RESUMO
Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.
Assuntos
Ácidos Graxos Insaturados/farmacologia , Dor/tratamento farmacológico , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Biópsia , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/toxicidade , Células Cultivadas , Modelos Animais de Doenças , Ácidos Graxos Insaturados/uso terapêutico , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/imunologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Dor/induzido quimicamente , Dor/imunologia , Dor/patologia , Técnicas de Patch-Clamp , Cultura Primária de Células , Prurido/induzido quimicamente , Prurido/imunologia , Prurido/patologia , Psoríase/complicações , Psoríase/imunologia , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/inervação , Canais de Cátion TRPV/metabolismoRESUMO
Opioids are the "gold standard" treatment for postoperative pain, but these drugs also have limiting adverse effects. Thus, adjuvant drugs might be useful in opioid therapy for postoperative pain. The aim of the present study was to evaluate the effect of Phα1ß, a dual blocker of Cav2 and TRPA1 channels, on antinociceptive and adverse actions of morphine in a model of postoperative pain. Phα1ß (100-300 pmol/site) or morphine (3-10 mg/kg), alone, largely reduced postoperative nociception. However, Phα1ß (100 pmol/site) or morphine (10 mg/kg) also produced motor impairment. Lower doses of Phα1ß (30 pmol/site) or morphine (1 mg/kg), that did not have an effect alone, showed antinociceptive effect when concomitantly administrated. Moreover, co-administration of Phα1ß (30 pmol/site) with morphine (1 or 10 mg/kg) was unable to cause motor impairment. Preoperative repeated treatment with morphine increased the expression of Cav2 and TRPA1 channels in spinal cord, and caused tolerance and withdrawal syndrome, which were reversed with a single injection of Phα1ß (30 pmol/site). When injected postoperatively, escalating doses of morphine worsened postoperative hyperalgesia, induced tolerance, and withdrawal syndrome. Similarly, Phα1ß (30 pmol/site) reversed these adverse effects. Single or repeated morphine caused constipation, which was not altered by Phα1ß. Thus, a low dose of Phα1ß potentiated the analgesia, and reversed some adverse effects of morphine on operated mice, indicating the potential use of this agent as an adjuvant drug in opioid therapy for postoperative pain.
Assuntos
Analgésicos Opioides/uso terapêutico , Quimioterapia Adjuvante/métodos , Dor Pós-Operatória/tratamento farmacológico , Venenos de Aranha/uso terapêutico , Analgésicos , Animais , Canais de Cálcio Tipo N/metabolismo , Hiperalgesia/induzido quimicamente , Camundongos , Morfina , Venenos de Aranha/farmacologia , Canal de Cátion TRPA1/metabolismoRESUMO
PURPOSE: Search for alternate pain medications has gained more importance in the past few years due to adverse effects associated with currently prescribed drugs including nervous system dysfunction with opioids, gastrointestinal discomfort with nonsteroidal anti-inflammatory drugs, and cardiovascular anomalies with cyclooxygenase-2 (COX-2) inhibitors. Phytomedicine has been explored for the treatment of pain, as these have been used for generations in regional communities and tend to lack major side effects in general. One such phytomedicine, incarvillateine (INCA), derived from the Chinese herb Incarvillea sinensis has its primary antinociceptive action through the adenosine receptor, a novel pain target. We hypothesized that derivatives of cinnamic acid dimers, which are structurally similar to INCA, would show potent antinociceptive action and that their effect would be mediated through adenosine receptor action. MATERIALS AND METHODS: Dimers of cinnamic acid (INCA analogs) were synthesized using cavitand-mediated photodimerization (CMP) method, which utilizes a macromolecule (γ-cyclodextrin) to control excited state reactivity of photoactive compounds. Acute pain response was assessed by using formalin-induced licking behavior in hind paw of mice, and neurologic function was monitored through locomotor activity, mechanical hyperalgesia, and thermal sensitivity upon administration of test compound. For mechanistic studies, binding to adenosine receptor was determined by using computer modeling. RESULTS: Ferulic acid dimer (FAD), which has the same chemical functionalities on the aromatic ring as INCA, showed significant suppression of formalin-induced acute pain. Antinociceptive effect was observed primarily in the inflammatory phase, and no apparent behavioral changes related to the nervous system were noticeable. Inhibition of opioid receptor did not reverse antinociceptive response, and modeling data suggest adenosine 3 receptor binding. CONCLUSION: FAD (INCA analog) shows potent nonopioid antinociceptive action mediated predominantly through A3AR - adenosine 3 receptor action. Further characterization and selection of such INCA analogs will help us generate a new class of antinociceptives with precise chemical modifications by using CMP methodology.
RESUMO
Stigmasterol is a common sterol found in plants, but the anti-nociceptive effect of this compound and its mechanism of action are not fully explored. Thus, in the present study, the anti-nociceptive effect of stigmasterol was investigated in acute and chronic models of pain and its mechanism of action. We used adult male albino Swiss mice (25-35 g) to observe the anti-nociceptive effect of stigmasterol in acetic-acid writhing test or in complete Freund's adjuvant injection, surgical incision in hind paw, or partial sciatic nerve ligation. Moreover, we investigate the involvement of opioid receptors (naloxone, 2 mg/kg, intraperitoneally) in stigmasterol anti-nociceptive effect and stigmasterol action on acetylcholinesterase activity. Some possible adverse effects caused by stigmasterol were also investigated. Stigmasterol (0.3-3 mg/kg, orally) exhibited an anti-nociceptive effect on acetic-acid-induced writhing test. Furthermore, it markedly attenuated the mechanical allodynia caused by surgical incision (after acute treatment with stigmasterol, preventive and curative effects were observed) and partial sciatic nerve ligation (after acute treatment with stigmasterol) and complete Freund's adjuvant (after acute or repeated treatment with stigmasterol). The anti-nociceptive effect of stigmasterol was not reversed by naloxone. Moreover, stigmasterol did not alter in vitro acetylcholinesterase activity in spinal cord or brain samples. Also, stigmasterol did not cause gastric ulcers or alter the gastrointestinal transit of mice. Taken together, these results support the potential anti-nociceptive effect of stigmasterol in different models of pain.
Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Estigmasterol/uso terapêutico , Ácido Acético , Acetilcolinesterase/metabolismo , Doença Aguda , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Doença Crônica , Adjuvante de Freund , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nervo Isquiático/cirurgia , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Estômago/anatomia & histologia , Estômago/efeitos dos fármacos , Estômago/fisiologiaRESUMO
Vitamin E (vit-E) is a lipophilic antioxidant, and its anti-inflammatory activity is still not full characterized. Thus, our goal was to investigate the anti-inflammatory effect of repeated vit-E treatment in the arthritis induced by the intraplantar injection of complete Freund's adjuvant (CFA). We observed an increase in arthritis scores, interleukin-1ß and H2O2 levels, neutrophil and macrophage infiltration, thermal hyperalgesia, mechanical allodynia, and loss of function induced by intraplantar CFA injection. These effects were unaltered after 1 day, partially reversed after 3 days, and inhibited after 9 days after vit-E treatment. Furthermore, the concentration of vit-E was reduced and that of tumor necrosis factor-alpha was increased in the CFA-injected paw. Both effects were reversed from 1 to 9 days after vit-E treatment. However, vit-E treatment did not alter CFA-induced edema at any time. Thus, vit-E treatment produced an anti-inflammatory effect of slow onset in CFA, which demonstrates a disease-modifying drug profile.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Vitamina E/uso terapêutico , Analgésicos/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Artrite Experimental/induzido quimicamente , Edema/tratamento farmacológico , Adjuvante de Freund , Peróxido de Hidrogênio/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-1beta/metabolismo , Macrófagos/imunologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Medição da Dor , Ratos , Ratos Wistar , Pele/metabolismo , Pele/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
UNLABELLED: Opioids are standard therapy for the treatment of pain; however, adverse effects limit their use. Voltage-gated calcium channel blockers may be used to increase opioid analgesia, but their effect on opioid-induced side effects is little known. Thus, the goal of this study was to evaluate the action of the peptide Phα1ß, a voltage-gated calcium channel blocker, on the antinociceptive and adverse effects produced by morphine in mice. A single administration of morphine (3-10 mg/kg) was able to reduce heat nociception as well as decrease gastrointestinal transit. The antinociception caused by a single injection of morphine was slightly increased by an intrathecal injection of Phα1ß (30 pmol/site). Repeated treatment with morphine caused tolerance, hyperalgesia, withdrawal syndrome, and constipation, and the Phα1ß (.1-30 pmol/site, intrathecal) was able to reverse these effects. Finally, the effects produced by the native form of Phα1ß were fully mimicked by a recombinant version of this peptide. Taken together, these data show that Phα1ß was effective in potentiating the analgesia caused by a single dose of morphine as well as in reducing tolerance and the adverse effects induced by repeated administration of morphine, indicating its potential use as an adjuvant drug in combination with opioids. PERSPECTIVE: This article presents preclinical evidence for a useful adjuvant drug in opioid treatment. Phα1ß, a peptide calcium channel blocker, could be used not only to potentiate morphine analgesia but also to reduce the adverse effects caused by repeated administration of morphine.
Assuntos
Analgésicos Opioides/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Morfina/uso terapêutico , Dor Nociceptiva/tratamento farmacológico , Peptídeos/uso terapêutico , Analgésicos Opioides/farmacologia , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Trânsito Gastrointestinal/efeitos dos fármacos , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Naloxona , Antagonistas de Entorpecentes , Medição da Dor/efeitos dos fármacos , Peptídeos/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Viola tricolor, popularly known as heartsease has been empirically used in several skin disorders, including burns. AIM OF THE STUDY: The objective of this study was investigate the antinociceptive and antiinflammatory effect of a gel containing extract of Viola tricolor flowers on thermal burn induced by UVB irradiation and to perform gel stability study. METHODS: The antinociceptive and antiinflammatory effect were evaluated by static and dynamic mechanical allodynia model, paw edema, and neutrophilic cell infiltration. Metabolites compounds were quantified by HPLC. The gel stability study was performed analyzing organoleptical aspects, besides pH, viscosity, and quantification of rutin by HPLC. RESULTS: In the results were evidenced changes in threshold in statical and dynamic mechanical allodynia (I(max)=100 ± 10% and 49 ± 10%, respectively), paw edema (I(max)=61 ± 6%), and myeloperoxidase activity (I(max)=89 ± 5%). Such effects may be attributed, in part, to rutin, salicylic and chlorogenic acids, and others compounds found in this species. No important changes were detected in the stability study, in all aspects analyzed in temperature below 25 °C. CONCLUSION: These findings suggest that Viola tricolor gel has an antinociceptive and antiinflammatory effect in the ultraviolet-B-induced burn, since maintain the temperature below 25 °C.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Extratos Vegetais/uso terapêutico , Queimadura Solar/tratamento farmacológico , Viola , Animais , Modelos Animais de Doenças , Estabilidade de Medicamentos , Edema/tratamento farmacológico , Edema/imunologia , Flores , Géis , Hiperalgesia/tratamento farmacológico , Hiperalgesia/imunologia , Masculino , Neutrófilos/imunologia , Ratos , Ratos Wistar , Queimadura Solar/imunologiaRESUMO
Pyrazole compounds are an intriguing class of compounds with potential analgesic activity; however, their mechanism of action remains unknown. Thus, the goal of this study was to explore the antinociceptive potential, safety and mechanism of action of novel 1-pyrazole methyl ester derivatives, which were designed by molecular simplification, using in vivo and in vitro methods in mice. First, tree 1-pyrazole methyl ester derivatives (DMPE, MPFE, and MPCIE) were tested in the capsaicin test and all presented antinociceptive effect; however the MPClE (methyl 5-trichloromethyl-3-methyl-1H-pyrazole-1-carboxylate) was the most effective. Thus, we selected this compound to assess the effects and mechanisms in subsequent pain models. MPCIE produced antinociception when administered by oral, intraperitoneal, intrathecal and intraplantar routes and was effective in the capsaicin and the acetic acid-induced nociception tests. Moreover, this compound reduced the hyperalgesia in diverse clinically-relevant pain models, including postoperative, inflammatory, and neuropathic nociception in mice. The antinociception produced by orally administered MPClE was mediated by κ-opioid receptors, since these effects were prevented by systemically pre-treatment with naloxone and the κ-opioid receptor antagonist nor-binaltorphimine. Moreover, MPCIE prevented binding of the κ-opioid ligand [(3)H]-CI-977 in vitro (IC50 of 0.68 (0.32-1.4) µM), but not the TRPV1 ([(3)H]-resiniferatoxin) or the α2-adrenoreceptor ([(3)H]-idazoxan) binding. Regarding the drug-induced side effects, oral administration of MPClE did not produce sedation, constipation or motor impairment at its active dose. In addition, MPCIE was readily absorbed after oral administration. Taken together, these results demonstrate that MPClE is a novel, potent, orally active and safe analgesic drug that targets κ-opioid receptors.
Assuntos
Analgésicos/farmacologia , Pirazóis/farmacologia , Receptores Opioides kappa/agonistas , Antagonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/administração & dosagem , Analgésicos/antagonistas & inibidores , Analgésicos/química , Animais , Benzofuranos , Diterpenos , Vias de Administração de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Idazoxano , Masculino , Camundongos , Estrutura Molecular , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor , Pirazóis/administração & dosagem , Pirazóis/antagonistas & inibidores , Pirazóis/química , Pirrolidinas , Ensaio Radioligante , Receptores Opioides kappa/antagonistas & inibidores , Canais de Cátion TRPV/efeitos dos fármacos , TrítioRESUMO
The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic extract produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compounds isolated from the dichloromethane fraction, only α-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, α-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. α-Spinasterol was able to displace [3H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and α-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mechanical threshold of naive mice. The treatment with α-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addition, α-spinasterol and the dichloromethane fraction reduced the edema, mechanical, and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and α-spinasterol did not affect body temperature or locomotor activity. In conclusion, α-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect.