternário/farmacologia , Transdução de Sinais/genética , Canais de Cátion TRPV/genética , beta-Arrestina 2/genética , beta-Arrestina 2/metabolismo
19.
PLoS One ; 14(4): e0215201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973927

RESUMO

INTRODUCTION: Interstitial Cystitis (IC) is a chronic condition diagnosed based on the presence of symptoms, such as suprapubic/ pelvic pain, pressure or discomfort in association with urgency and increased urinary frequency. Confusable diseases must be excluded. However, there is no objective test or marker to establish the presence of the disease. Diagnosis and patient management is often difficult, given the poor understanding of IC pathogenesis and its unknown etiology and genetics. As an attempt to find biomarkers related to IC, we assessed the association between 20 selected single nucleotide polymorphism (SNPs) with IC and pain severity. OBJECTIVES: To assess the presence of SNPs in IC patients' blood samples and correlate them with the disease and chronic pain condition. METHODS: A case-control study was conducted. We selected 34 female patients with IC diagnosed according to NIDDK criteria and 23 patients in the control group (previously healthy women with only stress urinary incontinence). IC patients were allocated into two groups according to reported chronic pain severity. We selected the following SNPs for analysis: rs1800871, rs1800872, rs1800896, rs1800471, rs1800629, rs361525, rs1800497, rs6311, rs6277, rs6276, rs6313, rs2835859, rs11127292, rs2243248, rs6887695, rs3212227, rs1799971, rs12579350, rs3813034, and rs6746030. Genotyping was performed by real-time PCR (q-PCR). RESULTS: The polymorphic allele of SNP rs11127292 exhibited a higher frequency in subjects with IC than in controls (p:0.01). The polymorphic allele of SNP rs6311 was more frequent in patients with severe pain (p:0.03). The frequency of the wild-type allele of SNP rs1799971 was higher in patients with mild to moderate pain (p:0.04). CONCLUSION: The results indicated differences in SNP frequency among subjects, suggesting that SNPs could serve either as a marker of IC or as a marker of pain severity in IC patients. The study showed promising results regarding IC and polymorphism associations. These associations have not been previously reported.


Assuntos
Cistite Intersticial/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Dor Crônica/genética , Dor Crônica/fisiopatologia , Cistite Intersticial/fisiopatologia , Feminino , Frequência do Gene , Marcadores Genéticos , Genótipo , Humanos , Pessoa de Meia-Idade , Dor Pélvica/genética , Dor Pélvica/fisiopatologia
20.
Kaohsiung J Med Sci ; 35(3): 139-145, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30887716

RESUMO

Accumulating evidences indicates that chronic neuropathic pain is a kind of neuro-immune disorder with enhanced activation of the immune system. Although the prevalence is very high, neuropathic pain remains extremely difficult to cure. miRNAs are a group of short nonprotein coding RNAs, regulating target genes expression via targeting 3'-untranslated region. More and more research indicates that altered miRNAs expression profile relates to the pathogenesis of neuropathic pain. In this study, we firstly detected the expression of six candidate miRNAs in the plasma samples from 23 patients with neuropathic pain and 10 healthy controls. Subsequently, the level of miR-132 and miR-101 was detected in the sural nerve biopsies. We found miR-101 level was significantly repressed in both the plasma samples and sural nerve biopsies from neuropathic pain patients. Predicted by bioinformatics tools and confirmed by dual luciferase assay and immunoblotting, we identified that KPNB1 is a direct target of miR-101. The negative correlation between miR-101 and KPNB1 was also confirmed in the sural nerve biopsies, and miR-101 reduction relates to the activation of NF-κB signaling in vivo and in vitro which contributes to the pathogenesis of neuropathic pain.


Assuntos
Dor Crônica/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Neuralgia/genética , Transdução de Sinais , beta Carioferinas/metabolismo , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Sequência de Bases , Estudos de Casos e Controles , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Dor Crônica/sangue , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Interleucina-1beta/metabolismo , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Neuralgia/sangue , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , beta Carioferinas/genética
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