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1.
Cell Mol Life Sci ; 79(1): 35, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34989866

RESUMO

Multiple representatives of eulipotyphlan mammals such as shrews have oral venom systems. Venom facilitates shrews to hunt and/or hoard preys. However, little is known about their venom composition, and especially the mechanism to hoard prey in comatose states for meeting their extremely high metabolic rates. A toxin (BQTX) was identified from venomous submaxillary glands of the shrew Blarinella quadraticauda. BQTX is specifically distributed and highly concentrated (~ 1% total protein) in the organs. BQTX shares structural and functional similarities to toxins from snakes, wasps and snails, suggesting an evolutional relevancy of venoms from mammalians and non-mammalians. By potentiating thrombin and factor-XIIa and inhibiting plasmin, BQTX induces acute hypertension, blood coagulation and hypokinesia. It also shows strong analgesic function by inhibiting elastase. Notably, the toxin keeps high plasma stability with a 16-h half-life in-vivo, which likely extends intoxication to paralyze or immobilize prey hoarded fresh for later consumption and maximize foraging profit.


Assuntos
Analgesia/métodos , Hipocinesia/fisiopatologia , Musaranhos/metabolismo , Toxinas Biológicas/metabolismo , Peçonhas/metabolismo , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Pressão Sanguínea/efeitos dos fármacos , Feminino , Membro Posterior/efeitos dos fármacos , Membro Posterior/fisiopatologia , Humanos , Macaca mulatta , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Dor/induzido quimicamente , Dor/fisiopatologia , Dor/prevenção & controle , Homologia de Sequência de Aminoácidos , Musaranhos/genética , Trombina/antagonistas & inibidores , Trombina/metabolismo , Toxinas Biológicas/administração & dosagem , Toxinas Biológicas/genética , Peçonhas/genética
2.
Biomolecules ; 11(12)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34944441

RESUMO

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Aldeídos/efeitos adversos , Dor/metabolismo , Proteína Quinase C-épsilon/metabolismo , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Carragenina/efeitos adversos , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Masculino , Camundongos , Mitocôndrias/metabolismo , Dor/induzido quimicamente , Transporte Proteico
3.
Front Immunol ; 12: 689453, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616393

RESUMO

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund's adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-treated female rats, the only experimental group that showed relapse-like behavior, exhibited specific alterations in the expression of phosphorylated NFκB, iNOS, and COX2 in the PFC and VTA. More interestingly, the analysis of the IBA1 expression revealed a decrease of the microglial activation in PFC during abstinence and an increase of its expression in the relapse phase, together with an augmentation of this activation in the NAc in both phases that only occur in female CFA-treated rats. Additionally, the expression of IL1ß also evidenced these dynamic changes through these two phases following similar expression patterns in both areas. Furthermore, the expression of the cytokine IL10 showed a different profile than that of IL1ß, indicating anti-inflammatory processes occurring only during abstinence in the PFC of CFA-female rats but neither during the reintroduction phase in PFC nor in the NAc. These data indicate a downregulation of microglial activation and pro-inflammatory processes during abstinence in the PFC, whereas an upregulation can be observed in the NAc during abstinence that is maintained during the reintroduction phase only in CFA-female rats. Secondly, our data reveal a correlation between the alterations observed in IL1ß, IBA1 levels, and MOR levels in the PFC and NAc of CFA-treated female rats. Although premature, our data suggest that neuroinflammatory processes, together with neural adaptations involving MOR, might play an important role in alcohol relapse in female rats, so further investigations are warranted.


Assuntos
Alcoolismo/metabolismo , Sistema Límbico/metabolismo , Microglia/metabolismo , Neuroimunomodulação , Dor/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores Opioides mu/metabolismo , Abstinência de Álcool , Alcoolismo/imunologia , Alcoolismo/fisiopatologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Adjuvante de Freund , Mediadores da Inflamação/metabolismo , Sistema Límbico/imunologia , Sistema Límbico/fisiopatologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/imunologia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Dor/induzido quimicamente , Dor/imunologia , Dor/fisiopatologia , Fosforilação , Córtex Pré-Frontal/imunologia , Córtex Pré-Frontal/fisiopatologia , Ratos Sprague-Dawley , Recidiva , Fatores Sexuais
4.
FASEB J ; 35(10): e21952, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34555210

RESUMO

Cyclophosphamide (CP) has been widely used in the treatment of various malignancies and autoimmune diseases, but acrolein, a byproduct of CP, causes severe hemorrhagic cystitis as the major side effect of CP. On the other hand, a large amount of prostacyclin (PGI2 ) is produced in bladder tissues, and PGI2 has been shown to play a critical role in bladder homeostasis. PGI2 is biosynthesized from prostaglandin (PG) H2 , the common precursor of PGs, by PGI2 synthase (PTGIS) and is known to also be involved in inflammatory responses. However, little is known about the roles of PTGIS-derived PGI2 in bladder inflammation including CP-induced hemorrhagic cystitis. Using both genetic and pharmacological approaches, we here revealed that PTGIS-derived PGI2 -IP (PGI2 receptor) signaling exacerbated CP-induced bladder inflammatory reactions. Ptgis deficiency attenuated CP-induced vascular permeability and chemokine-mediated neutrophil migration into bladder tissues and then suppressed hemorrhagic cystitis. Treatment with RO1138452, an IP selective antagonist, also suppressed CP-induced cystitis. We further found that cystitis-related nociceptive behavior was also relieved in both Ptgis-/- mice and RO1138452-treated mice. Our findings may provide new drug targets for bladder inflammation and inflammatory pain in CP-induced hemorrhagic cystitis.


Assuntos
Ciclofosfamida/efeitos adversos , Cistite/induzido quimicamente , Cistite/prevenção & controle , Epoprostenol/deficiência , Dor/prevenção & controle , Bexiga Urinária , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Cultivadas , Quimiotaxia de Leucócito , Cistite/complicações , Sistema Enzimático do Citocromo P-450/deficiência , Progressão da Doença , Epoprostenol/metabolismo , Feminino , Hemorragia/complicações , Hemorragia/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Tamanho do Órgão/efeitos dos fármacos , Dor/induzido quimicamente , Dor/complicações , Prostaglandina-E Sintases , Bexiga Urinária/efeitos dos fármacos
5.
Transplant Proc ; 53(8): 2630-2635, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34481645

RESUMO

Calcineurin-inhibitor induced pain syndrome (CIPS) also called the "symmetrical bone syndrome" is a condition describing reversible lower extremity pain in patients after organ transplantation who are receiving calcineurin inhibitors, especially tacrolimus. We present a case of CIPS after orthotopic heart transplant complicated with concurrent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We emphasize the presentation; diagnostic evaluation, and findings. We then discuss the proposed pathophysiologic mechanisms of CIPS and conclude with discussion of management strategies. Additionally, we present a table to guide clinicians in assessing posttransplant bone pain syndromes. To our knowledge, this is the first article to describe a case of CIPS with concurrent SARS-CoV-2 infection.


Assuntos
COVID-19 , Inibidores de Calcineurina , Transplante de Coração , Dor/induzido quimicamente , COVID-19/complicações , Calcineurina , Inibidores de Calcineurina/efeitos adversos , Humanos
6.
J Neurochem ; 159(3): 512-524, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34338322

RESUMO

Studies have verified that Fragile X mental retardation protein (FMRP), an RNA-binding protein, plays a potential role in the pathogenesis of formalin- and (RS)-3,5-dihydroxyphenylglycine-induced abnormal pain sensations. However, the role of FMRP in inflammatory pain has not been reported. Here, we showed an increase in FMRP expression in the spinal dorsal horn (SDH) in a rat model of inflammatory pain induced by complete Freund's adjuvant (CFA). Double immunofluorescence staining revealed that FMRP was mainly expressed in spinal neurons and colocalized with proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)]. After consecutive intrathecal injection of fragile X mental retardation 1 small interfering RNA for 3 days post-CFA injection, FMRP expression in the SDH was reduced, and CFA-induced hyperalgesia was decreased. In addition, the CFA-induced increase in spinal TNF-α and IL-6 production was significantly suppressed by intrathecal administration of fragile X mental retardation 1 small interfering RNA. Together, these results suggest that FMRP regulates TNF-α and IL-6 levels in the SDH and plays an important role in inflammatory pain.


Assuntos
Citocinas/biossíntese , Proteína do X Frágil de Retardo Mental/fisiologia , Inflamação/genética , Inflamação/patologia , Dor/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Animais , Proteína do X Frágil de Retardo Mental/genética , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Injeções Espinhais , Interleucina-6/metabolismo , Masculino , Dor/induzido quimicamente , Dor/genética , Células do Corno Posterior/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
7.
Toxicon ; 201: 105-114, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34425141

RESUMO

Snake venoms are substances mostly composed by proteins and peptides with high biological activity. Local and systemic effects culminate in clinical manifestations induced by these substances. Pain is the most uncomfortable condition, but it has not been well investigated. This review discusses Bothrops snakebite-induced nociception, highlighting molecules involved in the mediation of this process and perspectives in treatment of pain induced by Bothrops snake venoms (B. alternatus, B. asper, B. atrox, B. insularis, B. jararaca, B. pirajai, B. jararacussu, B. lanceolatus, B. leucurus, B. mattogrossensis, B. moojeni). We highlight, the understanding of the nociceptive signaling, especially in snakebite, enables more efficient treatment approaches. Finally, future perspectives for pain treatment concerning snakebite patients are discussed.


Assuntos
Bothrops , Venenos de Crotalídeos , Mordeduras de Serpentes , Animais , Venenos de Crotalídeos/toxicidade , Humanos , Nociceptividade , Dor/induzido quimicamente , Dor/tratamento farmacológico , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/toxicidade
8.
Int J Cancer ; 149(10): 1828-1832, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34270809

RESUMO

Triple-negative breast cancer (TNBC) cells are sensitive to PARP1 inhibitors in vitro. The combination of Olaparib and radiotherapy for TNBC is currently evaluated in the Phase I RADIOPARP trial. RADIOPARP is a monocentric prospective open-label Phase I dose-escalation trial evaluating the combination of breast radiotherapy and Olaparib in TNBC patients with inflammatory, locoregionally advanced or metastatic disease, or with residual disease after neoadjuvant chemotherapy. Olaparib was orally given at increasing dose levels (50, 100, 150 or 200 mg twice a day [BID]); radiotherapy consisted of 50 Gy to the breast or chest wall with or without lymph node irradiation. Twenty-four TNBC patients were enrolled between September 2017 and November 2019. Olaparib was escalated to 200 mg BID without dose-limiting toxicities. At 1-year follow-up, no treatment-related grade ≥3 toxicity was observed. One patient (4.2%) had persistent grade 2 adverse events (breast pain, fibrosis and deformity). There was no cardiac, pulmonary or digestive toxicity related to treatment. The 1-year follow-up report of the RADIOPARP Phase I trial, evaluating Olaparib associated with breast radiotherapy in TNBC patients, consequently demonstrated an excellent toxicity profile of this combination with few low-grade adverse events.


Assuntos
Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Radioterapia/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Adulto , Idoso , Terapia Combinada , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Hiperpigmentação/induzido quimicamente , Pessoa de Meia-Idade , Dor/induzido quimicamente , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Prospectivos , Dosagem Radioterapêutica , Resultado do Tratamento
9.
J Med Chem ; 64(13): 9458-9483, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34152138

RESUMO

Management of moderate to severe pain relies heavily on opioid analgesics such as morphine, oxycodone, and fentanyl in clinics. However, their prolonged use was associated with undesirable side effects. Many new strategies to reduce side effects have been proposed, but not without disadvantages. Using a hot plate model as a phenotypic screening method, our studies identified (3R,4S)-9d with a new scaffold as a potent analgesic with ED50 values of 0.54 mg/kg and 0.021 mg/kg in hot plate and antiwrithing models, respectively. Mechanistic studies showed that it elicited its analgesic effect via the active metabolite (3R,4S)-10a. The mechanism of (3R,4S)-10a-induced activation of the µ opioid receptor (MOR) was proposed by means of molecular dynamics (MD) simulation.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Dor/tratamento farmacológico , Receptores Opioides mu/metabolismo , Ácido Acético , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Feminino , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Dor/induzido quimicamente , Relação Estrutura-Atividade
10.
Toxicon ; 200: 3-12, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34153310

RESUMO

Scorpionism is a public health burden in Brazil. Tityus bahiensis is responsible for most accidents in the Southeastern region of Brazil. Here, the hyperalgesic mechanisms of Tityus bahiensis venom were investigated, focusing on the role of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 1 beta [IL-1ß]) and activation of the transcription factor NFκB. Intraplantar (i.pl.) administration of Tityus bahiensis venom (0.2, 0.6, 1.2 and 2.4 µg/20 µL i.pl.) induced mechanical hyperalgesia and thermal hyperalgesia. The 2.4 µg dose of Tityus bahiensis venom induced overt pain-like behavior and increased myeloperoxidase (MPO) and N-acetyl-beta-D-glucosaminidase (NAG) activities, TNF-α and IL-1ß levels in the paw tissue. Systemic pre-treatment with etanercept (soluble TNF-α receptor; 10 mg/kg), IL-1ra (IL-1 receptor antagonist; 30 mg/kg) and pyrrolidine dithiocarbamate (PDTC, nuclear factor kappa B [NFκB] inhibitor; 100 mg/kg) inhibited Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, MPO and NAG activity and overt pain-like behavior. These data demonstrate the involvement of TNF-α and IL-1ß signaling as well as NFκB activation in Tityus bahiensis venom-induced mechanical and thermal hyperalgesia, overt pain-like behavior, and MPO activity and NAG activity, indicating thus, that targeting these mechanisms might contribute to reducing the pain in this scorpionism.


Assuntos
Dor , Peçonhas , Animais , Hiperalgesia/induzido quimicamente , Dor/induzido quimicamente , Dor/tratamento farmacológico , Escorpiões , Fator de Necrose Tumoral alfa
12.
Cell Mol Life Sci ; 78(12): 5163-5177, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33970306

RESUMO

Velvet ants (Hymenoptera: Mutillidae) are a family of solitary parasitoid wasps that are renowned for their painful stings. We explored the chemistry underlying the stings of mutillid wasps of the genus Dasymutilla Ashmead. Detailed analyses of the venom composition of five species revealed that they are composed primarily of peptides. We found that two kinds of mutillid venom peptide appear to be primarily responsible for the painful effects of envenomation. These same peptides also have defensive utility against invertebrates, since they were able to incapacitate and kill honeybees. Both act directly on cell membranes where they directly increase ion conductivity. The defensive venom peptides of Dasymutilla bear a striking similarity, in structure and mode of action, to those of the ant Myrmecia gulosa (Fabricius), suggesting either retention of ancestral toxins, or convergence driven by similar life histories and defensive selection pressures. Finally, we propose that other highly expressed Dasymutilla venom peptides may play a role in parasitisation, possible in delay or arrest of host development. This study represents the first detailed account of the composition and function of the venoms of the Mutillidae.


Assuntos
Venenos de Artrópodes/química , Venenos de Artrópodes/toxicidade , Comportamento Animal/efeitos dos fármacos , Himenópteros/fisiologia , Mordeduras e Picadas de Insetos/induzido quimicamente , Dor/induzido quimicamente , Fragmentos de Peptídeos/toxicidade , Sequência de Aminoácidos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Homologia de Sequência
13.
J Med Chem ; 64(10): 7033-7043, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33949869

RESUMO

In a program to identify pain treatments with low addiction potential, we isolated five steroids, conosteroids A-E (1-5), from the hypobranchial gland of the mollusk Conus geographus. Compounds 1-5 were active in a mouse dorsal root ganglion (DRG) assay that suggested that they might be analgesic. A synthetic analogue 6 was used for a detailed pharmacological study. Compound 6 significantly increased the pain threshold in mice in the hot-plate test at 2 and 50 mg/kg. Compound 6 at 500 nM antagonizes type-A γ-aminobutyric acid receptors (GABAARs). In a patch-clamp experiment, out of the six subunit combinations tested, 6 exhibited subtype selectivity, most strongly antagonizing α1ß1γ2 and α4ß3γ2 receptors (IC50 1.5 and 1.0 µM, respectively). Although the structures of 1-6 differ from those of known neuroactive steroids, they are cell-type-selective modulators of GABAARs, expanding the known chemical space of neuroactive steroids.


Assuntos
Analgésicos/química , Caramujo Conus/química , Antagonistas GABAérgicos/química , Neuroesteroides/química , Receptores de GABA/química , Potenciais de Ação/efeitos dos fármacos , Analgésicos/síntese química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Caramujo Conus/metabolismo , Modelos Animais de Doenças , Antagonistas GABAérgicos/isolamento & purificação , Antagonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/uso terapêutico , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Neuroesteroides/isolamento & purificação , Neuroesteroides/farmacologia , Neuroesteroides/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/patologia , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Receptores de GABA/metabolismo
14.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806698

RESUMO

Nuclear factor of activated T cells (NFAT5) is a well-known transcription factor that regulates the expression of genes involved in osmotic stress. However, the role of NFAT5 in inflammatory pain remains unknown. Here, we studied the function of NFAT5 in inflammatory pain using NFAT5-heterozygous (Het) mice. To study inflammatory pain, we injected 10 µL of 2% formalin into the right hind paws of mice and monitored pain behaviors, such as licking, lifting, and flinching, for 60 min. After the first 15 min (phase I), there were no significant differences in pain behaviors between wild-type (WT) and NFAT5-Het mice. However, from 15-60 min (phase II), NFAT5-Het mice displayed significantly fewer pain behaviors compared to WT mice. Further, the expression levels of inflammatory-pain-related factors, including c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated n-methyl-D-aspartate receptor subunit 2B (p-NR2B), were significantly elevated in the spinal dorsal neurons of formalin-treated WT mice but was not elevated in NFAT5-Het mice. Similarly, c-Fos, p-ERK, and p-NR2B levels were significantly higher in glutamate-treated PC12 neuronal cells but were not affected by Nfat5 silencing in glutamate-treated PC12 cells. Altogether, our findings suggest that NFAT5 deficiency may mitigate formalin-induced inflammatory pain by upregulating mammalian target of rapamycin (mTOR) expression and downregulating its downstream factors in spinal dorsal neurons. Therefore, NFAT5 is a potential therapeutic target for the treatment of inflammatory pain.


Assuntos
Formaldeído/farmacologia , Inflamação/metabolismo , Dor/induzido quimicamente , Dor/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Medição da Dor/métodos , Ratos , Medula Espinal/metabolismo , Regulação para Cima/fisiologia
15.
PLoS One ; 16(4): e0249276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33793632

RESUMO

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.


Assuntos
Aconitina/uso terapêutico , Analgésicos/uso terapêutico , Dor/tratamento farmacológico , Ácido Acético/toxicidade , Animais , Aspirina/uso terapêutico , Modelos Animais de Doenças , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Feminino , Formaldeído/toxicidade , Adjuvante de Freund/toxicidade , Temperatura Alta , Camundongos , Camundongos Endogâmicos C57BL , Dor/induzido quimicamente , Dor/patologia , Limiar da Dor
16.
Molecules ; 26(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808667

RESUMO

Novel α-aminoamide derivatives containing different benzoheterocyclics moiety were synthesized and evaluated as voltage-gated sodium ion channels blocks the treatment of pain. Compounds 6a, 6e, and 6f containing the benzofuran group displayed more potent in vivo analgesic activity than ralfinamide in both the formalin test and the writhing assay. Interestingly, they also exhibited potent in vitro anti-Nav1.7 and anti-Nav1.8 activity in the patch-clamp electrophysiology assay. Therefore, compounds 6a, 6e, and 6f, which have inhibitory potency for two pain-related Nav targets, could serve as new leads for the development of analgesic medicines.


Assuntos
Amidas , Analgésicos , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Avaliação de Medicamentos , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Dor/induzido quimicamente , Dor/metabolismo , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia
17.
J Tradit Chin Med ; 41(2): 219-226, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33825401

RESUMO

OBJECTIVE: To investigate the possible antinociceptive effects of Salvia (S.) miltiorrhiza Bunge and its single components in monosodium urate (MSU)-induced pain model in mice and lipopolysaccharide (LPS)-induced inflammation model in RAW264.7 cells. METHODS: Pretreatment of S. miltiorrhiza Bunge extract (from 1 to 50 µg/mL) concentration-dependently attenuated LPS-induced nitric oxide (NO) release. The extract of S. miltiorrhiza Bunge (50 or 100 mg/kg) also caused reversals of decreased threshold for pain in the MSU-treated group as measured by Von-Frey test. Furthermore, we assessed the antinociceptive and anti-inflammatory properties of the active single components from S. miltiorrhiza Bunge such as 15, 16-dihydrotanshinone Ⅰ tanshinone Ⅱ cryptotanshinone, miltirone, tanshinone ⅡA, and salvianolic acid B. Some of them showed an anti-inflammatory effect in LPS-induced NO release model and an antinociceptive effect in MSU-treated pain model. RESULTS: Our results suggest that S. miltiorrhiza Bunge extract may exert anti-inflammatory effect by reducing LPS-induced NO release and an antinociceptive property in MSU-treated pain model. Especially, tanshinoneⅡA, miltirone, cryptotanshinone, and 15,16-dihydrotanshinone Ⅰ not only appear to be responsible for LPS-induced NO release induced by S. miltiorrhiza Bunge, but also in the production of S. miltiorrhiza Bunge extract-induced antinociception in MSU-treated pain model. CONCLUSION: Therefore, the analgesic and anti-inflammatory property of S. miltiorrhiza Bunge indicate it as a therapeutic potential candidate for the treatment of pain and inflammation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Salvia miltiorrhiza/química , Animais , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/imunologia , Dor/induzido quimicamente , Dor/imunologia , Células RAW 264.7 , Ácido Úrico/efeitos adversos
18.
Bioorg Chem ; 111: 104870, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33845382

RESUMO

Seventeen diterpenoids (1-17), classified into eight diverse carbon skeleton types, grayanane (1, 2, and 12), micranthane (3, 4, and 13), mollane (5-7 and 14), 1,5-seco-grayanane (8), kalmane (9-11), 1,5-seco-kalmane (15), A-homo-B-nor-ent-kaurane (16), and leucothane (17), respectively, were isolated from the leaves extract of Rhododendron micranthum. Among them, diterpenoids 1-9 are new compounds and their structures were elucidated via extensive spectroscopic methods, quantum chemical calculations including the 13C NMR-DP4+ analysis and electronic circular dichroism (ECD) calculations, and the single-crystal X-ray diffraction analysis. Micranthanol A (1) represents the first example of a 5αH,9αH-grayanane diterpenoid and a 6-hydroxy-6,10-epoxygrayanane diterpenoid, and micranthanone B (3) is the first 6,10-epoxymicranthane and the 5α-hydroxy-micranthane diterpenoids. 14-epi-Mollanol A (5) and mollanol B (6) represent the first examples of 14ß-hydroxymollane diterpenoids. It is the first time to report mollane, 1,5-seco-kalmane, and A-homo-B-nor-ent-kaurane type diterpenoids from Rhododendron micranthum. All the seventeen diterpenoids showed significant antinociceptive activities at a dose of 5.0 mg/kg, and it is the first time to evaluate the antinociceptive activity of 1,5-seco-kalmane diterpenoid. Among them, compounds 3, 11, 14, and 15 exhibited significant antinociceptive activities even at a lower dose of 1.0 mg/kg. A preliminary structure-activity relationship for the antinociceptive effects of diterpenoids 1-17 is discussed, which provided a new basis to develop novel potent analgesics.


Assuntos
Analgésicos/farmacologia , Diterpenos/farmacologia , Dor/tratamento farmacológico , Rhododendron/química , Ácido Acético , Analgésicos/química , Analgésicos/isolamento & purificação , Animais , Comportamento Animal/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Dor/induzido quimicamente , Relação Estrutura-Atividade
19.
Int J Mol Sci ; 22(8)2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920318

RESUMO

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0-4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15-20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients.


Assuntos
Fator 2 Relacionado a NF-E2/genética , Oxaliplatina/farmacologia , Oxazóis/farmacologia , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/patologia , Humanos , Camundongos , NF-kappa B/genética , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Oxaliplatina/efeitos adversos , Dor/induzido quimicamente , Dor/genética , Dor/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos
20.
Sci Rep ; 11(1): 9224, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33927235

RESUMO

Linalool odor exposure induces an analgesic effect in mice. This effect disappeared in the anosmic model mice, indicating that olfactory input evoked by linalool odor triggered this effect. Furthermore, hypothalamic orexinergic neurons play a pivotal role in this effect. However, the neuronal circuit mechanisms underlying this effect have not been fully addressed. In this study, we focused on the descending orexinergic projection to the spinal cord and examined whether this pathway contributes to the effect. We assessed the effect of intrathecal administration of orexin receptor antagonists on linalool odor-induced analgesia in the tail capsaicin test. We found that the selective orexin type 1 receptor antagonist, but not the selective orexin type 2 receptor antagonist, prevented the odor-induced analgesic effect. Furthermore, immunohistochemical analyses of c-Fos expression induced by the capsaicin test revealed that neuronal activity of spinal cord neurons was suppressed by linalool odor exposure, which was prevented by intrathecal administration of the orexin 1 receptor antagonist. These results indicate that linalool odor exposure drives the orexinergic descending pathway and suppresses nociceptive information flow at the spinal level.


Assuntos
Monoterpenos Acíclicos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Manejo da Dor/métodos , Dor/tratamento farmacológico , Medula Espinal/metabolismo , Analgesia/métodos , Animais , Modelos Animais de Doenças , Inseticidas/farmacologia , Masculino , Camundongos , Dor/induzido quimicamente , Dor/metabolismo , Dor/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Medula Espinal/efeitos dos fármacos
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