RESUMEN
Fibromyalgia is a heterogenous primary pain syndrome whose severity has been associated with descending pain modulatory system (DPMS) function and functional connectivity (FC) between pain processing areas. The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism has been linked to vulnerability to chronic pain. In this cross-sectional imaging genetics study, we investigated fibromyalgia, the relationship between BDNF Val66Met heterozygous genotypes (Val/Met), and the functional connectivity (FC) response pattern to acute pain stimulus in the motor (MC) and prefrontal (PFC) cortex assessed by near-infrared spectroscopy (fNIRS) before and after a cold pressor test utilizing water (0-1 °C). Also, we assessed the relationship between this genotype with the DPMS function and quality of life. We included 42 women (Val/Val = 30; Val/Met = 12) with fibromyalgia, ages 18-65. The MANCOVA comparing Val/Met to Val/Val genotypes showed higher ΔFC between left(l)-PFC-l-MC (ß = 0.357, p = 0.048), l-PFC-right(r)-PFC (ß = 0.249, p = 0.012), l-PFC-r-MC (ß = 0.226, p = 0.022), and l-MC-r-PFC (ß = 0.260, p = 0.016). Val/Met genotypes showed higher efficiency of the DPMS and lower disability due to pain. Here we show that fibromyalgia patients carrying the Val/Met BDNF genotype presented an increased ΔFC across MC and PFC in response to acute pain associated with differences in acute pain perception and fibromyalgia symptoms.
Asunto(s)
Dolor Agudo , Fibromialgia , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Factor Neurotrófico Derivado del Encéfalo/genética , Fibromialgia/genética , Dolor Agudo/genética , Calidad de Vida , Genotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Acute pain, the most prominent complication of sickle cell disease (SCD), results from vaso-occlusion triggered by sickling of deoxygenated red blood cells (RBCs). Concentration of 2,3-diphosphoglycerate (2,3-DPG) in RBCs promotes deoxygenation by preferentially binding to the low-affinity T conformation of HbS. 2,3-DPG is an intermediate substrate in the glycolytic pathway in which pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme; variants in PKLR may affect PKR activity, 2,3-DPG levels in RBCs, RBC sickling, and acute pain episodes (APEs). We performed a candidate gene association study using 2 cohorts: 242 adult SCD-HbSS patients and 977 children with SCD-HbSS or SCD-HbSß0 thalassemia. Seven of 47 PKLR variants evaluated in the adult cohort were associated with hospitalization: intron 4, rs2071053; intron 2, rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964. All 7 variants showed consistent effect directions in both cohorts and remained significant in weighted Fisher's meta-analyses of the adult and pediatric cohorts using P < .0071 as threshold to correct for multiple testing. Allele-specific expression analyses in an independent cohort of 52 SCD adults showed that the intronic variants are likely to influence APE by affecting expression of PKLR, although the causal variant and mechanism are not defined.
Asunto(s)
Dolor Agudo , Anemia de Células Falciformes , Piruvato Quinasa , 2,3-Difosfoglicerato/metabolismo , Dolor Agudo/genética , Dolor Agudo/metabolismo , Adulto , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Niño , Eritrocitos Anormales/metabolismo , Hemoglobina Falciforme/metabolismo , Humanos , Piruvato Quinasa/genética , Piruvato Quinasa/metabolismoRESUMEN
SP16 is an innovative peptide derived from the carboxyl-terminus of α1-Antitrypsin (AAT), corresponding to residues 364-380, and contains recognition sequences for the low-density lipoprotein receptor-related protein-1 (LRP1). LRP1 is an endocytic and cell-signaling receptor that regulates inflammation. Deletion of Lrp1 in Schwann cells increases neuropathic pain; however, the role of LRP1 activation in nociceptive and neuropathic pain regulation remains unknown. Herein, we show that SP16 is bioactive in sensory neurons in vitro. Neurite length and regenerative gene expression were increased by SP16. In PC12 cells, SP16 activated Akt and ERK1/2 cell-signaling in an LRP1-dependent manner. When formalin was injected into mouse hind paws, to model inflammatory pain, SP16 dose-dependently attenuated nociceptive pain behaviors in the early and late phases. In a second model of acute pain using capsaicin, SP16 significantly reduced paw licking in both male and female mice (p < .01) similarly to enzymatically inactive tissue plasminogen activator, a known LRP1 interactor. SP16 also prevented development of tactile allodynia after partial nerve ligation and this response was sustained for nine days (p < .01). Immunoblot analysis of the injured nerve revealed decreased CD11b (p < .01) and Toll-like receptor-4 (p < .005). In injured dorsal root ganglia SP16 reduced CD11b+ cells (p < .05) and GFAP (p < .005), indicating that inflammatory cell recruitment and satellite cell activation were inhibited. In conclusion, administration of SP16 blocked pain-related responses in three distinct pain models, suggesting efficacy against acute nociceptive, inflammatory, and neuropathic pain. SP16 also attenuated innate immunity in the PNS. These studies identify SP16 as a potentially effective treatment for pain.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Neuralgia/tratamiento farmacológico , Péptidos/farmacología , alfa 1-Antitripsina/química , Dolor Agudo/inducido químicamente , Dolor Agudo/genética , Dolor Agudo/metabolismo , Animales , Modelos Animales de Enfermedad , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Ratones , Neuralgia/inducido químicamente , Neuralgia/genética , Neuralgia/metabolismo , Neuritas/metabolismo , Células PC12 , Péptidos/química , Ratas , Ratas Sprague-Dawley , Células de Schwann/metabolismo , Células Receptoras Sensoriales/metabolismo , alfa 1-Antitripsina/genéticaRESUMEN
BACKGROUND: Hyperalgesic priming (HP) is a model of the transition from acute to chronic pain. Electroacupuncture (EA) could inhibit pain development through the peripheral dorsal root ganglia; however, it is unclear whether it can mitigate the transition from acute to chronic pain by attenuating protein expression in the p38 MAPK (mitogen-activated protein kinase)/tumour necrosis factor alpha (TNF-α) pathway in the spinal dorsal horn. AIMS: We aimed to determine whether EA could prevent the transition from acute to chronic pain by affecting the p38 MAPK/TNF-α pathway in the spinal dorsal horn in a rat model established using HP. METHODS: We first randomly subdivided 30 male Sprague-Dawley (SD) rats into 5 groups (n = 6 per group): control (N), sham HP (Sham-HP), HP, HP + SB203580p38 MAPK (HP+SB203580), and HP + Lenalidomide (CC-5013) (HP+Lenalidomide). We then randomly subdivided a further 30 male SD rats into 5 groups (n = 6 per group): Sham-HP, HP, sham EA (Sham EA), EA (EA), and EA + U-46619 p38 MAPK agonist (EA+U-46619). We assessed the effects of EA on the mechanical paw withdrawal threshold and p38 MAPK/TNF-α expression in the spinal dorsal horn of rats subjected to chronic inflammatory pain. RESULTS: Rats in the EA group had reduced p38 MAPK and TNF-α expression and had significantly reduced mechanical hyperalgesia compared with rats in the other groups. CONCLUSION: Our findings indicate that EA could increase the mechanical pain threshold in rats and inhibit the transition from acute pain to chronic pain. This mechanism could involve reduced p38 MAPK/TNF-α expression in the spinal dorsal horn.
Asunto(s)
Dolor Agudo/terapia , Dolor Crónico/terapia , Electroacupuntura , Asta Dorsal de la Médula Espinal/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Dolor Agudo/genética , Dolor Agudo/metabolismo , Animales , Dolor Crónico/genética , Dolor Crónico/metabolismo , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Carbenoxolone (CBX) is primarily used to relieve various types of neuropathic and inflammatory pain. However, little is known concerning the role of CBX in acute pain and its functional mechanisms therein and this was investigated in the present study. Rats underwent toe incision and behavioral tests were performed to assess mechanical hypersensitivity. The expression levels of pannexin 1 (Px1) and connexin 43 (Cx43) were detected using western blot analysis 2, 4, 6 or 24 h after toe incision, and the expression of TNFα, IL1ß and P substance (SP) was determined by ELISA; Px1 and Cx43 expression was also examined by immunofluorescence staining. At 2, 6 and 12 h posttoe incision, the postoperative pain threshold was significantly reduced, which was subsequently recovered at 2 and 6 h postsurgery following pretreatment with CBX or pannexin 1 mimetic inhibitory peptide. CBX reduced Px1 levels at 4 and 24 h postincision. However, Cx43 levels were reduced by CBX as little as 2 h postsurgery. Furthermore, CBX not only distinctly decreased the levels of Px1 and Cx43, but also reduced the colocalization of Px1 or Cx43 with glial fibrillary acidic protein, 2 h after incision. It was also observed that the protein levels of inflammatory makers (IL1ß, SP and TNFα) showed a tendency to decline at 2, 4, 6 and 24 h after incision. Collectively, the expression of Px1 and Cx43 in astrocytes may be involved in pain behaviors diminished by CBX, and CBX potentially reduces acute pain by decreasing Px1 and Cx43 levels. Px1 and Cx43 from spinal astrocytes may serve important roles in the early stages and maintenance of acute pain, while preoperative injection of CBX has the potential to relieve hyperalgesia.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Dolor Agudo/metabolismo , Carbenoxolona/farmacología , Dolor Agudo/genética , Animales , Astrocitos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Conexinas/metabolismo , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Hiperalgesia/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
SUMMARY: Background. Pain is one of the most common symptoms that weighs on life's quality and health expenditure. In a reality in which increasingly personalized therapies are needed, the early use of genetic tests that highlight the individual response to analgesic drugs could be a valuable help in clinical practice helping to reduce response times, to achieve a good level of analgesia and to reduce the risk of side effects and adverse events. The study aims to confront the clinical response to analgesic drugs with the result of pharmacogenetic testing in patients with persistent pain. Methods. This preliminary study compares the genetic results of pharmacological effectiveness and tolerability analyzed with a Pharmacogenetic Test with the results obtained in clinical practice in 5 patients suffering from acute and chronic pain. Results. Regarding the genetic results of the 5 samples analyzed, 2 reports were found to be completely comparable to what found in clinical practice, while 3 reports showed that the profile of tolerability and effectiveness were partially discordant. Conclusions. In light of the data, not completely overlapping with results observed in clinical practice, further studies would be appropriate in order to acquire more information on the use of the PGT in clinical practice.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Pruebas de Farmacogenómica/métodos , Dolor Agudo/genética , Anciano , Analgesia , Analgésicos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor Crónico/genética , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C9/genética , Sistema Enzimático del Citocromo P-450/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos Preliminares , Resultado del Tratamiento , Adulto JovenRESUMEN
The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain-action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matched controls performed a functional magnetic resonance imaging (fMRI) task designed to dissociate stimulus type (painful or innocuous) from current behavioral relevance (relevant or irrelevant), by instructing participants to either press or refrain from pressing a button during thermal stimulation. Carriers' subjective pain thresholds did not differ from controls', but the carrier group showed decreased task accuracy. Hemodynamic activation in AI covaried with task performance, revealing a functional role in pain-action integration with increased responses for task-relevant painful stimulation ("signal," requiring button-press execution) over task-irrelevant stimulation ("noise," requiring button-press suppression). As predicted, mid-ACC activation was associated with action execution regardless of pain. Functional connectivity between AI and mid-ACC increased as a function of reported urge to withdraw from the stimulus, suggesting a joint role for these regions in motivated action during pain. The carrier group showed greater activation of primary sensorimotor cortices-but not the AI and mid-ACC regions-during pain and action, suggesting compensatory processing. These findings indicate a critical role for the AI-mid-ACC axis in supporting a flexible, adaptive action selection during pain, alongside the accompanying subjective experience of an urge to escape the pain.
Asunto(s)
Corteza Cerebral/fisiología , Actividad Motora/fisiología , Fibras Nerviosas Amielínicas/fisiología , Percepción del Dolor/fisiología , Dolor Agudo/genética , Dolor Agudo/fisiopatología , Adulto , Femenino , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Mutación , Factor de Crecimiento Nervioso/genéticaRESUMEN
One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate protein synthesis in neurons and supporting cells (glia, leukocytes, and Schwann cells). The literature indicates that miRNA regulation is important in nociception. Here, we summarize the current evidence on the role of miRNAs on mechanisms involved in incisional, inflammatory, neuropathic, and cancer pain. We also discuss the role of modulating miRNA functions as potential therapeutic targets for analgesic use and opioid tolerance. Finally, we propose how the delivery of analog miRNAs (mimic-miRNAs or antago-miRNAs) could be introduced into clinical practice to provide analgesia in the perioperative period.
Asunto(s)
MicroARNs/metabolismo , Dolor Postoperatorio/genética , Dolor Postoperatorio/metabolismo , Dolor Agudo/genética , Dolor Agudo/metabolismo , Dolor Agudo/terapia , Analgesia , Analgésicos/administración & dosificación , Analgésicos Opioides/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor en Cáncer/terapia , Tolerancia a Medicamentos , Epigénesis Genética , Costos de la Atención en Salud , Humanos , Inflamación , Manejo del Dolor/métodos , Dimensión del Dolor , Dolor Postoperatorio/terapia , Periodo Perioperatorio , Calidad de Vida , Médula Espinal/metabolismoRESUMEN
Experimental and clinical acute pain research in relation to biological sex and genetics started in the 1980s. Research methods became more powerful and sensitive with the advancement in affordable gene sequencing methods and high-throughput genetic assays. Decades of research has identified several potential pharmaceutical targets, providing insights into future research direction, and understanding of acute pain and opioid analgesic effects in the clinical setting. However, there is insufficient evidence to make generalized recommendations for using genetic tests for clinical practice of acute pain management.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos Opioides/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Polimorfismo de Nucleótido Simple , Dolor Agudo/genética , Dolor Agudo/fisiopatología , Femenino , Humanos , Masculino , Percepción del Dolor/fisiología , Dolor Postoperatorio/genética , Dolor Postoperatorio/fisiopatología , Caracteres SexualesRESUMEN
Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.
Asunto(s)
Dolor Agudo/genética , Anemia de Células Falciformes/genética , Dolor Crónico/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Alelos , Catecol O-Metiltransferasa/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Feniletanolamina N-Metiltransferasa/genética , Adulto JovenRESUMEN
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.
Asunto(s)
Dolor Agudo/metabolismo , Conducta Animal , Encéfalo/metabolismo , Quemaduras/metabolismo , Dolor Crónico/metabolismo , Umbral del Dolor , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/deficiencia , Dolor Agudo/genética , Dolor Agudo/fisiopatología , Dolor Agudo/psicología , Adenosina Trifosfato/metabolismo , Animales , Encéfalo/fisiopatología , Quemaduras/genética , Quemaduras/fisiopatología , Quemaduras/psicología , Dolor Crónico/genética , Dolor Crónico/fisiopatología , Dolor Crónico/psicología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Haploinsuficiencia , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Tiempo de Reacción , Cicatrización de HeridasRESUMEN
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.
Asunto(s)
Dolor Agudo/metabolismo , Analgésicos Opioides/farmacología , Dolor Crónico/metabolismo , Naloxona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Transducción de Señal/efectos de los fármacos , Canales Catiónicos TRPV/metabolismo , Dolor Agudo/inducido químicamente , Dolor Agudo/tratamiento farmacológico , Dolor Agudo/genética , Analgesia , Animales , Dolor Crónico/inducido químicamente , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Modelos Animales de Enfermedad , Adyuvante de Freund/efectos adversos , Adyuvante de Freund/farmacología , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Ratones , Ratones Noqueados , Naloxona/farmacología , Compuestos de Amonio Cuaternario/farmacología , Transducción de Señal/genética , Canales Catiónicos TRPV/genética , Arrestina beta 2/genética , Arrestina beta 2/metabolismoRESUMEN
Acute pain and opioid analgesia demonstrate inter-individual variability and polygenic influence. In 241 children of African American and 277 of European Caucasian ancestry, we sought to replicate select candidate gene associations with morphine dose and postoperative pain and then to estimate dose prediction limits. Twenty-seven single-nucleotide polymorphisms (SNPs) from nine genes (ABCB1, ARRB2, COMT, DRD2, KCNJ6, MC1R, OPRD1, OPRM1, and UGT2B7) met selection criteria and were analyzed along with TAOK3. Few associations replicated: morphine dose (mcg/kg) in African American children and ABCB1 rs1045642 (A allele, ß = -9.30, 95% CI: -17.25 to -1.35, p = 0.02) and OPRM1 rs1799971 (G allele, ß = 23.19, 95% CI: 3.27-43.11, p = 0.02); KCNJ6 rs2211843 and high pain in African American subjects (T allele, OR 2.08, 95% CI: 1.17-3.71, p = 0.01) and in congruent European Caucasian pain phenotypes; and COMT rs740603 for high pain in European Caucasian subjects (A allele, OR: 0.69, 95% CI: 0.48-0.99, p = 0.046). With age, body mass index, and physical status as covariates, simple top SNP candidate gene models could explain theoretical maximums of 24.2% (European Caucasian) and 14.6% (African American) of morphine dose variances.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Dolor Agudo/genética , Analgésicos Opioides/uso terapéutico , Negro o Afroamericano/genética , Morfina/uso terapéutico , Dolor Postoperatorio/genética , Población Blanca/genética , Alelos , Niño , Femenino , Genotipo , Humanos , Masculino , Manejo del Dolor/métodos , Dolor Postoperatorio/tratamiento farmacológico , Polimorfismo de Nucleótido Simple/genética , Estudios RetrospectivosRESUMEN
The transmission of normal sensory and/or acute noxious information requires intact expression of pain-associated genes within the pain pathways of nervous system. Expressional changes of these genes after peripheral nerve injury are also critical for neuropathic pain induction and maintenance. Methyl-CpG-binding domain protein 1 (MBD1), an epigenetic repressor, regulates gene transcriptional activity. We report here that MBD1 in the primary sensory neurons of DRG is critical for the genesis of acute pain and neuropathic pain as DRG MBD1-deficient mice exhibit the reduced responses to acute mechanical, heat, cold, and capsaicin stimuli and the blunted nerve injury-induced pain hypersensitivities. Furthermore, DRG overexpression of MBD1 leads to spontaneous pain and evoked pain hypersensitivities in the WT mice and restores acute pain sensitivities in the MBD1-deficient mice. Mechanistically, MDB1 represses Oprm1 and Kcna2 gene expression by recruiting DNA methyltransferase DNMT3a into these two gene promoters in the DRG neurons. DRG MBD1 is likely a key player under the conditions of acute pain and neuropathic pain.SIGNIFICANCE STATEMENT In the present study, we revealed that the mice with deficiency of methyl-CpG-binding domain protein 1 (MBD1), an epigenetic repressor, in the DRG displayed the reduced responses to acute noxious stimuli and the blunted neuropathic pain. We also showed that DRG overexpression of MBD1 produced the hypersensitivities to noxious stimuli in the WT mice and rescued acute pain sensitivities in the MBD1-deficient mice. We have also provided the evidence that MDB1 represses Oprm1 and Kcna2 gene expression by recruiting DNA methyltransferase DNMT3a into these two gene promoters in the DRG neurons. DRG MBD1 may participate in the genesis of acute pain and neuropathic pain likely through regulating DNMT3a-controlled Oprm1 and Kcna2 gene expression in the DRG neurons.
Asunto(s)
Dolor Agudo/metabolismo , Proteínas de Unión al ADN/biosíntesis , Epigénesis Genética/fisiología , Canal de Potasio Kv.1.2/biosíntesis , Neuralgia/metabolismo , Receptores Opioides mu/biosíntesis , Dolor Agudo/genética , Animales , Células Cultivadas , Proteínas de Unión al ADN/genética , Ganglios Espinales/química , Ganglios Espinales/metabolismo , Silenciador del Gen/fisiología , Canal de Potasio Kv.1.2/antagonistas & inhibidores , Canal de Potasio Kv.1.2/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuralgia/genética , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/genética , Células Receptoras Sensoriales/química , Células Receptoras Sensoriales/metabolismoRESUMEN
AIM: Pain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease. METHOD: Acute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score. RESULTS & CONCLUSION: rs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p < 0.001 additive; IRR = 2.25, p = 0.021 dominant; IRR = 2.07, p < 0.001 recessive) and rs9324918 C allele (IRR = 1.43, p = 0.021 additive) were associated with higher utilization rates, indicating the potential contribution of NR3C1 polymorphisms to acute pain heterogeneity in sickle cell disease.
Asunto(s)
Dolor Agudo/genética , Anemia de Células Falciformes/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Receptores de Glucocorticoides/genética , Adolescente , Adulto , Anciano , Alelos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIM: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. METHODS: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. RESULTS & CONCLUSION: We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.
Asunto(s)
Dolor Agudo/etiología , Dolor Agudo/genética , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Haplotipos/genética , Polimorfismo Genético/genética , Canales de Potencial de Receptor Transitorio/genética , Dolor Agudo/epidemiología , Adolescente , Adulto , Anciano , Anemia de Células Falciformes/epidemiología , Servicios Médicos de Urgencia/estadística & datos numéricos , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Canal Catiónico TRPA1/genética , Canales Catiónicos TRPV/genética , Adulto JovenRESUMEN
Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel, which can detect various noxious stimuli that cause pain, inflammation, hyperalgesia, and itch. TRPV1 knock-out mice show deficiency in nociception, but the in vivo effects of persistent activation of TRPV1 are not completely understood. Here, we generated TRPV1 knock-in mice with a G564S mutation. In the heterologous expression system, an electrophysiological study showed that the G564S mutation in mouse TRPV1 caused increased basal current and a leftward shift of voltage dependence. Intriguingly, using behavioral analysis, we found that knock-in mice showed a thermosensory defect, impaired inflammatory thermal pain, and capsaicin sensitivity. We also demonstrated an attenuated behavioral response to the pruritic agent histamine in the knock-in mice. Indeed, calcium imaging together with electrophysiology showed that the overactive mutant had decreased capsaicin sensitivity. Western blot analysis revealed that the G564S mutant reduced TRPV1 phosphorylation and cell membrane trafficking. Together, we have generated a mouse model with a gain-of-function mutation in Trpv1 gene and demonstrated that the pain and histamine-dependent itch sensations in these mice are impaired due to a decreased phosphorylation level and reduced membrane localization of TRPV1.
Asunto(s)
Mutación con Ganancia de Función/genética , Dolor/genética , Dolor/fisiopatología , Prurito/genética , Prurito/fisiopatología , Sensación , Canales Catiónicos TRPV/genética , Dolor Agudo/complicaciones , Dolor Agudo/genética , Dolor Agudo/patología , Dolor Agudo/fisiopatología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Conducta Animal , Calcio/metabolismo , Capsaicina/farmacología , Membrana Celular/metabolismo , Técnicas de Sustitución del Gen , Células HEK293 , Histamina , Humanos , Hiperalgesia/complicaciones , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Inflamación/complicaciones , Inflamación/patología , Inflamación/fisiopatología , Espacio Intracelular/metabolismo , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Dolor/complicaciones , Fosforilación , Prurito/complicaciones , Canales Catiónicos TRPV/química , Canales Catiónicos TRPV/metabolismo , TemperaturaRESUMEN
BACKGROUND: A major research emphasis has been focused on defining the molecular changes that occur from acute to chronic pain to identify potential therapeutic targets for chronic pain. As the endocannabinoid system is dynamically involved in pain signaling, a plausible mechanism that may contribute to chronic pain vulnerability involves alterations in the amount of circulating endocannabinoids. Therefore, this study sought to examine cannabinoid type 1 (CNR1), type 2 (CNR2) receptors, fatty acid amide hydrolase (FAAH), and the vanilloid receptor (transient receptor potential cation channel subfamily V member 1 [TRPV1]) gene expression profiles among individuals with acute and chronic low back pain (cLBP) at their baseline visit. We also assessed associations among selected single nucleotide polymorphisms (SNPs) of FAAH and CNR2 and measures of somatosensory function and self-report pain measures.Using a previously established quantitative sensory testing protocol, we comprehensively assessed somatosensory parameters among 42 acute LBP, 42 cLBP, and 20 pain-free participants. Samples of whole blood were drawn to examine mRNA expression and isolate genomic DNA for genotyping.CNR2 mRNA was significantly upregulated in all LBP patients compared with controls. However, FAAH mRNA and TRPV1 mRNA were significantly upregulated in cLBP compared with controls. A significant association was observed between FAAH SNP genotype and self-report pain measures, mechanical and cold pain sensitivity among LBP participants. cLBP participants showed increased FAAH and TRPV1 mRNA expression compared with acute LBP patients and controls.Further research to characterize pain-associated somatosensory changes in the context of altered mRNA expression levels and SNP associations may provide insight on the molecular underpinnings of maladaptive chronic pain.
Asunto(s)
Dolor Crónico/genética , Endocannabinoides/genética , Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Dolor de la Región Lumbar/genética , Polimorfismo de Nucleótido Simple/genética , Dolor Agudo/genética , Adolescente , Adulto , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Endocannabinoides/metabolismo , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Lineales , Dolor de la Región Lumbar/metabolismo , Dolor de la Región Lumbar/psicología , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Umbral del Dolor/fisiología , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Autoinforme , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Transcriptoma , Adulto JovenRESUMEN
The NLRP3 inflammasome is a multi-protein complex that assembles in response to tissue damage or infection, triggering activation of caspase-1, an enzyme that converts interleukin (IL)-1ß into its active form. A role for the NLRP3 inflammasome is emerging in inflammatory pain, but its influence in other pain types is largely unexamined. Therefore the aim of this study was to assess the role of the NLRP3 inflammasome and its downstream product caspase-1 in a model of acute burn-induced pain in male mice. A superficial burn was induced on the plantar surface of the left hind paw using a hot plate set at 52.5°C for 25s. Development of burn-induced mechanical allodynia, thermal allodynia, edema and weight bearing changes was assessed in Nlrp3-/- and caspase-1-deficient (Ice-/-) mice, and in mice administered the selective NLRP3 inflammasome inhibitor MCC950. Burn-induced mechanical and thermal allodynia developed normally in Nlrp3-/- and Ice-/- mice and mice administered MCC950. Burn-induced edema was significantly reduced in Ice-/- mice only. Burn-induced weight bearing changes were attenuated in Nlrp3-/- mice and mice administered MCC950 72h after burn only. This study suggests that NLRP3 and its downstream product caspase-1 have a limited role in the development of burn-induced pain.