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1.
Eur J Pharmacol ; 959: 176058, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37739305

RESUMO

The aberrant activation of Wnt/ß-catenin and atypical Wnt/Ryk signaling pathways in the spinal cord is critical for the development and maintenance of neuropathic pain. Crotalphine is a structural analog to a peptide first identified in Crotalus durissus terrificus snake venom, which induces antinociception by activating kappa-opioid and CB2 cannabinoid receptors. Consistent with previous data, we showed that the protein levels of the canonical Wnt/ß-catenin and the atypical Wnt/Ryk signaling pathways are increased in neuropathic rats. Importantly, the administration of crotalphine downregulates these protein levels, including its downstream cascades, such as TCF4 from the canonical pathway and NR2B glutamatergic receptor and Ca2+-dependent signals, via the Ryk receptor. The CB2 receptor antagonist, AM630, abolished the crotalphine-induced atypical Wnt/Ryk signaling pathway activation. However, the selective CB2 agonist affects both canonical and non-canonical Wnt signaling in the spinal cord. Next, we showed that crotalphine blocked hypersensitivity and significantly decreased the concentration of IL-1ɑ, IL-1ß, IL-6, IL-10, IL-18, TNF-ɑ, MIP-1ɑ and MIP-2 induced by intrathecal injection of exogenous Wnt-3a agonist. Taken together, our findings show that crotalphine induces analgesia in a neuropathic pain model by down-regulating the canonical Wnt/ß-catenin and the atypical Wnt/Ryk signaling pathways and, consequently controlling neuroinflammation. This effect is, at least in part, mediated by CB2 receptor activation. These results open a perspective for new approaches that can be used to target Wnt signaling in the context of chronic pain. PERSPECTIVE: Our work identified that crotalphine-induced activation of CB2 receptors plays a critical role in the impairment of Wnt signaling during neuropathic pain. This work suggests that drugs with opioid/cannabinoid activity may be a useful strategy to target Wnt signaling in the context of chronic pain.


Assuntos
Analgesia , Dor Crônica , Neuralgia , Ratos , Animais , beta Catenina/metabolismo , Via de Sinalização Wnt , Analgésicos Opioides , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Peptídeos/farmacologia
2.
J Leukoc Biol ; 106(3): 541-551, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31150565

RESUMO

The development of neuropathic pain after peripheral nerve injury involves neuroimmune-glial interactions in the spinal cord. However, whether the development of neuropathic pain depends on the infiltration of peripheral immune cells, such as monocytes, into the spinal cord parenchyma after peripheral nerve damage remains unclear. Here, we used a combination of different techniques such as transgenic reporter mouse (Cx3cr1GFP/+ and Ccr2RFP/+ mice), bone marrow chimeric mice, and parabiosis to investigate this issue in spared nerve injury (SNI) model. Herein, we provided robust evidence that, although microglial cells are activated/proliferate at the dorsal horn of the spinal cord after SNI, peripheral hematopoietic cells (including monocytes) are not able to infiltrate into the spinal cord parenchyma. Furthermore, there was no evidence of CCR2 expression in intrinsic cells of the spinal cord. However, microglial cells activation/proliferation in the spinal cord and mechanical allodynia after SNI were reduced in Ccr2-deficient mice. These results suggest that blood-circulating leukocytes cells are not able to infiltrate the spinal cord parenchyma after distal peripheral nerve injury. Nevertheless, they indicate that CCR2-expressing cells might be indirectly regulating microglia activation/proliferation in the spinal cord after SNI. In conclusion, our study supports that CCR2 inhibition could be explored as an interventional approach to reduce microglia activation and consequently neuropathic pain development after peripheral nerve injury.


Assuntos
Leucócitos/patologia , Traumatismos dos Nervos Periféricos/sangue , Traumatismos dos Nervos Periféricos/patologia , Medula Espinal/patologia , Animais , Proliferação de Células , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Endotélio Vascular/patologia , Feminino , Células-Tronco Hematopoéticas/metabolismo , Hiperalgesia/sangue , Hiperalgesia/complicações , Hiperalgesia/imunologia , Hiperalgesia/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/patologia , Monócitos/patologia , Neuralgia/sangue , Neuralgia/complicações , Neuralgia/imunologia , Neuralgia/patologia , Receptores CCR2/deficiência , Receptores CCR2/metabolismo
3.
Pain ; 160(1): 102-116, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30169421

RESUMO

Neuropathic pain is one of the most important types of chronic pain. It is caused by neuronal damage. Clinical and experimental studies suggest a critical role for neuroimmune interactions in the development of neuropathic pain. In this article, we have shown that the cytoplasmic receptor Nod-like receptor-2, NOD2, and its adaptor-signaling molecule RIPK2 participate in the development of neuropathic pain after peripheral nerve injury (spared nerve injury model). The activation of NOD2 signaling in peripheral macrophage mediates the development of neuropathic pain through the production of pronociceptive cytokines (tumor necrosis factor and IL-1ß). This study found that peripheral nerve injury promoted a systemic increase in the NOD2 ligand. These results highlight a previously undetermined role for NOD2 signaling in the development of neuropathic pain, suggesting a new potential target for preventing neuropathic pain.


Assuntos
Macrófagos/metabolismo , Neuralgia/patologia , Neuralgia/fisiopatologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Animais , Transplante de Medula Óssea , Carragenina/toxicidade , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Minociclina/uso terapêutico , Neuralgia/genética , Neuralgia/cirurgia , Fármacos Neuroprotetores/uso terapêutico , Proteína Adaptadora de Sinalização NOD2/genética , RNA Interferente Pequeno/uso terapêutico , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Xantinas/uso terapêutico
4.
Rev. bras. farmacogn ; 25(3): 228-232, May-June 2015. tab, ilus
Artigo em Inglês | LILACS | ID: lil-757434

RESUMO

AbstractArrabidaea brachypoda Bureau, Bignoniaceae, known as "cipó-una", is widely used in traditional medicine in Southeastern and Northeastern Brazil for kidney stones and painful joints. This study was aimed at evaluating the anti-inflammatory proprieties of the oleanane-type triterpenoid 3β-estearioxy-olean-12-ene isolated from the roots of A. brachypoda. Carrageenan-induced paw oedema, formalin test and hot plate test were used to investigate the antiinflammatory activity of 3β-estearioxy-olean-12-ene in animals. We observed that 3β-estearioxy-olean-12-ene at doses of 5, 10 and 15 mg/kg p.o. demonstrated anti-inflammatory effects, by reduced (p < 0.05) paw oedema induced by carrageenan and by decreased (p < 0.05) licking time caused by a subplantar injection of formalin. In conclusion, 3β-estearioxy-olean-12-ene, a triterpene isolated from the roots of A. brachypoda, demonstrate anti-inflammatory effect in different tests. Thus, it may be useful in the treatment of inflammatory disorders, which supports previous claims of its traditional use.

5.
Rev. bras. farmacogn ; 22(1): 162-168, Jan.-Feb. 2012. graf
Artigo em Inglês | LILACS | ID: lil-607612

RESUMO

Pyrostegia venusta (Ker Gawl.) Miers, Bignoniaceae, is native to the Brazilian Cerrado and popularly known as "cipó-de-são-joão". In Brazilian folk medicine, the flowers of P. venusta are used as a general tonic and a treatment for diarrhea, vitiligo, cough, and common infections and inflammatory diseases of the respiratory system. Nevertheless, there are still no studies on its possible anti-inflammatory and antinociceptive effects. The P. venusta hydroethanolic extract (PvHE) was used to evaluate the anti-inflammatory and analgesic effects in carrageenan-induced paw edema, peritonitis induced by lipopolysaccharide, acetic acid-induced writhing, and formalin-induced paw-licking tests in Swiss male mice. PvHE at doses of 30-300 mg/kg p.o. demonstrated anti-inflammatory effect. PvHE reduced paw edema induced by carrageenan and inhibited leukocyte recruitment into the peritoneal cavity. The extracts showed antinociceptive activity in acetic acid-induced writhing and formalin tests. Our results showed that the PvHE demonstrated anti-inflammatory and antinociceptive action in mice. All the anti-inflammatory actions obtained are also suggested to due the presence of acacetin-7-O-β-glucopyranoside.

6.
J Ethnopharmacol ; 137(3): 1469-76, 2011 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-21878381

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Byrsonima intermedia A. Juss. is popularly known as "murici pequeno" and is native to the Brazilian Cerrado. This species has been used as an antimicrobial, anti-hemorrhagic, anti-diarrheal and anti-inflammatory. Nevertheless, scientific information regarding Byrsonima intermedia is limited; there are no reports related to its possible anti inflammatory and antinociceptive effects. This study employed in vivo inflammatory and nociceptive models to evaluate the scientific basis for the traditional use of Byrsonima intermedia. MATERIALS AND METHODS: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation tests were used to investigate the anti-inflammatory activity of Byrsonima intermedia aqueous extract (BiAE) in rats. Mechanical nociceptive paw, formalin and hot plate tests were used to evaluate the antinociceptive activity in mice. High-performance liquid chromatography (HPLC), phytochemistry screening and determination of total phenolics and flavonoids were used to determine the chemical profile of the BiAE. RESULTS: BiAE at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced carrageenan-induced paw edema, by inhibited leukocyte recruitment into the peritoneal cavity and, in the model of chronic inflammation, by using the cotton pellet-induced fibrovascular tissue growth in rats. The extracts at test doses of 30-300 mg/kg p.o. clearly demonstrated antinociceptive activity in all tests. Administration of the opioid receptor antagonist naloxone completely inhibited the antinociceptive effect induced by BiAE (100 mg/kg). CONCLUSION: BiAE markedly exhibits anti-inflammatory action in rats and antinociceptive activity in mice. Thus, it may be useful in the treatment of inflammatory hyperalgesic disorders, which supports previous claims of its traditional use.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Edema/prevenção & controle , Granuloma de Corpo Estranho/prevenção & controle , Malpighiaceae , Dor/prevenção & controle , Peritonite/prevenção & controle , Extratos Vegetais/farmacologia , Analgésicos/química , Analgésicos/isolamento & purificação , Analgésicos/toxicidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/toxicidade , Comportamento Animal/efeitos dos fármacos , Carragenina , Cromatografia Líquida de Alta Pressão , Fibra de Algodão , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Flavonoides/análise , Formaldeído , Granuloma de Corpo Estranho/etiologia , Temperatura Alta , Lipopolissacarídeos , Masculino , Malpighiaceae/química , Camundongos , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/etiologia , Dor/fisiopatologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Peritonite/induzido quimicamente , Fenóis/análise , Casca de Planta , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Caules de Planta , Plantas Medicinais , Ratos , Ratos Wistar , Fatores de Tempo
7.
J Ethnopharmacol ; 133(2): 396-401, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-20950679

RESUMO

AIM OF THE STUDY: Arrabidaea brachypoda (DC.) Bureau has been used to relieve general pain, painful joints and kidney stones in Brazilian folk medicine. Nevertheless, scientific information regarding this species is scarce; there are no reports related to its possible analgesic and anti-inflammatory effects. This study was aimed at evaluating the traditional use of Arrabidaea brachypoda root using in vivo inflammatory and nociceptive models. MATERIALS AND METHODS: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti-inflammatory activity of Arrabidaea brachypoda roots ethanolic extract (AbEE) in rats. Formalin and acetic acid-induced writhing tests were used to investigate the antinociceptive activity in mice. High-performance liquid chromatography (HPLC) was used to determine the fingerprint chromatogram of AbEE. RESULTS: The AbEE at test doses of 30-300 mg/kg p.o. demonstrated anti-inflammatory effects. AbEE reduced paw edema induced by carrageenan, inhibited leukocyte recruitment into the peritoneal cavity and, in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, significantly inhibited the formation of granulomatous tissue. The extracts at test doses of 30-300 mg/kg p.o. clearly demonstrated antinociceptive activity, except during the first phase of the formalin test. The presence of quercetin and phenolic compounds in the extract Arrabidaea brachypoda was confirmed using HPLC. CONCLUSION: Arrabidaea brachypoda ethanol extract markedly demonstrated anti-inflammatory action in rats and antinociceptive activity in mice, which supports the previous claims of traditional use.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Bignoniaceae/química , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios não Esteroides/isolamento & purificação , Brasil , Edema/tratamento farmacológico , Etnofarmacologia , Granuloma de Corpo Estranho/tratamento farmacológico , Masculino , Medicina Tradicional , Camundongos , Medição da Dor , Peritonite/tratamento farmacológico , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Raízes de Plantas/química , Plantas Medicinais/química , Ratos , Ratos Wistar
8.
J Ethnopharmacol ; 133(2): 467-73, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-20955772

RESUMO

AIM OF THE STUDY: In Brazilian folk medicine, the leaves of Garcinia brasiliensis are used to treat tumors, inflammation of the urinary tract and arthritis as well as to relieve pain. Nevertheless, scientific information regarding Garcinia brasiliensis is limited; there are no reports related to its possible anti-inflammatory and antinociceptive effects. This study employed in vivo inflammatory and nociceptive models to evaluate the scientific basis for the traditional use of Garcinia brasiliensis. MATERIALS AND METHODS: Carrageenan-induced paw edema, peritonitis and fibrovascular tissue growth induced by s.c. cotton pellet implantation were used to investigate the anti-inflammatory activity of Garcinia brasiliensis ethanolic extract (GbEE) in rats. Formalin and acetic acid-induced writhing tests were used to investigate the antinociceptive activity in mice. RESULTS: GbEE at test doses of 30-300 mg/kg p.o. clearly demonstrated anti-inflammatory effects by reduced paw edema induced by carrageenan, inhibited leukocyte recruitment into the peritoneal cavity, and in the model of chronic inflammation using the cotton pellet-induced fibrovascular tissue growth in rats, the GbEE significantly inhibited the formation of granulomatous tissue. The extracts at test doses of 30-300 mg/kg, p.o., clearly demonstrated antinociceptive activity, except for the first phase of the formalin test. CONCLUSION: GbEE markedly demonstrated anti-inflammatory action in rats and antinociceptive activity in mice, which supports previous claims of the traditional use of species of the Garcinia genus for inflammation and pain.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Garcinia , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Brasil , Edema/tratamento farmacológico , Etnofarmacologia , Feminino , Garcinia/química , Garcinia/toxicidade , Masculino , Medicina Tradicional , Camundongos , Dor/tratamento farmacológico , Fitoterapia , Folhas de Planta/química , Plantas Medicinais/química , Plantas Medicinais/toxicidade , Ratos , Ratos Wistar
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