Asunto(s)

Mutación , Dolor , Humanos , Dolor/genética , Mutación/genética , Animales

RESUMEN

This case-control study investigated single nucleotide polymorphism (SNP) genotypes (CXC motif chemokine ligand 8 (CXCL8): rs2227306 and rs2227307 and tumor necrosis factor (TNF): rs1800629) in 85 patients with pain-related temporomandibular disorders (TMDp) and 85 controls to explore their associations with TMDp presence, pain intensity (low/high), and the presence of chronic arthralgia/myalgia. TMDp was diagnosed using a validated protocol, and polymorphisms were genotyped from buccal mucosa swabs using TaqMan assays. High pain intensity individuals had an increased risk for carrying minor allele "G" (rs2227307) and "T" (rs2227306) compared to controls (76% vs. 55.3%, p = 0.012; 72% vs. 54.1%, p = 0.030, respectively). Carriers of the minor allele "G" (rs2227307) were more prevalent in TMDp patients with arthralgia compared to controls (70.30% vs. 55.30%, p = 0.037). According to logistic regression, the most important predictors for high pain intensity were minor allele "G" of rs2227307 (OR 2.435, 95% CI 1.123-5.282), increasing age (OR 1.038, 95% CI 1.002-1.075), and female sex (OR 4.592, 95% CI 1.289-16.361). The explored gene polymorphisms were not significant risk factors for TMDp presence. These findings highlight the importance of genetic variations, particularly rs2227307, in understanding the diverse clinical manifestations of temporomandibular disorders.

Asunto(s)

Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Trastornos de la Articulación Temporomandibular , Humanos , Trastornos de la Articulación Temporomandibular/genética , Femenino , Masculino , Adulto , Estudios de Casos y Controles , Persona de Mediana Edad , Alelos , Genotipo , Citocinas/genética , Dolor/genética , Factor de Necrosis Tumoral alfa/genética

RESUMEN

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain.

Asunto(s)

Capsaicina , Dolor , Canales Catiónicos TRPV , Animales , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Capsaicina/farmacología , Masculino , Femenino , Ratones , Dolor/metabolismo , Dolor/genética , Hormonas Esteroides Gonadales/metabolismo , Ciclo Estral/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Caracteres Sexuales , ARN Mensajero/metabolismo , ARN Mensajero/genética

RESUMEN

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain-depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain-depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein-protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain-depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population.

Asunto(s)

Biomarcadores , Comorbilidad , Biología Computacional , Depresión , Redes Reguladoras de Genes , Estrés Oxidativo , Dolor , Mapas de Interacción de Proteínas , Estrés Oxidativo/genética , Humanos , Biología Computacional/métodos , Dolor/genética , Dolor/epidemiología , Mapas de Interacción de Proteínas/genética , Depresión/genética , Depresión/epidemiología , Perfilación de la Expresión Génica , Transducción de Señal/genética

RESUMEN

There has been significant progress in our understanding of the molecular basis by which nociceptors transduce and transmit noxious (tissue damaging) stimuli. This is dependent on ion channels, many of which are selectively expressed in nociceptors. Mutations in such proteins have recently been linked to inherited pain disorders in humans. An exemplar is the voltage-gated sodium channel (VGSC) NaV1.7. Loss of function mutations in NaV1.7 result in congenital inability to experience pain while gain-of-function mutations can cause a number of distinct neuropathic pain disorders, including erythromelalgia, paroxysmal extreme pain disorder, and small-fiber neuropathy. Furthermore, variants in the VGSCs 1.8 and 1.9 have also been linked to human pain disorders. There is a correlation between the impact of mutations on the biophysical properties of the ion channel and the severity of the clinical phenotype. Pain channelopathies are not restricted to VGSCs: a mutation in the ligand-gated ion channel TRPA1, (which responds to environmental irritants) causes a familial episodic pain disorder. Ion channel variants have also been linked to more common neuropathic pain disorders such as painful diabetic neuropathy. Not only do these ion channels present targets for novel analgesics, but stratification based on genotype may improve treatment selection of existing analgesics.

Asunto(s)

Canalopatías , Humanos , Canalopatías/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Dolor/genética , Neuralgia/genética

RESUMEN

Multiple approaches have targeted voltage-gated sodium (Nav) channels for analgesia. In this issue of the JCI, Shin et al. identified a peptide aptamer, NaViPA1, carrying a short polybasic motif flanked by serine residues in a structurally disordered region of loop 1 in tetrodotoxin-sensitive (TTX-S) but not tetrodotoxin-resistant (TTX-R) channels. NaViPA1h inhibited TTX-S NaV channels and attenuated excitability of sensory neurons. Delivery of NaViPA1 in vivo via adeno-associated virions restricted its expression to peripheral sensory neurons and induced analgesia in rats. Targeting of short linear motifs in this manner may provide a gene therapy modality, with minimal side effects due to its peripherally-restricted biodistribution, which opens up a therapeutic strategy for hyperexcitability disorders, including pain.

Asunto(s)

Terapia Genética , Animales , Humanos , Ratas , Canales de Sodio Activados por Voltaje/genética , Canales de Sodio Activados por Voltaje/metabolismo , Canales de Sodio Activados por Voltaje/química , Células Receptoras Sensoriales/metabolismo , Dolor/genética , Dolor/metabolismo , Dolor/tratamiento farmacológico , Secuencias de Aminoácidos

RESUMEN

Itch is a unique sensory experience that is responded to by scratching. How pruritogens, which are mechanical and chemical stimuli with the potential to cause itch, engage specific pathways in the peripheral and central nervous system has been a topic of intense investigation over the last few years. Studies employing recently developed molecular, physiological, and behavioral techniques have delineated the dedicated mechanisms that transmit itch information to the brain. This review outlines the genetically defined and evolutionary conserved circuits for itch ranging from the skin-innervating peripheral neurons to the cortical neurons that drive scratching. Moreover, scratch suppression of itch is attributed to the concurrent activation of pain and itch pathways. Hence, we discuss the similarities between circuits driving pain and itch.

Asunto(s)

Vías Nerviosas , Prurito , Prurito/fisiopatología , Prurito/patología , Prurito/genética , Humanos , Animales , Neuronas/metabolismo , Piel/patología , Dolor/patología , Dolor/fisiopatología , Dolor/genética , Encéfalo/fisiopatología

RESUMEN

Pain is estimated to affect more than 20% of the global population, imposing incalculable health and economic burdens. Effective pain management is crucial for individuals suffering from pain. However, the current methods for pain assessment and treatment fall short of clinical needs. Benefiting from advances in neuroscience and biotechnology, the neuronal circuits and molecular mechanisms critically involved in pain modulation have been elucidated. These research achievements have incited progress in identifying new diagnostic and therapeutic targets. In this review, we first introduce fundamental knowledge about pain, setting the stage for the subsequent contents. The review next delves into the molecular mechanisms underlying pain disorders, including gene mutation, epigenetic modification, posttranslational modification, inflammasome, signaling pathways and microbiota. To better present a comprehensive view of pain research, two prominent issues, sexual dimorphism and pain comorbidities, are discussed in detail based on current findings. The status quo of pain evaluation and manipulation is summarized. A series of improved and innovative pain management strategies, such as gene therapy, monoclonal antibody, brain-computer interface and microbial intervention, are making strides towards clinical application. We highlight existing limitations and future directions for enhancing the quality of preclinical and clinical research. Efforts to decipher the complexities of pain pathology will be instrumental in translating scientific discoveries into clinical practice, thereby improving pain management from bench to bedside.

Asunto(s)

Dolor , Humanos , Dolor/genética , Dolor/patología , Manejo del Dolor , Animales

RESUMEN

The dark genome, the nonprotein-coding part of the genome, is replete with long noncoding RNAs (lncRNAs). These functionally versatile transcripts, with specific temporal and spatial expression patterns, are critical gene regulators that play essential roles in health and disease. In recent years, FAAH-OUT was identified as the first lncRNA associated with an inherited human pain insensitivity disorder. Several other lncRNAs have also been studied for their contribution to chronic pain and genome-wide association studies are frequently identifying single nucleotide polymorphisms that map to lncRNAs. For a long time overlooked, lncRNAs are coming out of the dark and into the light as major players in human pain pathways and as potential targets for new RNA-based analgesic medicines.

Asunto(s)

Dolor , ARN Largo no Codificante , ARN Largo no Codificante/genética , Humanos , Dolor/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Animales , Regulación de la Expresión Génica/genética

RESUMEN

(1) Introduction: Despite documented clinical and pain discrepancies between male and female osteoarthritis (OA) patients, the underlying mechanisms remain unclear. Synovial myofibroblasts, implicated in synovial fibrosis and OA-related pain, offer a potential explanation for these sex differences. Additionally, interleukin-24 (IL24), known for its role in autoimmune disorders and potential myofibroblast production, adds complexity to understanding sex-specific variations in OA. We investigate its role in OA and its contribution to observed sex differences. (2) Methods: To assess gender-specific variations, we analyzed myofibroblast marker expression and IL24 levels in synovial tissue samples from propensity-matched male and female OA patients (each n = 34). Gene expression was quantified using quantitative polymerase chain reaction (qPCR). The association between IL24 expression levels and pain severity, measured by a visual analog scale (VAS), was examined to understand the link between IL24 and OA pain. Synovial fibroblast subsets, including CD45-CD31-CD39- (fibroblast) and CD45-CD31-CD39+ (myofibroblast), were magnetically isolated from female patients (n = 5), and IL24 expression was compared between these subsets. (3) Results: Females exhibited significantly higher expression of myofibroblast markers (MYH11, ET1, ENTPD2) and IL24 compared to males. IL24 expression positively correlated with pain severity in females, while no correlation was observed in males. Further exploration revealed that the myofibroblast fraction highly expressed IL24 compared to the fibroblast fraction in both male and female samples. There was no difference in the myofibroblast fraction between males and females. (4) Conclusions: Our study highlights the gender-specific role of myofibroblasts and IL24 in OA pathogenesis. Elevated IL24 levels in females, correlating with pain severity, suggest its involvement in OA pain experiences. The potential therapeutic implications of IL24, demonstrated in autoimmune disorders, open avenues for targeted interventions. Notwithstanding the limitations of the study, our findings contribute to understanding OA's multifaceted nature and advocate for future research exploring mechanistic underpinnings and clinical applications of IL24 in synovial myofibroblasts. Additionally, future research directions should focus on elucidating the precise mechanisms by which IL24 contributes to OA pathology and exploring its potential as a therapeutic target for personalized medicine approaches.

Asunto(s)

Interleucinas , Miofibroblastos , Osteoartritis , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Interleucinas/genética , Interleucinas/inmunología , Miofibroblastos/inmunología , Osteoartritis/genética , Osteoartritis/inmunología , Dolor/genética , Dolor/inmunología , Puntaje de Propensión , Factores Sexuales , Membrana Sinovial/inervación

RESUMEN

Estimates suggest that only 24.9% of infants born in 2019 were exclusively breastfed before 6 months of age, despite the known health benefits of exclusive breastfeeding. Breast and nipple pain is one of the primary determinants of exclusive breastfeeding. Environmental contributions to breastfeeding success have been reported extensively in the literature, but the contribution(s) of maternal genetics has yet to be discovered. The purpose of the study was to identify an association between pain and lactation-related gene variants with exclusive breastfeeding determinants. We selected 4 genes having single nucleotide polymorphisms (SNPs) with potential functional significance in breastfeeding and pain: prolactin receptor (PRLR), oxytocin receptor (OXTR), catechol-O-methyltransferase (COMT), and milk fat globule epidermal growth factor and factor V/VIII domain containing (MFGE8). We performed a cross-sectional secondary analysis of a longitudinal randomized controlled trial study, Promoting Self-Management of Breast and Nipple Pain with Biomarkers and Technology for Breastfeeding Women (NCT05262920). Breast and nipple pain, perceived insufficient milk, and breastfeeding self-efficacy were examined using total scale scores for the Brief Pain Inventory, Visual Analog Scale, H&H Lactation Scale, and the Breastfeeding Self-efficacy Scale-short form, respectively. Of the candidate genes examined, SNPs within COMT were significantly associated with breastfeeding-related outcomes. Specifically, COMT rs4633 and rs4680 minor allele carriers (T, A) reported higher breast and nipple pain intensity than women homozygous for the major allele (C, G). COMT is the most widely researched "pain gene" and has been linked to cold, postoperative, and postpartum pain. This study is the first to identify a contribution of COMT variants to breast and nipple pain and, as a result, to breastfeeding exclusivity. PERSPECTIVE: Two SNPs in the pain gene COMT are associated with breast and nipple pain. Clinically, a minor allele in COMT rs4633 and rs4680 may increase a woman's rating of moderate breast and nipple pain. TRIAL REGISTRATION: PROMPT was registered in ClinicalTrials.gov (protocol #NCT05262920).

Asunto(s)

Lactancia Materna , Catecol O-Metiltransferasa , Pezones , Polimorfismo de Nucleótido Simple , Humanos , Catecol O-Metiltransferasa/genética , Femenino , Adulto , Estudios Transversales , Dolor/genética , Estudios Longitudinales , Adulto Joven , Mastodinia/genética , Lactancia/genética

RESUMEN

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-ß response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.

Asunto(s)

Proteínas de la Membrana , Nociceptores , Animales , Ratones , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nociceptores/metabolismo , Ganglios Espinales/metabolismo , Interferón beta/genética , Interferón beta/metabolismo , Inflamación/genética , Inflamación/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Dolor/metabolismo , Dolor/genética , Transducción de Señal , Masculino

RESUMEN

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Neiguan" (PC6) on pain response in mice injected with complete Freund's adjuvant (CFA) in the hind paw, so as to investigate the mechanism of orexin 1 receptor (OX1R) -endogenous cannabinoid 1 receptor (CB1R) pathway in acupuncture analgesia. METHODS: A total of 48 male C57BL/6 mice were used in the present study. In the first part of this study, 18 mice were randomized into control, model and EA groups, with 6 mice in each group. In the second part of this study, 30 mice were randomized into control, model, EA, EA+Naloxone, EA+OX1R antagonist (SB33486) groups, with 6 mice in each group. Inflammatory pain model was established by subcutaneous injection of 20 µL CFA solution in the left hind paw. EA (2 Hz, 2 mA ) was applied to bilateral PC6 for 20 min, once a day for 5 consecutive days. The mice in the EA+Naloxone and EA+SB33486 groups were intraperitoneally injected with naloxone (10 mg/kg) or SB33486 (15 mg/kg) 15 min before EA intervention on day 5, respectively. Tail-flick method and Von Frey method were used to detect the thermal pain threshold and mechanical pain threshold of mice. Quantitative real-time PCR was used to detect the expression level of ß-endorphin mRNA in periaqueductal gray (PAG) of mice. The expression of OX1R positive cells in the lateral hypothalamic area (LH) and CB1R positive cells in the ventrolateral periaqueductal gray (vlPAG) were detected by immunofluorescence. RESULTS: Compared with the control group, the thermal pain threshold and mechanical pain threshold of the model group were decreased (P<0.001), the expression level of ß-endorphin mRNA in PAG was decreased (P<0.001), and the numbers of OX1R positive cells in LH and CB1R positive cells in vlPAG were decreased (P<0.05, P<0.001). Compared with the model group, the thermal pain threshold and mechanical pain threshold of the EA group were significantly increased (P<0.001), and the numbers of OX1R positive cells in LH and CB1R positive cells in vlPAG were increased (P<0.01, P<0.001). Compared with the EA group, the mechanical pain threshold in the EA+SB33486 group was significantly decreased (P<0.01), but there was no significant difference in the mechanical pain threshold between the EA+Naloxone group and EA group, and the numbers of OX1R positive neurons in LH and CB1R positive neurons in vlPAG were decreased in the EA+SB33486 group (P<0.001). CONCLUSIONS: EA at PC6 can achieve analgesic effect on CFA mice by activating the OX1R-CB1R pathway in the brain, and this effect is opioid-independent.

Asunto(s)

Puntos de Acupuntura , Encéfalo , Electroacupuntura , Receptores de Orexina , Dolor , Animales , Humanos , Masculino , Ratones , Encéfalo/metabolismo , Inflamación/terapia , Inflamación/metabolismo , Inflamación/genética , Ratones Endogámicos C57BL , Receptores de Orexina/metabolismo , Receptores de Orexina/genética , Dolor/metabolismo , Dolor/genética , Manejo del Dolor

RESUMEN

Pain and inflammation are biologically intertwined responses that warn the body of potential danger. In this issue of the JCI, Defaye, Bradaia, and colleagues identified a functional link between inflammation and pain, demonstrating that inflammation-induced activation of stimulator of IFN genes (STING) in dorsal root ganglia nociceptors reduced pain-like behaviors in a rodent model of inflammatory pain. Utilizing mice with a gain-of-function STING mutation, Defaye, Bradaia, and colleagues identified type I IFN regulation of voltage-gated potassium channels as the mechanism of this pain relief. Further investigation into mechanisms by which proinflammatory pathways can reduce pain may reveal druggable targets and insights into new approaches for treating persistent pain.

Asunto(s)

Ganglios Espinales , Proteínas de la Membrana , Dolor , Animales , Ratones , Ganglios Espinales/metabolismo , Dolor/genética , Dolor/metabolismo , Dolor/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Humanos , Nociceptores/metabolismo , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Canales de Potasio con Entrada de Voltaje/inmunología , Interferón Tipo I/metabolismo , Interferón Tipo I/genética , Interferón Tipo I/inmunología

RESUMEN

OBJECTIVES: To observe whether acupuncture up-regulates chemokine CXC ligand 1 (CXCL1) in the brain to play an analgesic role through CXCL1/chemokine CXC receptor 2 (CXCR2) signaling in adjuvant induced arthritis (AIA) rats, so as to reveal its neuro-immunological mechanism underlying improvement of AIA. METHODS: BALB/c mice with relatively stable thermal pain reaction were subjected to planta injection of complete Freund adjuvant (CFA) for establishing AIA model, followed by dividing the AIA mice into simple AF750 (fluorochrome) and AF750+CXCL1 groups (n=2 in each group). AF750 labeled CXCL1 recombinant protein was then injected into the mouse's tail vein to induce elevation of CXCL1 level in blood for simulating the effect of acupuncture stimulation which has been demonstrated by our past study. In vivo small animal imaging technology was used to observe the AF750 and AF750+CXCL1-labelled target regions. After thermal pain screening, the Wistar rats with stable pain reaction were subjected to AIA modeling by injecting CFA into the rat's right planta, then were randomized into model and manual acupuncture groups (n=12 in each group). Other 12 rats that received planta injection of saline were used as the control group. Manual acupuncture (uniform reinforcing and reducing manipulations) was applied to bilateral "Zusanli" (ST36) for 4×2 min, with an interval of 5 min between every 2 min, once daily for 7 days. The thermal pain threshold was assessed by detecting the paw withdrawal latency (PWL) using a thermal pain detector. The contents of CXCL1 in the primary somatosensory cortex (S1), medial prefrontal cortex, nucleus accumbens, amygdala, periaqueductal gray and rostroventromedial medulla regions were assayed by using ELISA, and the expression levels of CXCL1, CXCR2 and mu-opioid receptor (MOR) mRNA in the S1 region were detected using real time-quantitative polymerase chain reaction. The immune-fluorescence positive cellular rate of CXCL1 and CXCR2 in S1 region was observed after immunofluorescence stain. The immunofluorescence double-stain of CXCR2 and astrocyte marker glial fibrillary acidic protein (GFAP) or neuron marker NeuN or MOR was used to determine whether there is a co-expression between them. RESULTS: In AIA mice, results of in vivo experiments showed no obvious enrichment signal of AF750 or AF750+CXCL1 in any organ of the body, while in vitro experiments showed that there was a stronger fluorescence signal of CXCL1 recombinant protein in the brain. In rats, compared with the control group, the PWL from day 0 to day 7 was significantly decreased (P<0.01) and the expression of CXCR2 mRNA in the S1 region significantly increased in the model group (P<0.05), while in comparison with the model group, the PWL from day 2 to day 7, CXCL1 content, CXCR2 mRNA expression and CXCR2 content, and MOR mRNA expression in the S1 region were significantly increased in the manual acupuncture group (P<0.05, P<0.01). Immunofluorescence stain showed that CXCR2 co-stained with NeuN and MOR in the S1 region, indicating that CXCR2 exists in neurons and MOR-positive neurons but not in GFAP positive astrocytes. CONCLUSIONS: Acupuncture can increase the content of CXCL1 in S1 region, up-regulate CXCR2 on neurons in the S1 region and improve MOR expression in S1 region of AIA rats, which may contribute to its effect in alleviating inflammatory pain.

Asunto(s)

Terapia por Acupuntura , Artritis Experimental , Quimiocina CXCL1 , Receptores de Interleucina-8B , Corteza Somatosensorial , Animales , Humanos , Masculino , Ratones , Ratas , Puntos de Acupuntura , Artritis Experimental/terapia , Artritis Experimental/metabolismo , Artritis Experimental/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/genética , Inflamación/terapia , Inflamación/metabolismo , Inflamación/genética , Ratones Endogámicos BALB C , Dolor/metabolismo , Dolor/genética , Manejo del Dolor , Ratas Wistar , Receptores de Interleucina-8B/metabolismo , Receptores de Interleucina-8B/genética , Transducción de Señal , Corteza Somatosensorial/metabolismo

RESUMEN

RNAs are meticulously controlled by proteins. Through direct and indirect associations, every facet in the brief life of an mRNA is subject to regulation. RNA-binding proteins (RBPs) permeate biology. Here, we focus on their roles in pain. Chronic pain is among the largest challenges facing medicine and requires new strategies. Mounting pharmacologic and genetic evidence obtained in pre-clinical models suggests fundamental roles for a broad array of RBPs. We describe their diverse roles that span RNA modification, splicing, stability, translation, and decay. Finally, we highlight opportunities to expand our understanding of regulatory interactions that contribute to pain signaling. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications Translation > Regulation RNA in Disease and Development > RNA in Disease.

Asunto(s)

Empalme del ARN , Proteínas de Unión al ARN , Humanos , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Dolor/genética

RESUMEN

PURPOSE: Lumbar spinal stenosis (LSS) is common in our aging population resulting in pain and functional impairment. Recent advances in pain research have identified several single nucleotide polymorphisms (SNP) associated with inter-individual symptom and treatment response. The goal of the current study was to investigate the association of SNPs in Neuropeptide Y (NPY) and Catechol-O-methyltransferase (COMT) with pain, function, and treatment outcomes in Lumbar spinal stenosis (LSS) patients receiving non-surgical treatments. METHODS: An exploratory observational biomarker study was performed ancillary to a previously published clinical trial evaluating three different non-surgical treatments for LSS. Saliva samples were obtained for single nucleotide polymorphism genotyping and blood samples were collected for NPY protein. Data on pain and function collected as part of the clinical trial at baseline, 2 and 6 months were examined for association with known polymorphisms in NPY and COMT. RESULTS: Subjects with the NPY rs16147 TT genotype exhibited higher baseline symptom severity but also a higher likelihood of responding to non-surgical treatments. Subjects with the COMT rs4680 GG genotype also exhibited higher baseline symptom severity but did not demonstrate greater response to treatment. CONCLUSIONS: NPY rs16147 and COMT rs4680 are important potential biomarkers associated with pain and function. NPY genotype may be useful in predicting response to non-surgical treatments in older adults with LSS.

Asunto(s)

Catecol O-Metiltransferasa , Vértebras Lumbares , Neuropéptido Y , Polimorfismo de Nucleótido Simple , Estenosis Espinal , Humanos , Estenosis Espinal/genética , Femenino , Masculino , Anciano , Catecol O-Metiltransferasa/genética , Resultado del Tratamiento , Neuropéptido Y/genética , Persona de Mediana Edad , Dolor/genética , Dolor/etiología , Anciano de 80 o más Años

RESUMEN

AIM: Pain is reconstructed by brain activities and its subjectivity comes from an interplay of multiple factors. The current study aims to understand the contribution of genetic factors to the neural processing of pain. Focusing on the single-nucleotide polymorphism (SNP) of opioid receptor mu 1 (OPRM1) A118G (rs1799971) and catechol-O-methyltransferase (COMT) val158met (rs4680), we investigated how the two pain genes affect pain processing. METHOD: We integrated a genetic approach with functional neuroimaging. We extracted genomic DNA information from saliva samples to genotype the SNP of OPRM1 and COMT. We used a percept-related model, in which two different levels of perceived pain intensities ("low pain: mildly painful" vs "high pain: severely painful") were employed as experimental stimuli. RESULTS: Low pain involves a broader network relative to high pain. The distinct effects of pain genes were observed depending on the perceived pain intensity. The effects of low pain were found in supramarginal gyrus, angular gyrus, and anterior cingulate cortex (ACC) for OPRM1 and in middle temporal gyrus for COMT. For high pain, OPRM1 affected the insula and cerebellum, while COMT affected the middle occipital gyrus and ACC. CONCLUSION: OPRM1 primarily affects sensory and cognitive components of pain processing, while COMT mainly influences emotional aspects of pain processing. The interaction of the two pain genes was associated with neural patterns coding for high pain and neural activation in the ACC in response to pain. The proteins encoded by the OPRM1 and COMT may contribute to the firing of pain-related neurons in the human ACC, a critical center for subjective pain experience.

Asunto(s)

Catecol O-Metiltransferasa , Dolor , Polimorfismo de Nucleótido Simple , Receptores Opioides mu , Humanos , Catecol O-Metiltransferasa/genética , Receptores Opioides mu/genética , Masculino , Adulto , Femenino , Adulto Joven , Dolor/genética , Dolor/fisiopatología , Imagen por Resonancia Magnética , Percepción del Dolor/fisiología , Encéfalo/fisiopatología , Neuroimagen Funcional

RESUMEN

T-type Ca2+ channels and TRPA1 expressed in sensory neurons are involved in pain. We previously demonstrated a functional interaction of these channels under physiological conditions. Here we investigated the possible involvement of these channels in inflammatory pain condition. We also evaluated the relationship of these channels endogenously expressed in RIN-14B, a rat pancreatic islet tumor cell line. In dorsal root ganglion (DRG) neurons innervated inflammatory side, [Ca2+]i increases induced by 15 mM KCl (15K) were enhanced in neurons responded to AITC. This enhancement was not observed in genetically TRPA1-deficient neurons. The T-type and AITC-induced currents were larger in neurons of the inflammatory side than in those of the control one. In DRGs of the inflammatory side, the protein expression of Cav3.2, but not TRPA1, was increased. In RIN-14B, 15K-induced [Ca2+]i increases were decreased by blockers of T-type Ca2+ channel and TRPA1, and by TRPA1-silencing. Immunoprecipitation suggested the coexistent of these channels in sensory neurons and RIN-14B. In mice with inflammation, mechanical hypersensitivity was suppressed by blockers of both channels. These data suggest that the interaction of Cav3.2 with TRPA1 in sensory neurons is enhanced via the augmentation of the activities of both channels under inflammatory conditions, indicating that both channels are therapeutic targets for inflammatory pain.

Asunto(s)

Calcio , Isotiocianatos , Nocicepción , Animales , Ratones , Ratas , Calcio/metabolismo , Ganglios Espinales/metabolismo , Dolor/genética , Dolor/metabolismo , Células Receptoras Sensoriales/metabolismo , Canal Catiónico TRPA1/genética

RESUMEN

The hypothalamic molecular processes participate in the regulation of the neuro-immune-endocrine system, including hormone, metabolite, chemokine circulation, and corresponding physiological and behavioral responses. RNA-sequencing profiles were analyzed to understand the effect of juvenile immune and metabolic distress 100 days after virally elicited maternal immune activation during gestation in pigs. Over 1,300 genes exhibited significant additive or interacting effects of gestational immune activation, juvenile distress, and sex. One-third of these genes presented multiple effects, emphasizing the complex interplay of these factors. Key functional categories enriched among affected genes included sensory perception of pain, steroidogenesis, prolactin, neuropeptide, and inflammatory signaling. These categories underscore the intricate relationship between gestational immune activation during gestation, distress, and the response of hypothalamic pathways to insults. These effects were sex-dependent for many genes, such as Prdm12, Oprd1, Isg20, Prl, Oxt, and Vip. The prevalence of differentially expressed genes annotated to proinflammatory and cell cycle processes suggests potential implications for synaptic plasticity and neuronal survival. The gene profiles affected by immune activation, distress, and sex pointed to the action of transcription factors SHOX2, STAT1, and REST. These findings underscore the importance of considering sex and postnatal challenges when studying causes of neurodevelopmental disorders and highlight the complexity of the "two-hit" hypothesis in understanding their etiology. Our study furthers the understanding of the intricate molecular responses in the hypothalamus to gestational immune activation and subsequent distress, shedding light on the sex-specific effects and the potential long-lasting consequences on pain perception, neuroendocrine regulation, and inflammatory processes.NEW & NOTEWORTHY The interaction of infection during gestation and insults later in life influences the molecular mechanisms in the hypothalamus that participate in pain sensation. The response of the hypothalamic transcriptome varies between sexes and can also affect synapses and immune signals. The findings from this study assist in the identification of agonists or antagonists that can guide pretranslational studies to ameliorate the effects of gestational insults interacting with postnatal challenges on physiological or behavioral disorders.

Asunto(s)

Hormonas , Hipotálamo , Masculino , Femenino , Animales , Porcinos , Hipotálamo/metabolismo , Hormonas/metabolismo , Percepción del Dolor , Dolor/genética , Dolor/metabolismo , Sensación