RESUMO
Bone cancer pain (BCP) represents a prevalent symptom among cancer patients with bone metastases, yet its underlying mechanisms remain elusive. This study investigated the transcriptional regulation mechanism of Kv7(KCNQ)/M potassium channels in DRG neurons and its involvement in the development of BCP in rats. We show that HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes, which encode Kv7(KCNQ)/M potassium channels in dorsal root ganglion (DRG), contributes to the sensitization of DRG neurons and the pathogenesis of BCP in rats. Also, HDAC2 requires the formation of a corepressor complex with MeCP2 and Sin3A to execute transcriptional regulation of kcnq2/kcnq3 genes. Moreover, EREG is identified as an upstream signal molecule for HDAC2-mediated kcnq2/kcnq3 genes transcription repression. Activation of EREG/EGFR-ERK-Runx1 signaling, followed by the induction of HDAC2-mediated transcriptional repression of kcnq2/kcnq3 genes in DRG neurons, leads to neuronal hyperexcitability and pain hypersensitivity in tumor-bearing rats. Consequently, the activation of EREG/EGFR-ERK-Runx1 signaling, along with the subsequent transcriptional repression of kcnq2/kcnq3 genes by HDAC2 in DRG neurons, underlies the sensitization of DRG neurons and the pathogenesis of BCP in rats. These findings uncover a potentially targetable mechanism contributing to bone metastasis-associated pain in cancer patients.
Assuntos
Neoplasias Ósseas , Dor do Câncer , Receptores ErbB , Gânglios Espinais , Histona Desacetilase 2 , Canal de Potássio KCNQ2 , Animais , Histona Desacetilase 2/metabolismo , Histona Desacetilase 2/genética , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Ósseas/patologia , Ratos , Dor do Câncer/genética , Dor do Câncer/metabolismo , Dor do Câncer/patologia , Receptores ErbB/metabolismo , Receptores ErbB/genética , Canal de Potássio KCNQ3/genética , Canal de Potássio KCNQ3/metabolismo , Transcrição Gênica , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Complexo Correpressor Histona Desacetilase e Sin3/genética , Transdução de Sinais/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Humanos , Feminino , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Ratos Sprague-Dawley , Sistema de Sinalização das MAP Quinases/genéticaRESUMO
OBJECTIVES: To observe the effect of electroacupuncture (EA) of "Zusanli" (ST36) and "Sanyinjiao" (SP6) on cancer pain and concomitant negative emotion in cancer pain model mice, and to explore its molecular mechanisms in the basolateral amygdala (BLA) by using transcriptomics techniques. METHODS: C57BL/6 mice were randomized into sham operation, model and EA groups, with 10 mice in each group. The cancer pain model was established by injecting PBS suspension containing Lewis lung cancer cells into the femur. The mice in the EA group received EA stimulation(1 mA, 2 Hz) on ST36 and SP6 from the 10th day after modeling, 20 min per day for 12 successive days. The bone damage of the distal femur was observed with X-ray and H.E. staining, respectively. The mechanical pain threshold (MPT) was detected by using von Frey. The depression-like behavior was detected by using sucrose-preference test (sucrose preference index in 12 h), and the immobility (feeling of despair) duration of forced swimming within 4 min. The BLA tissue was extracted for RNA sequencing (RNA library construction, and screening differential gene profiling by transcriptomic sequencing) and bioinformatics analysis. The real-time PCR was used to validate the mRNA expression of differentially expressed genesï¼tumor necrosis factor superfamily 8 (Tnfsf8), bone marrow stromal cell antigen 1 (Bst1), prodynorphin (Pdyn) and voltage-gated sodium channelß4 (Scn4b). RESULTS: H.E. staining and X-ray showed significant bone damage in the distal femur in cancer pain mice. In contrast to the sham operation group, the MPT on the 1st , 4th, 7th , 10th, 14th and 21st day after modeling and sucrose preference index were significantly decreased (P<0.001, P<0.000 1), and the immobility time of the forced swimming was considerably increased in the model group (P<0.001). In contrast to the model group, the MPT values on the 14th and 21st day and sucrose preference index were obviously increased (P<0.000 1, P<0.05), and the immobility time was strikingly decreased in the EA group (P<0.01). RNA sequencing showed that a total of 404 differentially expressed genes (205 up-regulated, 199 down-regulated) were screened in the model group compared with the sham operation group, and a total of 329 differentially expressed genes (206 up-regulated and 123 down-regulated) were screened in the EA group compared with the model group. Venn diagram analysis of the differentially expressed genes showed that 45 up-regulated and 28 down-regulated genes in the model group were completely reversed by EA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the screened differentially expressed genes revealed that the above differential genes were mainly enriched in the ligand receptor activity, cytokine receptor binding, and cytokine activity related to neuro-inflammation, as well as in neuropeptide signaling pathways related to neuronal excitability, and calcium ion mediated signal transduction. The analysis of KEGG pathway showed that the differentially expressed genes were mainly enriched in the inflammation-related pathways, such as interleukin-17 pathway. Validation analysis of the differentially expressed genes showed that the expression levels of Tnfsf8 and Bst1 were significantly up-regulated in the model group compared with the sham operation group (P<0.01, P<0.05), and down-regulated by EA (P<0.01, P<0.05), while the expression levels of Pdyn and Scn4b were down-regulated in the model group in comparison with the sham operation group (P<0.01), and up-regulated by EA (P<0.05, P<0.01), which was consistent with the changing trend of the gene sequencing results. CONCLUSIONS: Acupuncture of ST36 and SP6 can significantly relieve cancer pain and concomitant negative emotion in cancer pain mice, which may be related to its functions in alleviating neuro-inflammation and relieving the abnormal activities of specific neurons in the BLA.
Assuntos
Dor do Câncer , Depressão , Eletroacupuntura , Camundongos Endogâmicos C57BL , Animais , Camundongos , Depressão/terapia , Depressão/metabolismo , Depressão/genética , Depressão/etiologia , Humanos , Dor do Câncer/terapia , Dor do Câncer/metabolismo , Dor do Câncer/genética , Masculino , Complexo Nuclear Basolateral da Amígdala/metabolismo , Transcriptoma , Feminino , Pontos de Acupuntura , Encefalinas/metabolismo , Encefalinas/genéticaRESUMO
The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently. As the ABCB1 gene encodes for the transporter P-glycoprotein in the brain and intestine involved in the pharmacokinetics of opioids, we investigated the effects of ABCB1 genetic polymorphisms on doses of opioids for pain relief and determined which pharmacokinetic process was affected in cancer pain patients. Sixty-eight cancer pain patients admitted for intrathecal therapy (ITT) were included. The association between ABCB1 genetic polymorphisms (C3435T, C1236T, G2677T/A and A61G) and systemic doses of opioids before ITT were investigated. Concentrations of oxycodone in plasma and cerebrospinal fluid (CSF) were determined by HPLC-MS/MS in 17 patients treated with oral oxycodone before ITT, and the influences of ABCB1 genetic polymorphisms on plasma-concentration to oral-dose ratios and CSF-concentration to plasma-concentration ratios of oral oxycodone were further analyzed. ABCB1 C3435T and G2677T/A polymorphisms were significantly associated with systemic doses of opioids before ITT, which coincided with the influences of ABCB1 C3435T and G2677T/A polymorphisms on the ratios of plasma-concentration to oral-dose. However, no significant difference was found in ratios of CSF-concentration to plasma-concentration among ABCB1 SNP genotypes. The present study provided the first evidence that ABCB1 C3435T and G2677T/A polymorphisms affect opioid requirement in cancer pain patients via altering transportation function of P-glycoprotein in the intestine, which will further expand our knowledge about pharmacokinetics of opioids and could contribute to the individualization of opioids use.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Analgésicos Opioides , Oxicodona , Polimorfismo de Nucleotídeo Único , Humanos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Masculino , Feminino , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/administração & dosagem , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Idoso , Oxicodona/farmacocinética , Oxicodona/administração & dosagem , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Adulto , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Mucosa Intestinal/metabolismo , GenótipoRESUMO
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) µM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
Assuntos
Analgésicos Opioides , Dor do Câncer , Preparações de Ação Retardada , Morfina , Farmacogenética , Humanos , Morfina/efeitos adversos , Morfina/farmacocinética , Morfina/administração & dosagem , Masculino , Feminino , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Pessoa de Meia-Idade , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Idoso , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/genética , Derivados da Morfina/farmacocinética , Derivados da Morfina/efeitos adversos , Adulto , Variantes Farmacogenômicos , Receptor 2 Toll-Like/genéticaRESUMO
Bone cancer pain (BCP) is refractory to currently used analgesics. Recently, sirtuin 2 (SIRT2) was reported to play a vital role in neuropathic pain but its role in BCP remains unknown. It was hypothesized that spinal SIRT2 attenuates BCP by deacetylating FoxO3a and suppressing oxidative stress. The mouse model of BCP established by injecting tumor cells into the intramedullary space of the femur demonstrated that spinal SIRT2 and FoxO3a were downregulated in BCP development. Intrathecal administration of LV-SIRT2 reduced pain hypersensitivity (mechanical and thermal nociception) in BCP mice. Spinal SIRT2 overexpression upregulated FoxO3a and antioxidant genes (SOD2 and catalase) and inhibited FoxO3a acetylation, phosphorylation, and ubiquitination. Moreover, intrathecal administration of SIRT2 shRNA induced pain hypersensitivity in normal mice. Spinal SIRT2 knockdown downregulated FoxO3a and antioxidant genes and increased FoxO3a acetylation, phosphorylation, and ubiquitination. In summary, spinal SIRT2 increases FoxO3a expression in BCP mice and inhibits oxidative stress by deacetylating FoxO3a and further reducing FoxO3a phosphorylation, ubiquitination, and degradation, leading to BCP relief.
Assuntos
Neoplasias Ósseas , Dor do Câncer , Neuralgia , Animais , Camundongos , Antioxidantes , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Dor do Câncer/genética , Dor do Câncer/metabolismo , Sirtuína 2/genéticaRESUMO
Cancer pain is the most feared symptom at end of life. Methadone has advantages over other opioids but is associated with significant variability in clinical response, making dosing challenging in practice. OPRM1 is the most studied pharmacogene associated with the pharmacodynamics of opioids, however reports on the association of the A118G polymorphism on opioid dose requirements are conflicting, with no reports including methadone as the primary intervention. This association study on OPRM1 A118G and response to methadone for pain management, includes a review of this genetic factor's role in inter-patient variability. Fifty-four adult patients with advanced cancer were recruited in a prospective, multi-centre, open label dose individualization study. Patient characteristics were not shown to influence methadone response, and no significant associations were observed for methadone dose or pain score. The findings of our review of association studies for OPRM1 A118G in advanced cancer pain demonstrate the importance of taking ancestry into account. While our sample size was small, our results were consistent with European populations, but in contrast to studies in Chinese patients, where carriers of the A118G polymorphism were associated with higher opioid dose requirements. Pharmacogenetic studies in palliative care are challenging, continued contribution will support future genotype-based drug dosing guidelines.
Assuntos
Dor do Câncer , Neoplasias , Adulto , Humanos , Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Genótipo , Metadona/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/genética , Manejo da Dor , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Receptores Opioides mu/genéticaRESUMO
BACKGROUND/OBJECTIVES: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. METHODS: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. RESULTS: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4ß-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. CONCLUSION: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.
Assuntos
Analgésicos Opioides , Caquexia , Dor do Câncer , Citocromo P-450 CYP3A , Naltrexona , Polimorfismo Genético , Humanos , Masculino , Feminino , Caquexia/genética , Caquexia/tratamento farmacológico , Caquexia/etiologia , Pessoa de Meia-Idade , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Naltrexona/análogos & derivados , Naltrexona/farmacocinética , Naltrexona/uso terapêutico , Naltrexona/efeitos adversos , Estudos Prospectivos , Idoso , Citocromo P-450 CYP3A/genética , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/complicações , Genótipo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Constipação Induzida por Opioides/genética , Constipação Induzida por Opioides/tratamento farmacológico , Defecação/efeitos dos fármacosRESUMO
AIMS: Pain is a profoundly debilitating symptom in cancer patients, leading to disability, immobility, and a marked decline in their quality of life. This study aimed to investigate the potential roles of miR-199a-3p in a murine model of bone cancer pain induced by tumor cell implantation in the medullary cavity of the femur. MATERIALS AND METHODS: We assessed pain-related behaviors, including the paw withdrawal mechanical threshold (PWMT) and the number of spontaneous flinches (NSF). To investigate miRNA expression and its targets in astrocytes, we employed a combination of RNA-seq analysis, qRT-PCR, Western blotting, EdU, TUNEL, ChIP, ELISA, and luciferase reporter assays in mice (C3H/HeJ) with bone cancer pain and control groups. KEY FINDINGS: On days 10, 14, 21, and 28 post-surgery, we observed significant differences in PWTL, PWMT, and NSF when compared to the sham group (P < 0.001). qRT-PCR assays and miRNA sequencing results confirmed reduced miR-199a-3p expression in astrocytes of mice with bone cancer pain. Gain- and loss-of-function experiments demonstrated that miR-199a-3p suppressed astrocyte activation and the expression of inflammatory cytokines. In vitro investigations revealed that miR-199a-3p mimics reduced the levels of inflammatory factors in astrocytes and MyD88/NF-κB proteins. Furthermore, treatment with a miR-199a-3p agonist resulted in reduced expression of MyD88, TAK1, p-p65, and inflammatory mediators, along with decreased astrocyte activation in the spinal cord. SIGNIFICANCE: Collectively, these findings demonstrate that upregulation of miR-199a-3p may offer a therapeutic avenue for mitigating bone cancer pain in mice by suppressing neuroinflammation and inhibiting the MyD88/NF-κB signaling pathway.
Assuntos
Neoplasias Ósseas , Dor do Câncer , MicroRNAs , Osteossarcoma , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Dor do Câncer/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos C3H , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Doenças Neuroinflamatórias , NF-kappa B/metabolismo , Osteossarcoma/genética , Qualidade de VidaRESUMO
Long noncoding RNA (lncRNA) is implicated in both cancer development and pain process. However, the role of lncRNA in the development of cancer-induced bone pain (CIBP) is unclear. LncRNA NONRATT014888.2 is highly expressed in tibia related dorsal root ganglions (DRGs) in CIBP rats which function is unknown. CIBP was induced by injection of Walker 256 mammary gland tumor cells into the tibia canal of female SD rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of rats were measured. Down-regulation of NONRATT014888.2 by siRNA in CIBP rats markedly attenuated hind-paw mechanical pain hypersensitivity. LncRNA-predicted target mRNAs analysis and mRNA sequencing results cued Socs3, Npr3 were related with NONRATT014888.2. Intrathecal injection of NONRATT014888.2-siR206 upregulated Npr3 both in mRNA and protein level. Npr3 was co-expressed in NONRATT014888.2-positive DRGs neurons and mainly located in cytoplasm, but not in Glial fibrillary acidic protein (GFAP)-positive cells. Intrathecal injection of ADV-Npr3 upregulated Npr3 expression and enhanced the PWT of CIBP rats. Our results suggest that upregulated lncRNA NONRATT014888.2 contributed to hyperalgesia in CIBP rats, and the mechanism may through downregulation of Npr3.
Assuntos
Neoplasias Ósseas , Dor do Câncer , Neoplasias , RNA Longo não Codificante , Ratos , Feminino , Animais , RNA Longo não Codificante/genética , Regulação para Baixo , Ratos Sprague-Dawley , Dor/genética , Dor/metabolismo , Dor do Câncer/genética , Dor do Câncer/patologia , Hiperalgesia/genética , RNA Mensageiro/metabolismo , Peptídeos Natriuréticos/metabolismo , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismoRESUMO
Due to its complex pathological mechanisms, bone cancer pain (BCP) has become an increasingly challenging clinical issue, there is an urgent need to identify the underlying mechanisms of BCP. In our present study, we found that decreased expression of miR-199a-3p in spinal dorsal horn (SDH) neurons contributed to BCP hypersensitivity. Intrathecal administration of miR-199a-3p agomir alleviated the initiation of tumor inoculation induced pain hypersensitivity and suppressed the expression of DNMT3A. Subsequently, luciferase assays confirmed direct binding between miR-199a-3p and Dnmt3a mRNA. AAV-DNMT3A-shRNA microinjection relieved mechanical hyperalgesia and upregulated the expression of Nrf2 levels in BCP. In naïve rats, Overexpression of DNMT3A yielded the opposite effects. Finally, increase of DNMT3A by lentiviral vector abolished miR-199a-3p-mediated alleviation hypersensitivity effects on BCP progression. Taken these together, our findings highlighted a novel contribution of miR-199a-3p to BCP and provided a fresh outlook on potential mechanism research for BCP.
Assuntos
Neoplasias Ósseas , Dor do Câncer , MicroRNAs , Osteossarcoma , Ratos , Animais , Dor do Câncer/genética , Dor do Câncer/metabolismo , Regulação para Cima , Dor/metabolismo , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Células do Corno Posterior/metabolismo , Osteossarcoma/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
INTRODUCTION: The CYP2D6 enzyme metabolizes opioids commonly prescribed for cancer-related pain, and CYP2D6 polymorphisms may contribute to variability in opioid response. We evaluated the feasibility of implementing CYP2D6-guided opioid prescribing for patients with cancer and reported pilot outcome data. METHODS: Adult patients from two cancer centers were prospectively enrolled into a hybrid implementation-effectiveness clinical trial and randomized to CYP2D6-genotype-guided opioid selection, with clinical recommendations, or usual care. Implementation metrics, including provider response, medication changes consistent with recommendations, and patient-reported pain and symptom scores at baseline and up to 8 weeks, were assessed. RESULTS: Most (87/114, 76%) patients approached for the study agreed to participate. Of 85 patients randomized, 71% were prescribed oxycodone at baseline. The median (range) time to receive CYP2D6 test results was 10 (3-37) days; 24% of patients had physicians acknowledge genotype results in a clinic note. Among patients with CYP2D6-genotype-guided recommendations to change therapy (n = 11), 18% had a change congruent with recommendations. Among patients who completed baseline and follow-up questionnaires (n = 48), there was no difference in change in mean composite pain score (-1.01 ± 2.1 vs. -0.41 ± 2.5; p = 0.19) or symptom severity at last follow-up (3.96 ± 2.18 vs. 3.47 ± 1.78; p = 0.63) between the usual care arm (n = 26) and genotype-guided arm (n = 22), respectively. CONCLUSION: Our study revealed high acceptance of pharmacogenetic testing as part of a clinical trial among patients with cancer pain. However, provider response to genotype-guided recommendations was low, impacting assessment of pain-related outcomes. Addressing barriers to utility of pharmacogenetics results and clinical recommendations will be critical for implementation success.
Assuntos
Dor do Câncer , Neoplasias , Adulto , Humanos , Analgésicos Opioides/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Citocromo P-450 CYP2D6/genética , Padrões de Prática Médica , Dor/tratamento farmacológico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
Recently, epigenetics involved in the regulation of gene expression has become a research hotspot. This study evaluated N4-acetylcytidine (ac4c) RNA acetylation in the spinal dorsal horn (SDH) of rats with cancer-induced bone pain (CIBP). The ac4C-specific RIP sequencing and NAT10-specific RIP sequencing were performed to identify the differences in ac4C acetylation and gene expression in the SDH between CIBP and sham groups, the relationship with the acetylation-modifying enzyme NAT10, and association analysis was performed. By interfering with the NAT10 expression, the relationship between some up-regulated genes and ac4C acetylation in CIBP was verified. In this study, we demonstrated that bone cancer increases the levels of NAT10 and the overall acetylation, inducing differential ac4C patterns in the SDH of rats. Through verification experiments, it was found that ac4C acetylation of some genes is regulated by NAT10, and differential ac4C patterns in RNA determine the expression of this RNA. We exposed that some CIBP-related gene expression was altered in the SDH of rats, which was regulated by differentially expressed ac4C acetylation.
Assuntos
Neoplasias Ósseas , Dor do Câncer , Ratos , Animais , Acetilação , RNA/metabolismo , Dor do Câncer/genética , Dor do Câncer/complicações , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Corno Dorsal da Medula Espinal/metabolismoRESUMO
Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.
Assuntos
Dor do Câncer , Dor Nociceptiva , Humanos , Analgésicos Opioides/efeitos adversos , Medição da Dor , Polimorfismo de Nucleotídeo Único , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genéticaRESUMO
Patients experience interindividual variation in response to analgesics, which may be partially explained by genetics. This commentary discusses a recently published trial on COMT genotype and opioid dose requirements and describes the potential role for COMT and other genes (eg, CYP2D6) on opioid therapy and the current evidence for germline pharmacogenetics and resources for opioid pharmacogenetics.
Assuntos
Dor do Câncer , Neoplasias , Humanos , Manejo da Dor , Farmacogenética , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Oxicodona/uso terapêutico , Morfina/uso terapêutico , Analgésicos Opioides/uso terapêutico , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Genótipo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/uso terapêuticoRESUMO
BACKGROUND: We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. METHODS: A randomized, multicenter, open-label trial was conducted at a Japanese hospital's palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reductionâ ≥â 33% from baseline and up toâ ≤â 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. RESULTS: Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; Pâ =â .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; Pâ =â 0.098). CONCLUSION: Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.
Assuntos
Dor do Câncer , Neoplasias , Humanos , Morfina/uso terapêutico , Oxicodona/uso terapêutico , Oxicodona/efeitos adversos , Analgésicos Opioides/uso terapêutico , Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Dor do Câncer/genética , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/uso terapêutico , Dor/etiologia , Dor/genética , Genótipo , Biomarcadores , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
ABSTRACT: Bone cancer pain (BCP) is a pervasive clinical symptom which impairs the quality life. Long noncoding RNAs (lncRNAs) are enriched in the central nervous system and play indispensable roles in numerous biological processes, while its regulatory function in nociceptive information processing remains elusive. Here, we reported that functional modulatory role of ENSRNOT00000071132 (lncRNA71132) in the BCP process and sponging with miR-143 and its downstream GPR85-dependent signaling cascade. Spinal lncRNA71132 was remarkably increased in the rat model of bone cancer pain. The knockdown of spinal lncRNA71132 reverted BCP behaviors and spinal c-Fos neuronal sensitization. Overexpression of spinal lncRNA71132 in naive rat generated pain behaviors, which were accompanied by increased spinal c-Fos neuronal sensitization. Furthermore, it was found that lncRNA71132 participates in the modulation of BCP by inversely regulating the processing of miR-143-5p. In addition, an increase in expression of spinal lncRNA71132 resulted in the decrease in expression of miR-143 under the BCP state. Finally, it was found that miR-143-5p regulates pain behaviors by targeting GPR85. Overexpression of miR-143-5p in the spinal cord reverted the nociceptive behaviors triggered by BCP, accompanied by a decrease in expression of spinal GPR85 protein, but no influence on expression of gpr85 mRNA. The findings of this study indicate that lncRNA71132 works as a miRNA sponge in miR-143-5p-mediated posttranscriptional modulation of GPR85 expression in BCP. Therefore, epigenetic interventions against lncRNA71132 may potentially work as novel treatment avenues in treating nociceptive hypersensitivity triggered by bone cancer.
Assuntos
Neoplasias Ósseas , Dor do Câncer , MicroRNAs , Animais , Ratos , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Dor do Câncer/genética , Dor do Câncer/complicações , MicroRNAs/genética , MicroRNAs/metabolismo , Dor/metabolismo , Medula Espinal/metabolismo , Regulação para Cima , RNA Longo não Codificante/genéticaRESUMO
Cancer-induced bone pain (CIBP) occurs frequently among advanced cancer patients. Voltage-gated sodium channels (VGSCs) have been associated with chronic pain, but how VGSCs function in CIBP is poorly understood. Here, we aimed to investigate the specific role of VGSCs in the dorsal root ganglia (DRGs) in CIBP. A CIBP rat model was generated by the intratibial inoculation of MRMT-1 breast carcinoma cells. Transcriptome sequencing was conducted to assess the gene expression profiles. The expression levels of key genes and differentiated genes related to activated pathways were measured by Western blotting and qPCR. We implanted a catheter intrathecally for the administration of lentivirus and drugs. Then, the changes in the mechanical withdrawal threshold (MWT) were measured. We identified 149 differentially expressed mRNAs (DEmRNAs) in the DRGs of CIBP model rats. The expression of Nav1.6, which was among these DEmRNAs, was significantly upregulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the DEmRNAs showed that they were mainly enriched in the mitogen-activated protein kinase (MAPK) pathway. The decrease in MWT induced by bone cancer was attenuated by Nav1.6 knockdown. Western blot analysis revealed that a p38 inhibitor decreased the expression of Nav1.6 and attenuated pain behavior. Our study shows that the upregulation of Nav1.6 expression by p38 MAPK in the DRGs of rats contributes to CIBP.
Assuntos
Dor do Câncer , Canal de Sódio Disparado por Voltagem NAV1.6 , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Ratos , Neoplasias Ósseas/complicações , Neoplasias Ósseas/metabolismo , Gânglios Espinais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Dor/genética , Dor/metabolismo , Ratos Sprague-Dawley , Regulação para Cima , Canais de Sódio Disparados por Voltagem/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Dor do Câncer/genética , Dor do Câncer/metabolismoRESUMO
In addition to the poor prognosis, excruciating abdominal pain is a major challenge in pancreatic cancer. Neurotropism appears to be the underlying mechanism leading to neuronal invasion. However, there is a lack of animal models suitable for translationally bridging in vitro findings with clinical trials. We characterized KPC (KrasG12D/+; Trp53R172H/+; P48-Cre) and KPPC (KrasG12D/+; Trp53R172H/R172H; P48-Cre) mice with genetically determined pancreatic ductal adenocarcinoma (PDAC) and compared them with an orthotopic pancreatic cancer mouse model, healthy littermates and human tissue. We analyzed behavioral correlates of cancer-associated pain and well-being, and studied neuronal remodeling and cytokine expression. Histologically, we found similarities between KPC and KPPC tissue with human samples. Compared to healthy littermates, we detect nerve fiber hypertrophy, which was not restricted to a certain fiber type. Interestingly, while KPPC mice showed significantly reduced well-being, KPC mice emerged to be better suited for studying long-lasting cancer pain that emerges over a slow course of tumor progression. To address the neuroinflammatory correlate of loss of well-being, we studied cytokine levels in KPPC mice and observed a significant upregulation of CXCL16, TNFRSF5, CCL24, CXCL1, CCL22, CLL20 and CX2CL1. In summary, we demonstrate that the KPC mouse model is best suited to studying cancer pain, whereas the KPPC model can be employed to study cancer-associated reduction in well-being.
Assuntos
Dor do Câncer , Neoplasias Pancreáticas , Dor Abdominal , Animais , Dor do Câncer/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias PancreáticasRESUMO
BACKGROUND: Noncoding microRNAs have emerged as critical players of gene expression in the nervous system, where they contribute to regulating nervous disease. As stated in previous research, the miR-155-5p upregulation happens in the spinal cord at the nociceptive state. It was unclear if miR-155-5p is linked to bone cancer pain (BCP). Herein, we aimed at investigating the miR-155-5p functional regulatory function in BCP process and delineating the underlying mechanism. METHODS: The miRNA-155-5p levels and cellular distribution were determined by RNA sequencing, fluorescent in situ hybridization (FISH), and quantitative real-time PCR (qPCR). Immunoblotting, qPCR, dual-luciferase reporter gene assays, immunofluorescence, recombinant overexpression adeno-associated virus, small interfering RNA, intraspinal administration, and behavioral tests were utilized for exploring the downstream signaling pathway. RESULTS: The miR-155-5p high expression in spinal neurons contributes to BCP maintenance. The miR-155-5p blockage via the intrathecal injection of miR-155-5p antagomir alleviated the pain behavior; in contrast, upregulating miR-155-5p by agomir induced pain hypersensitivity. The miR-155-5p bounds directly to TCF4 mRNA's 3' UTR. BCP significantly reduced protein expression of TCF4 versus the Sham group. The miR-155-5p inhibition relieved the spinal TCF4 protein's down-expression level, while miR-155-5p upregulation by miR-155-5p agomir intrathecal injection decreased TCF4 protein expression in naïve rats. Additionally, TCF4 overexpression in BCP rats could increase Kv1.1. Moreover, TCF4 knockdown inhibited Kv1.1 expression in BCP rats. Indeed, TCF4 and Kv1.1 were co-expressed in BCP spinal cord neurons. CONCLUSION: The study findings stated the miR-155-5p pivotal role in regulating BCP by directly targeting TCF4 in spinal neurons and suggested that miR-155-5p could be a promising target in treating BCP.
Assuntos
Neoplasias Ósseas , Dor do Câncer , MicroRNAs , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Dor do Câncer/genética , Dor do Câncer/metabolismo , Hibridização in Situ Fluorescente , Luciferases/genética , Luciferases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Dor/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Medula Espinal/metabolismoRESUMO
Tapentadol (TAP) and oxycodone/naloxone (OXN) potentially offer an improved opioid tolerability. However, real-world studies in chronic non-cancer pain (CNCP) remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. An observational study was developed with ambulatory test cases under TAP (n = 194) or OXN (n = 175) prescription with controls (prescribed with other opioids (control), n = 216) CNCP patients. Pain intensity and relief, quality of life, morphine equivalent daily doses (MEDD), concomitant analgesic drugs, adverse events (AEs), hospital frequentation and genetic variants of OPRM1 (rs1799971, A118G) and COMT (rs4680, G472A) genes, were analysed. Test CNCP cases evidenced a significantly higher pain relief predictable due to pain intensity and quality of life (R2 = 0.3), in front of controls. Here, OXN achieved the greatest pain relief under a 28% higher MEDD, 8-13% higher use of pregabalin and duloxetine, and 23% more prescription change due to pain, compared to TAP. Whilst, TAP yielded a better tolerability due the lower number of 4 [0-6] AEs/patient, in front of OXN. Furthermore, OXN COMT-AA homozygotes evidenced higher rates of erythema and vomiting, especially in females. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. Further research is necessary to clarify the potential influence of COMT and sex on OXN side-effects.