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1.
FASEB J ; 35(10): e21852, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34499774

RESUMO

Postoperative pain and delayed healing in surgical wounds, which require complex management strategies have understudied complicated mechanisms. Here we investigated temporal changes in behavior, tissue structure, and transcriptomic profiles in a rat model of a surgical incision, using hyperalgesic behavioral tests, histological analyses, and next-generation RNA sequencing, respectively. The most rapidly (1 hour) expressed genes were the chemokines, Cxcl1 and Cxcl2. Consequently, infiltrating leukocytes were abundantly observed starting at 6 and peaking at 24 hours after incising which was supported by histological analysis and appearance of the neutrophil markers, S100a8 and S100a9. At this time, hyperalgesia was at a peak and overall transcriptional activity was most highly activated. At the 1-day timepoint, Nppb, coding for natriuretic peptide precursor B, was the most strongly upregulated gene and was localized by in situ hybridization to the epidermal keratinocytes at the margins of the incision. Nppb was basically unaffected in a peripheral inflammation model transcriptomic dataset. At the late phase of wound healing, five secreted, incision-specific peptidases, Mmp2, Aebp1, Mmp23, Adamts7, and Adamtsl1, showed increased expression, supporting the idea of a sustained tissue remodeling process. Transcripts that are specifically upregulated at each timepoint in the incision model may be potential candidates for either biomarkers or therapeutic targets for wound pain and wound healing. This study incorporates the examination of longitudinal temporal molecular responses, corresponding anatomical localization, and hyperalgesic behavioral alterations in the surgical incision model that together provide important and novel foundational knowledge to understand mechanisms of wound pain and wound healing.


Assuntos
Hiperalgesia/patologia , Dor Pós-Operatória/patologia , Placa Plantar/fisiologia , RNA-Seq/métodos , Ferida Cirúrgica/complicações , Transcriptoma , Cicatrização , Animais , Comportamento Animal , Edema/etiologia , Edema/metabolismo , Edema/patologia , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/metabolismo , Ratos , Ratos Sprague-Dawley
2.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445514

RESUMO

Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 µg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.


Assuntos
Astrócitos/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/efeitos adversos , Compostos Fitoquímicos/administração & dosagem , Canais de Cátion TRPV/metabolismo , Aconitum/química , Administração Oral , Angelica/química , Animais , Astrócitos/efeitos dos fármacos , Temperatura Baixa , Modelos Animais de Doenças , Regulação para Baixo , Gengibre/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Camundongos , Compostos Fitoquímicos/farmacologia , Coluna Vertebral/metabolismo , Canais de Cátion TRPV/genética
3.
Biomed Pharmacother ; 139: 111653, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243625

RESUMO

The clinical application of opioids may be accompanied by a series of adverse consequences, such as opioid tolerance, opioid-induced hyperalgesia, opioid dependence or addiction. In view of this issue, clinicians are faced with the dilemma of treating various types of pain with or without opioids. In this review, we discuss that Src protein tyrosine kinase plays an important role in these adverse consequences, and Src inhibitors can solve these problems well. Therefore, Src inhibitors have the potential to be used in combination with opioids to achieve synergy. How to combine them together to maximize the analgesic effect while avoiding unnecessary trouble provides a topic for follow-up research.


Assuntos
Analgésicos Opioides/farmacologia , Dor Crônica/tratamento farmacológico , Tolerância a Medicamentos/fisiologia , Hiperalgesia/induzido quimicamente , Inibidores de Proteínas Quinases/farmacologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Quinases da Família src/antagonistas & inibidores , Analgésicos Opioides/metabolismo , Animais , Dor Crônica/metabolismo , Humanos , Hiperalgesia/metabolismo
4.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281158

RESUMO

Thymic stromal lymphopoietin (TSLP) is a well-known cytokine for T helper 2 inflammatory responses. A nerve injury activates the neuroinflammation cascade and neuron-glia interaction in dorsal root ganglions (DRG)s, leading to neuropathic pain. Therefore, this study was to investigate the role of TSLP after nerve injury. Male Sprague-Dawley rats were divided as an experimental group with chronic constriction injury (CCI) to the sciatic nerve and a control group. The mechanical pain threshold response was determined by calibration forceps. After assessment of mechanical allodynia, the ipsilateral spinal cord, DRG, sciatic nerve and skin were harvested. Immunofluorescence staining was performed to identify cell types with various markers. Western blot analyses were performed to evaluate protein expressions. Mechanical allodynia developed after CCI and persisted for the next 14 days. Astrocyte reactions occurred and continued until day 14, too. After CCI, DRG and the sciatic nerve also had significantly increased expressions of TSLP/TSLP-R/STAT5. The TSLPR was localized to sensory neuronal endings innervating the skin. This study is the first to demonstrate that the TSLP complex and the STAT5 pathway in nerve are potential therapeutic targets because of their roles in pain regulation after nerve injury.


Assuntos
Lesões por Esmagamento/metabolismo , Citocinas/metabolismo , Neurônios/metabolismo , Animais , Constrição Patológica/metabolismo , Lesões por Esmagamento/genética , Citocinas/genética , Gânglios Espinais/metabolismo , Expressão Gênica/genética , Hiperalgesia/metabolismo , Masculino , Tecido Nervoso/metabolismo , Neuralgia/metabolismo , Neuroglia/metabolismo , Limiar da Dor , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/metabolismo , Células Receptoras Sensoriais/metabolismo
5.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281164

RESUMO

Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to the development and maintenance of chronic pain as well as in their expression of chronic pain features such as allodynia, hyperalgesia and extraterritorial sensory spread. The variability suggests that genetic as well as environmental factors may contribute to the development and maintenance of chronic orofacial pain. This article reviews these features of chronic orofacial pain, and outlines findings from studies in animal models of the behavioural characteristics and underlying mechanisms related to the development and maintenance of chronic orofacial pain and trigeminal neuropathic pain in particular. The review also considers the role of environmental and especially genetic factors in these models, focussing on findings of differences between animal strains in the features and underlying mechanisms of chronic pain. These findings are not only relevant to understanding underlying mechanisms and the variability between patients in the development, expression and maintenance of chronic orofacial pain, but also underscore the importance for considering the strain of the animal to model and explore chronic orofacial pain processes.


Assuntos
Dor Facial/etiologia , Dor Facial/genética , Dor Facial/fisiopatologia , Animais , Dor Crônica/metabolismo , Modelos Animais de Doenças , Interação Gene-Ambiente , Humanos , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Gânglio Trigeminal/metabolismo
6.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203300

RESUMO

Pain symptoms in temporomandibular disorders (TMD) predominantly affect reproductive women, suggesting that estrogen regulates pain perception. However, how estrogen contributes to chronic TMD pain remains largely unclear. In the present study, we performed behavioral tests, electrophysiology, Western blot and immunofluorescence to investigate the role and underlying mechanisms of estrogen in dental experimental occlusal interference (EOI)-induced chronic masseter mechanical hyperalgesia in rats. We found that long-term 17ß-estradiol (E2) replacement exacerbated EOI-induced masseter hyperalgesia in a dose-dependent manner in ovariectomized (OVX) rats. Whole-cell patch-clamp recordings demonstrated that E2 (100 nM) treatment enhanced the excitability of isolated trigeminal ganglion (TG) neurons in OVX and OVX EOI rats, and EOI increased the functional expression of transient receptor potential vanilloid-1 (TRPV1). In addition, E2 replacement upregulated the protein expression of TRPV1 in EOI-treated OVX rats. Importantly, intraganglionic administration of the TRPV1 antagonist AMG-9810 strongly attenuated the facilitatory effect of E2 on EOI-induced masseter mechanical sensitivity. These results demonstrate that E2 exacerbated EOI-induced chronic masseter mechanical hyperalgesia by increasing TG neuronal excitability and TRPV1 function. Our study helps to elucidate the E2 actions in chronic myogenic TMD pain and may provide new therapeutic targets for relieving estrogen-sensitive pain.


Assuntos
Hiperalgesia/tratamento farmacológico , Neurônios Aferentes/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Gânglio Trigeminal/metabolismo , Acrilamidas/farmacologia , Animais , Western Blotting , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Estradiol/genética , Estradiol/metabolismo , Feminino , Imunofluorescência , Hiperalgesia/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Gânglio Trigeminal/efeitos dos fármacos
7.
Biomed Res Int ; 2021: 6641701, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212036

RESUMO

Introduction: Animal models are valid for in vivo research on the pathophysiological process and drug screening of gout arthritis. Intra-articular injection of monosodium urate (MSU) is the most common method, while stable MSU deposition enveloped by inflammatory cells was rarely reported. Objective: To develop a modified gouty arthritis rat model characterized by intra-articular MSU deposition and continuous joint pain with a minimally invasive method. Method: A total of twenty-four rats were randomly allocated into six groups. Three intervention groups of rats received intra-articular MSU embedment. Sham groups received pseudosurgeries with equal normal saline (NS). Gross parameters and pathological features of synovium harvested from anterior capsule were estimated. Mechanical pain threshold tests were conducted over a 96-hour period postoperatively. Moreover, quantitative immunofluorescence was conducted to assess tissue inflammation. Result: After MSU embedding, rats got more persistent arthritic symptoms as well as tissue MSU deposition. More significant synovial swelling was detected in the MSU group compared to sham groups (P < 0.025). Behavioral tests showed that the embedding of MSU resulted in prolonged mechanical hyperalgesia during 2 hours to 96 hours postoperatively (P < 0.05). MSU depositions enveloped by inflammatory cells that express IL-1ß and TNF-α were detected in embedding groups. Quantitative immunofluorescence suggested that the frequencies of MSU interventions upregulated expression of proinflammatory factors including IL-1ß and TNF-α (P < 0.05). Conclusion: A minimally invasive method was developed to establish modified rat model of intra-articular MSU deposition. This model was proved to be a simple reproducible method to mimic the pathological characteristics of persistent gouty arthritis.


Assuntos
Artrite Gotosa/induzido quimicamente , Artrite Gotosa/patologia , Ácido Úrico/farmacologia , Animais , Artrite Gotosa/metabolismo , Modelos Animais de Doenças , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/metabolismo , Inflamação/patologia , Injeções Intra-Articulares/métodos , Interleucina-1beta/metabolismo , Masculino , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
8.
Anesth Analg ; 133(3): 794-810, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166321

RESUMO

BACKGROUND: Remifentanil can induce postinfusion cold hyperalgesia. N-methyl-d-aspartate receptor (NMDAR) activation and upregulation of transient receptor potential melastatin 8 (TRPM8) membrane trafficking in dorsal root ganglion (DRG) are critical to cold hyperalgesia derived from neuropathic pain, and TRPM8 activation causes NMDAR-dependent cold response. Contribution of P2Y1 purinergic receptor (P2Y1R) activation in DRG to cold pain hypersensitivity and NMDAR activation induced by P2Y1R upregulation in neurons are also unraveled. This study explores whether P2Y1R contributes to remifentanil-induced cold hyperalgesia via TRPM8-dependent regulation of NMDAR phosphorylation in DRG. METHODS: Rats with remifentanil-induced cold hyperalgesia were injected with TRPM8 antagonist or P2Y1R antagonist at 10 minutes before remifentanil infusion. Cold hyperalgesia (paw lift number and withdrawal duration on cold plate) was measured at -24, 2, 6, 24, and 48 hours following remifentanil infusion. After the last behavioral test, P2Y1R expression, TRPM8 expression and membrane trafficking, and NMDAR subunit (NR1 and NR2B) expression and phosphorylation in DRG were detected by western blot, and colocalization of P2Y1R with TRPM8 was determined by double-labeling immunofluorescence. Two-way repeated measures analysis of variance (ANOVA) or 2 × 2 factorial design ANOVA with repeated measures was used to analyze behavioral data of cold hyperalgesia. One-way ANOVA followed by Bonferroni post hoc comparisons was used to analyze the data in western blot and immunofluorescence. RESULTS: Remifentanil infusion (1 µg·kg-1·min-1 for 60 minutes) induced cold hyperalgesia (hyperalgesia versus control, paw lift number and withdrawal duration on cold plate at 2-48 hours, P < .0001) with upregulated NR1 (hyperalgesia versus naive, 48 hours, mean ± standard deviation [SD], 114.00% ± 12.48% vs 41.75% ± 5.20%, P < .005) and NR2B subunits expression (104.13% ± 8.37% vs 24.63% ± 4.87%, P < .005), NR1 phosphorylation at Ser896 (91.88% ± 7.08% vs 52.00% ± 7.31%, P < .005) and NR2B phosphorylation at Tyr1472 (115.75% ± 8.68% vs 59.75% ± 7.78%, P < .005), TRPM8 expression (115.38% ± 9.27% vs 40.50% ± 4.07%, P < .005) and membrane trafficking (112.88% ± 5.62% vs 48.88% ± 6.49%, P < .005), and P2Y1R expression (128.25% ± 14.86% vs 45.13% ± 7.97%, P < .005) in DRG. Both TRPM8 and P2Y1R antagonists attenuated remifentanil-induced cold hyperalgesia and downregulated increased NR1 and NR2B expression and phosphorylation induced by remifentanil (remifentanil + RQ-00203078 versus remifentanil + saline, NR1 phosphorylation, 69.38% ± 3.66% vs 92.13% ± 4.85%; NR2B phosphorylation, 72.25% ± 6.43% vs 111.75% ± 11.00%, P < .0001). NMDAR activation abolished inhibition of TRPM8 and P2Y1R antagonists on remifentanil-induced cold hyperalgesia. P2Y1R antagonist inhibited remifentanil-evoked elevations in TRPM8 expression and membrane trafficking and P2Y1R-TRPM8 coexpression (remifentanil + 2'-deoxy-N6-methyl adenosine 3',5'-diphosphate [MRS2179] versus remifentanil + saline, coexpression, 8.33% ± 1.33% vs 22.19% ± 2.15%, P < .0001). CONCLUSIONS: Attenuation of remifentanil-induced cold hyperalgesia by P2Y1R inhibition is attributed to downregulations in NMDAR expression and phosphorylation via diminishing TRPM8 expression and membrane trafficking in DRG.


Assuntos
Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Limiar da Dor , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Canais de Cátion TRPM/metabolismo , Analgésicos/farmacologia , Animais , Comportamento Animal , Temperatura Baixa , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiopatologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Hiperalgesia/prevenção & controle , Masculino , Limiar da Dor/efeitos dos fármacos , Fosforilação , Transporte Proteico , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/efeitos dos fármacos , Remifentanil , Transdução de Sinais , Canais de Cátion TRPM/antagonistas & inibidores
9.
Elife ; 102021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061020

RESUMO

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CalcaCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aß primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Hiperalgesia/metabolismo , Interneurônios/metabolismo , Mecanotransdução Celular , Limiar da Dor , Células do Corno Posterior/metabolismo , Animais , Comportamento Animal , Peptídeo Relacionado com Gene de Calcitonina/genética , Modelos Animais de Doenças , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Estimulação Física , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
10.
Front Immunol ; 12: 672498, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122430

RESUMO

Inflammation-associated chronic pain is a global clinical problem, affecting millions of people worldwide. However, the underlying mechanisms that mediate inflammation-associated chronic pain remain unclear. A rat model of cutaneous inflammation induced by Complete Freund's Adjuvant (CFA) has been widely used as an inflammation-induced pain hypersensitivity model. We present the transcriptomics profile of CFA-induced inflammation in the rat dorsal root ganglion (DRG) via an approach that targets gene expression, DNA methylation, and post-transcriptional regulation. We identified 418 differentially expressed mRNAs, 120 differentially expressed microRNAs (miRNAs), and 2,670 differentially methylated regions (DMRs), which were all highly associated with multiple inflammation-related pathways, including nuclear factor kappa B (NF-κB) and interferon (IFN) signaling pathways. An integrated analysis further demonstrated that the activator protein 1 (AP-1) network, which may act as a regulator of the inflammatory response, is regulated at both the transcriptomic and epigenetic levels. We believe our data will not only provide drug screening targets for the treatment of chronic pain and inflammation but will also shed light on the molecular network associated with inflammation-induced hyperalgesia.


Assuntos
Hiperalgesia/metabolismo , Inflamação/metabolismo , Fator de Transcrição AP-1/metabolismo , Animais , Dor Crônica/induzido quimicamente , Dor Crônica/metabolismo , Modelos Animais de Doenças , Adjuvante de Freund/toxicidade , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Hiperalgesia/induzido quimicamente , Inflamação/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley
11.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1131-G1141, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949199

RESUMO

Chronic abdominal pain is a common clinical condition experienced by patients with irritable bowel syndrome (IBS). A general lack of suitable treatment options for the management of visceral pain is the major contributing factor to the debilitating nature of the disease. Understanding the underlying causes of chronic visceral pain is pivotal to identifying new effective therapies for IBS. This review provides the current evidence, demonstrating that mediators and receptors that induce itch in the skin also act as "gut irritants" in the gastrointestinal tract. Activation of these receptors triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system leading to visceral hypersensitivity and visceral pain. Accumulating evidence points to significant roles of irritant mediators and their receptors in visceral hypersensitivity and thus constitutes potential targets for the development of more effective therapeutic options for IBS.


Assuntos
Colo/metabolismo , Hiperalgesia/metabolismo , Síndrome do Intestino Irritável/metabolismo , Dor Visceral/metabolismo , Histamina/metabolismo , Humanos , Mastócitos/metabolismo
12.
Neurochem Res ; 46(8): 2181-2191, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34032956

RESUMO

Application of chemotherapeutic oxaliplatin represses gene transcription through induction of DNA methylation, which may contribute to oxaliplatin-induced chronic pain. Here, Ddr1, which showed an increased methylation in the promoter, was screened from the SRA methylation database (PRJNA587622) after oxaliplatin treatment. qPCR and MeDIP assays verified that oxaliplatin treatment increased the methylation in Ddr1 promoter region and decreased the expression of DDR1 in the neurons of spinal dorsal horn. In addition, overexpression of DDR1 by intraspinal injection of AAV-hSyn-Ddr1 significantly alleviated the mechanical allodynia induced by oxaliplatin. Furthermore, we found that oxaliplatin treatment increased the expression of DNMT3b and ZEB1 in dorsal horn neurons, and promoted the interaction between DNMT3b and ZEB1. Intrathecal injection of ZEB1 siRNA inhibited the enhanced recruitment of DNMT3b and the hypermethylation in Ddr1 promoter induced by oxaliplatin. Finally, ZEB1 siRNA rescued the DDR1 downregulation and mechanical allodynia induced by oxaliplatin. In conclusion, these results suggested that the ZEB1 recruited DNMT3b to the Ddr1 promoter, which induced the DDR1 downregulation and contributed to the oxaliplatin-induced chronic pain.


Assuntos
Dor Crônica/metabolismo , Metilação de DNA/fisiologia , Receptor com Domínio Discoidina 1/genética , Oxaliplatina/efeitos adversos , Corno Dorsal da Medula Espinal/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Dor Crônica/induzido quimicamente , DNA/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Regiões Promotoras Genéticas/fisiologia , RNA Interferente Pequeno/farmacologia , Ratos Sprague-Dawley , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
13.
Am J Physiol Gastrointest Liver Physiol ; 320(6): G1093-G1104, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33908261

RESUMO

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.


Assuntos
Motilidade Gastrointestinal/fisiologia , Hiperalgesia/fisiopatologia , Morfina/farmacologia , Constipação Induzida por Opioides/fisiopatologia , Animais , Ciclo-Oxigenase 2/metabolismo , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Hiperalgesia/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Constipação Induzida por Opioides/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo
14.
Diabetes Res Clin Pract ; 176: 108790, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33812900

RESUMO

AIMS: The pathophysiological alteration of diabetic neuropathic pain (DNP) in brain is unclear. Here we aimed to explore the metabolomic characteristics of brain in rats over the progression of DNP through metabolomic analysis. METHODS: Adult rats were randomly divided into control group and DNP group. Body weight, blood glucose and behavioral assessment of neuropathic pain were measured every week after streptozotocin (STZ) injection. Finally, the brains of 2 rats from control group and 6 rats from DNP group were removed every 4 weeks after STZ injection for metabolomics analysis. RESULTS: After 4 weeks of STZ-injection, the rats with diabetes developed DNP, which was characterized as mechanical allodynia and thermal nociception. As for metabolomic analysis, differentially expressed metabolites (DE metabolites) showed a dynamic alteration over the development of DNP and affected several KEGG pathways associated with amino acid metabolism. Furthermore, the expression of l-Threonine, l-Methionine, d-Proline, l-Lysine and N-Acetyl-l-alanine were significantly decreased at all time points of DNP group. The amino acids which were precursor of analgesic neurotransmitters were downregulated over the progression of DNP, including l-tryptophan, l-histidine and l-tyrosine. CONCLUSIONS: The impairment of amino acid metabolism in brain might contribute to the progression of DNP through decreasing analgesic neurotransmitters.


Assuntos
Aminoácidos/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/etiologia , Neuralgia/etiologia , Aminoácidos/análise , Aminoácidos/fisiologia , Animais , Química Encefálica/fisiologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Hiperalgesia/complicações , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Metabolômica , Neuralgia/metabolismo , Neuralgia/patologia , Ratos , Ratos Sprague-Dawley , Estreptozocina
15.
PLoS One ; 16(4): e0251013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33914819

RESUMO

Neuropathic pain refers to pain caused by lesions or diseases of the somatosensory nervous system that is characteristically different from nociceptive pain. Moreover, neuropathic pain occurs in the maxillofacial region due to various factors and is treated using tricyclic antidepressants and nerve block therapy; however, some cases do not fully recover. Netrin is a secreted protein crucially involved in neural circuit formation during development, including cell migration, cell death, neurite formation, and synapse formation. Recent studies show Netrin-4 expressed in the dorsal horn of the spinal cord is associated with chronic pain. Here we found involvement of Netrin-4 in neuropathic pain in the maxillofacial region. Netrin-4, along with one of its receptors, Unc5B, are expressed in the caudal subnucleus of the trigeminal spinal tract nucleus. Inhibition of its binding by anti-Netrin-4 antibodies not only shows a behavioral analgesic effect but also neuronal activity suppression. There was increased Netrin-4 expression at 14 days after infraorbital nerve injury. Our findings suggest that Netrin-4 induced by peripheral nerve injury causes neuropathic pain via Unc5B.


Assuntos
Hiperalgesia/metabolismo , Netrinas/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Receptores de Superfície Celular/metabolismo , Neuralgia do Trigêmeo/metabolismo , Regulação para Cima , Animais , Modelos Animais de Doenças , Hiperalgesia/etiologia , Masculino , Medição da Dor , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/etiologia , Ratos , Nervo Trigêmeo/metabolismo , Neuralgia do Trigêmeo/etiologia
16.
Neurochem Res ; 46(7): 1759-1770, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33846883

RESUMO

Diabetic neuropathy is one of the most common complications of diabetes mellitus. Excess glutamate release and oxidative stress are hypothesized to be involved in the pathophysiology of diabetes-induced neuropathy. This study was designed to investigate the effect of clavulanic acid (CLAV), a competitive beta-lactamase inhibitor, on the streptozocin (STZ)-induced neuropathic pain and possible mechanisms in the spinal cord of rats. Male Wistar rats were divided into naive group; control group which got a single dose of STZ (50 mg/kg, i.p.), as a model of diabetic neuropathic pain; prophylactic groups: animals received CLAV (10, 20 and 40 mg/kg, i.p.) 1 week after STZ for 10 days; and therapeutic group: animals received 20 mg/kg CLAV, 21 days after STZ for 10 days. Study of pain behaviors was started on days 0, 7, 14, 21, 28, 35 and 42 after STZ. The expression of the glutamate transport 1 (GLT1), genes of oxidative stress including inducible nitric oxide synthase (iNOS), proinflammatory cytokine, tumor necrosis factor alpha (TNF-α), as well as genes involved in the apoptosis including bcl2, bcl2-associated x (bax) were measured in the spinal cord tissue by Real Time PCR, on day 42. On day 21 post injection of STZ, diabetic animals showed significant mechanical allodynia, cold allodynia and thermal hyperalgesia. CLAV in all doses of 10, 20 and 40 mg/kg reduced symptoms of allodynia and hyperalgesia, in both prophylactic and therapeutic regimens. While iNOS, TNF-α, bax/bcl2 were found significantly overexpressed in spinal cord of diabetic animals, their expression in animals received CLAV had been reduced. In contrast, GLT1 that had decreased in the spinal cord of diabetic animals, significantly increased in those received CLAV. CLAV was found a promising candidate for reliving neuropathic pain in diabetes mellitus. Such beneficial effect of CLAV could be, in part, attributed to the increased expression of GLT 1, inhibition of nitrosative stress, anti-inflammation, and inhibition of some apoptotic mediators followed by administration into diabetic animals.


Assuntos
Analgésicos/uso terapêutico , Ácido Clavulânico/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Neuralgia/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/metabolismo , Expressão Gênica/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Neuralgia/etiologia , Neuralgia/metabolismo , Teste de Campo Aberto/efeitos dos fármacos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Estreptozocina
17.
Int J Mol Sci ; 22(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918267

RESUMO

Transient receptor potential vanilloid 1 (TRPV1) channels contribute to the development of several chronic pain states and represent a possible therapeutic target in many painful disease treatment. Proinflammatory mediator bradykinin (BK) sensitizes TRPV1, whereas noxious peripheral stimulation increases BK level in the spinal cord. Here, we investigated the involvement of spinal TRPV1 in thermal and mechanical hypersensitivity, evoked by intrathecal (i.t.) administration of BK and an endogenous agonist of TRPV1, N-oleoyldopamine (OLDA), using behavioral tests and i.t. catheter implantation, and administration of BK-induced transient thermal and mechanical hyperalgesia and mechanical allodynia. All these hypersensitive states were enhanced by co-administration of a low dose of OLDA (0.42 µg i.t.), which was ineffective only under the control conditions. Intrathecal pretreatment with TRPV1 selective antagonist SB366791 prevented hypersensitivity induced by i.t. co-administration of BK and OLDA. Our results demonstrate that both thermal and mechanical hypersensitivity evoked by co-administration of BK and OLDA is mediated by the activation of spinal TRPV1 channels.


Assuntos
Hiperalgesia/metabolismo , Medula Espinal/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Bradicinina , Dopamina/análogos & derivados , Injeções Espinhais , Masculino , Ratos Wistar , Canais de Cátion TRPV/agonistas
18.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806699

RESUMO

Nociceptors sense hazards via plasmalemmal cation channels, including transient receptor potential vanilloid 1 (TRPV1). Nerve growth factor (NGF) sensitises TRPV1 to capsaicin (CAPS), modulates nociceptor excitability and induces thermal hyperalgesia, but cellular mechanisms remain unclear. Confocal microscopy was used to image changes in intracellular Ca2+ concentration ([Ca2+]i) across neuronal populations in dorsal root ganglia (DRG) explants from pirt-GCaMP3 adult mice, which express a fluorescent reporter in their sensory neurons. Raised [Ca2+]i was detected in 84 neurons of three DRG explants exposed to NGF (100 ng/mL) and most (96%) of these were also excited by 1 µM CAPS. NGF elevated [Ca2+]i in about one-third of the neurons stimulated by 1 µM CAPS, whether applied before or after the latter. In neurons excitable by NGF, CAPS-evoked [Ca2+]i signals appeared significantly sooner (e.g., respective lags of 1.0 ± 0.1 and 1.9 ± 0.1 min), were much (>30%) brighter and lasted longer (6.6 ± 0.4 vs. 3.9 ± 0.2 min) relative to those non-responsive to the neurotrophin. CAPS tachyphylaxis lowered signal intensity by ~60% but was largely prevented by NGF. Increasing CAPS from 1 to 10 µM nearly doubled the number of cells activated but only modestly increased the amount co-activated by NGF. In conclusion, a sub-population of the CAPS-sensitive neurons in adult mouse DRG that can be excited by NGF is more sensitive to CAPS, responds with stronger signals and is further sensitised by transient exposure to the neurotrophin.


Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Capsaicina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Animais , Feminino , Gânglios Espinais/metabolismo , Hiperalgesia/metabolismo , Masculino , Camundongos , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Nociceptores/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo
19.
Int J Mol Sci ; 22(5)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33804568

RESUMO

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30-60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Glicina/líquido cefalorraquidiano , Hiperalgesia/prevenção & controle , Neuralgia/tratamento farmacológico , Sarcosina/análogos & derivados , Animais , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Masculino , Atividade Motora , Neuralgia/metabolismo , Neuralgia/patologia , Ratos , Ratos Wistar , Sarcosina/farmacologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia
20.
Life Sci ; 276: 119469, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33811892

RESUMO

AIMS: Breast cancer-induced chronic pain is usually treated with opioids, but these compounds cause various adverse effects. Transient receptor potential ankyrin 1 (TRPA1) is involved in cancer pain; also, endogenous TRPA1 agonists are associated with cancer pain development. The aim of this study was to observe the antinociceptive effect of a repeated-dose TRPA1 antagonist administration and the production of endogenous TRPA1 agonists and TRPA1 expression in bone tissue in a model of breast cancer pain in mice. Second, we used a sequence reading archive (SRA) strategy to observe the presence of this channel in the mouse bone and in mouse bone cell lines. MAIN METHODS: We used BALB/c mice for experiments. The animals were subjected to the tumor cell inoculation (4 T1 strain). HC-030031 (a TRPA1 antagonist) treatment was done from day 11 to day 20 after tumor inoculation. TRPA1 expression and biochemical tests of oxidative stress were performed in the bone of mice (femur). SRA strategy was used to detect the TRPA1 presence. KEY FINDINGS: Repeated treatment with the TRPA1 antagonist produced an antinociceptive effect. There was an increase in hydrogen peroxide levels, NADPH oxidase and superoxide dismutase activities, but the expression of TRPA1 in the bone tissue was not altered. SRA did not show TRPA1 residual transcription in the osteoblast and osteoclast cell lines, as well as for mice cranial tissue and in mouse osteoclast precursors. SIGNIFICANCE: The TRPA1 receptor is a potential target for the development of new painkillers for the treatment of bone cancer pain.


Assuntos
Acetanilidas/farmacologia , Osso e Ossos/efeitos dos fármacos , Dor do Câncer/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Neoplasias Mamárias Animais/complicações , Nociceptividade/efeitos dos fármacos , Purinas/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores , Acetanilidas/administração & dosagem , Animais , Osso e Ossos/metabolismo , Dor do Câncer/etiologia , Dor do Câncer/metabolismo , Dor do Câncer/patologia , Feminino , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Purinas/administração & dosagem
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