RESUMO

Cleaning and shaping the root canal system are essential steps for performing successful endodontic therapy, and are challenging procedures in the apical region. This study aimed to conduct an ex vivo assessment of the debridement ability of the WaveOne Gold (Medium 35/.06) and TruNatomy (Medium 36/.03) systems in the apical third of round root canals of mandibular premolars. Forty-eight teeth, extracted for orthodontic or periodontal reasons, were divided into three groups (n=16), as follows: Group C, control (without instrumentation or irrigation); Group WOG, instrumentation with WaveOne Gold; Group TN, instrumentation with TruNatomy. A total of 40 mL of 2.5% sodium hypochlorite and 5 mL of 17% ethylenediamine tetraacetic acid were used per root canal in all the groups. Ten 0.5-µm serial cross-sections per specimen were obtained every 0.2 mm from a 2-mm segment of the apical region, extending from 1 to 3 mm short of the root apex. The sections were stained with hematoxylin-eosin and analyzed under a digital microscope (100x). The percentages of unprepared walls and remaining debris were quantified using ImageJ software. Generalized linear models were used to analyze the results (α=5%). Groups WOG and TN had significantly lower percentages of unprepared walls and remaining debris than Group C (p<0.05). There was no significant difference between groups WOG and TN for either of the variables studied (p>0.05). Instrumentation with the WaveOne Gold Medium and TruNatomy Medium instruments was associated with equivalent percentages of unprepared walls and remaining debris in the apical third of round canals of mandibular premolars.

Assuntos

Cavidade Pulpar , Preparo de Canal Radicular , Humanos , Preparo de Canal Radicular/instrumentação , Preparo de Canal Radicular/métodos , Dente Pré-Molar , Hipoclorito de Sódio/uso terapêutico , Ápice Dentário , Desbridamento/métodos , Irrigantes do Canal Radicular , Técnicas In Vitro

RESUMO

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.

Assuntos

Ketamina , Monoaminoxidase , Estresse Oxidativo , Resveratrol , Animais , Resveratrol/farmacologia , Resveratrol/administração & dosagem , Ketamina/farmacologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Monoaminoxidase/metabolismo , Monoaminoxidase/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Interleucina-6/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Interação Social/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos

RESUMO

Burns are a global health problem and can be caused by several factors, including ultraviolet (UV) radiation. Exposure to UVB radiation can cause sunburn and a consequent inflammatory response characterised by pain, oedema, inflammatory cell infiltration, and erythema. Pharmacological treatments available to treat burns and the pain caused by them include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antimicrobials and glucocorticoids, which are associated with adverse effects. Therefore, the search for new therapeutic alternatives is needed. Diosmetin, an aglycone of the flavonoid diosmin, has antinociceptive, antioxidant and anti-inflammatory properties. Thus, we evaluated the antinociceptive and anti-inflammatory effects of topical diosmetin (0.01, 0.1 and 1%) in a UVB radiation-induced sunburn model in mice. The right hind paw of the anaesthetised mice was exposed only once to UVB radiation (0.75 J/cm2) and immediately treated with diosmetin once a day for 5 days. The diosmetin antinociceptive effect was evaluated by mechanical allodynia and pain affective-motivational behaviour, while its anti-inflammatory activity was assessed by measuring paw oedema and polymorphonuclear cell infiltration. Mice exposed to UVB radiation presented mechanical allodynia, increased pain affective-motivational behaviour, paw oedema and polymorphonuclear cell infiltration into the paw tissue. Topical Pemulen® TR2 1% diosmetin reduced the mechanical allodynia, the pain affective-motivational behaviour, the paw oedema and the number of polymorphonuclear cells in the mice's paw tissue similar to that presented by Pemulen® TR2 0.1% dexamethasone. These findings indicate that diosmetin has therapeutic potential and may be a promising strategy for treating patients experiencing inflammatory pain, especially those associated with sunburn.

Assuntos

Anti-Inflamatórios , Modelos Animais de Doenças , Flavonoides , Inflamação , Nociceptividade , Queimadura Solar , Raios Ultravioleta , Animais , Queimadura Solar/tratamento farmacológico , Queimadura Solar/patologia , Camundongos , Raios Ultravioleta/efeitos adversos , Inflamação/tratamento farmacológico , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Flavonoides/farmacologia , Flavonoides/administração & dosagem , Nociceptividade/efeitos dos fármacos , Administração Tópica , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Edema/tratamento farmacológico , Hiperalgesia/tratamento farmacológico

RESUMO

BACKGROUND AND PURPOSE: Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain and co-morbid symptoms such as anxiety and depression. An imbalance of oxidants and antioxidants is proposed to play a pivotal role in the pathogenesis of fibromyalgia symptoms. However, the precise mechanisms by which oxidative stress contributes to fibromyalgia-induced pain remain unclear. The transient receptor potential ankyrin 1 (TRPA1) channel, known as both a pain sensor and an oxidative stress sensor, has been implicated in various painful conditions. EXPERIMENTAL APPROACH: The feed-forward mechanism that implicates reactive oxygen species (ROS) driven by TRPA1 was investigated in a reserpine-induced fibromyalgia model in C57BL/6J mice employing pharmacological interventions and genetic approaches. KEY RESULTS: Reserpine-treated mice developed pain-like behaviours (mechanical/cold hypersensitivity) and early anxiety-depressive-like disorders, accompanied by increased levels of oxidative stress markers in the sciatic nerve tissues. These effects were not observed upon pharmacological blockade or global genetic deletion of the TRPA1 channel and macrophage depletion. Furthermore, we demonstrated that selective silencing of TRPA1 in Schwann cells reduced reserpine-induced neuroinflammation (NADPH oxidase 1-dependent ROS generation and macrophage increase in the sciatic nerve) and attenuated fibromyalgia-like behaviours. CONCLUSION AND IMPLICATIONS: Activated Schwann cells expressing TRPA1 promote an intracellular pathway culminating in the release of ROS and recruitment of macrophages in the mouse sciatic nerve. These cellular and molecular events sustain mechanical and cold hypersensitivity in the reserpine-evoked fibromyalgia model. Targeting TRPA1 channels on Schwann cells could offer a novel therapeutic approach for managing fibromyalgia-related behaviours.

Assuntos

Fibromialgia , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Espécies Reativas de Oxigênio , Reserpina , Células de Schwann , Canal de Cátion TRPA1 , Animais , Reserpina/farmacologia , Fibromialgia/induzido quimicamente , Fibromialgia/metabolismo , Canal de Cátion TRPA1/metabolismo , Canal de Cátion TRPA1/antagonistas & inibidores , Canal de Cátion TRPA1/genética , Estresse Oxidativo/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/efeitos dos fármacos , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Dor/metabolismo , Dor/induzido quimicamente , Nervo Isquiático/metabolismo , Modelos Animais de Doenças , Camundongos Knockout , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genética

RESUMO

Fibromyalgia is a potentially disabling idiopathic disease characterized by widespread chronic pain associated with comorbidities such as fatigue, anxiety, and depression. Current therapeutic approaches present adverse effects that limit adherence to therapy. Diosmetin, an aglycone of the flavonoid glycoside diosmin found in citrus fruits and the leaves of Olea europaea L., has antinociceptive, anti-inflammatory, and antioxidant properties. Here, we investigated the effect of diosmetin on nociceptive behaviors and comorbidities in an experimental fibromyalgia model induced by reserpine in mice. To induce the experimental fibromyalgia model, a protocol of subcutaneous injections of reserpine (1 mg/kg) was used once a day for three consecutive days in adult male Swiss mice. Mice received oral diosmetin on the fourth day after the first reserpine injection. Nociceptive (mechanical allodynia, muscle strength, and thermal hyperalgesia) and comorbid (depressive-like and anxiety behavior) parameters were evaluated. Potential adverse effects associated with diosmetin plus reserpine (locomotor alteration, cataleptic behavior, and body weight and temperature changes) were also evaluated. Oral diosmetin (0.015-1.5 mg/kg) reduced the mechanical allodynia, thermal hyperalgesia, and loss of muscle strength induced by reserpine. Diosmetin (0.15 mg/kg) also attenuated depressive-like and anxiety behaviors without causing locomotor alteration, cataleptic behavior, and alteration in weight and body temperature of mice. Overall, diosmetin can be an effective and safe therapeutic alternative to treat fibromyalgia symptoms, such as pain, depression and anxiety.

Assuntos

Modelos Animais de Doenças , Fibromialgia , Flavonoides , Hiperalgesia , Reserpina , Animais , Reserpina/farmacologia , Fibromialgia/tratamento farmacológico , Fibromialgia/induzido quimicamente , Camundongos , Masculino , Flavonoides/farmacologia , Hiperalgesia/tratamento farmacológico , Analgésicos/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Comportamento Animal/efeitos dos fármacos

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system (CNS) generating neuropathic pain and anxiety. Primary progressive MS (PPMS) is the most disabling clinical form, and the patients present an intense neurodegenerative process. In this context, the advanced oxidation protein products (AOPPs) are oxidized compounds and their accumulation in plasma has been related to clinical disability in MS patients. However, the involvement of AOPPs in neuropathic pain- and anxiety-like symptoms was not previously evaluated. To assess this, female mice C57BL/6J were used to induce progressive experimental autoimmune encephalomyelitis (PMS-EAE). Clinical score, weight, strength of plantar pressure, rotarod test, mechanical allodynia, and cold hypersensitivity were evaluated before induction (baseline) and on days 7th, 10th, and 14th post-immunization. We assessed nest building, open field, and elevated plus-maze tests 13 days post-immunization. Animals were killed at 14 days post-immunization; then, AOPPs levels, NADPH oxidase, and myeloperoxidase (MPO) activity were measured in the prefrontal cortex, hippocampus, and spinal cord samples. The clinical score increased 14th post-immunization without changes in weight and mobility. Reduced paw strength, mechanical allodynia, and cold allodynia increased in the PMS-EAE animals. PMS-EAE mice showed spontaneous nociception and anxiety-like behavior. AOPPs concentration, NADPH oxidase, and MPO activity increase in CNS structures. Multivariate analyses indicated that the rise of AOPPs levels, NADPH oxidase, and MPO activity influenced the clinical score and cold allodynia. Thus, we indicated the association between non-stimuli painful perception, anxiety-like, and CNS oxidative damage in the PMS-EAE model.

Assuntos

Produtos da Oxidação Avançada de Proteínas , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Animais , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/psicologia , Feminino , Camundongos , Produtos da Oxidação Avançada de Proteínas/metabolismo , Nociceptividade/fisiologia , Hiperalgesia/metabolismo , Medula Espinal/metabolismo , Ansiedade/etiologia , Ansiedade/psicologia

RESUMO

Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain.

RESUMO

Dexamethasone has a high anti-inflammatory efficacy in treating skin inflammation. However, its use is related to the rebound effect, rosacea, purple, and increased blood glucose levels. Nanotechnology approaches have emerged as strategies for drug delivery due to their advantages in improving therapeutic effects. To reduce dexamethasone-related adverse effects and improve the anti-inflammatory efficacy of treatments, we developed nanocarriers containing this corticosteroid and oleic acid. Nanocapsules and nanoemulsion presented dexamethasone content close to the theoretical value and controlled dexamethasone release in an in vitro assay. Gellan gum-based hydrogels were successfully prepared to employ the nanostructured systems. A permeation study employing porcine skin showed that hydrogels containing non-nanoencapsulated dexamethasone (0.025%) plus oleic acid (3%) or oleic acid (3%) plus dexamethasone (0.025%)-loaded nanocapsules provided a higher amount of dexamethasone in the epidermis compared to non-nanoencapsulated dexamethasone (0.5%). Hydrogels containing oleic acid plus dexamethasone-loaded nanocapsules effectively inhibited mice ear edema (with inhibitions of 89.26 ± 3.77% and 85.11 ± 2.88%, respectively) and inflammatory cell infiltration (with inhibitions of 49.58 ± 4.29% and 27.60 ± 11.70%, respectively). Importantly, the dexamethasone dose employed in hydrogels containing the nanocapsules that effectively inhibited ear edema and cell infiltration was 20-fold lower (0.025%) than that of non-nanoencapsulated dexamethasone (0.5%). Additionally, no adverse effects were observed in preliminary toxicity tests. Our study suggests that nanostructured hydrogel containing a reduced effective dose of dexamethasone could be a promising therapeutic alternative to treat inflammatory disorders with reduced or absent adverse effects. Additionally, testing our formulation in a clinical study on patients with skin inflammatory diseases would be very important to validate our study.

RESUMO

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.

Assuntos

Fibromialgia , Mastocitose , Camundongos , Masculino , Animais , Fibromialgia/metabolismo , Mastócitos/metabolismo , Hiperalgesia/metabolismo , Serotonina/metabolismo , Reserpina/efeitos adversos , Mastocitose/metabolismo , Mastocitose/patologia

RESUMO

Anastrozole, an aromatase inhibitor, induces painful musculoskeletal symptoms, which affect patients' quality of life and lead to therapy discontinuation. Efforts have been made to understand the mechanisms involved in these painful symptoms to manage them better. In this context, we explored the role of the Transient Receptor Potential Vanilloid 4 (TRPV4), a potential transducer of several nociceptive mechanisms, in anastrozole-induced musculoskeletal pain in mice. Besides, we evaluated the possible sensibilization of TRPV4 by signalling pathways downstream, PLC, PKC and PKCε from kinin B2 (B2R) and B1 (B1R) receptors activation in anastrozole-induced pain. Anastrozole caused mechanical allodynia and muscle strength loss in mice. HC067047, TRPV4 antagonist, reduced the anastrozole-induced mechanical allodynia and muscle strength loss. In animals previously treated with anastrozole, the local administration of sub-nociceptive doses of the TRPV4 (4α-PDD or hypotonic solution), B2R (Bradykinin) or B1R (DABk) agonists enhanced the anastrozole-induced pain behaviours. The sensitizing effects induced by local injection of the TRPV4, B2R and B1R agonists in animals previously treated with anastrozole were reduced by pre-treatment with TRPV4 antagonist. Furthermore, inhibition of PLC, PKC or PKCε attenuated the mechanical allodynia and muscle strength loss induced by TRPV4, B2R and B1R agonists. The generation of painful conditions caused by anastrozole depends on direct TRPV4 activation or indirect, e.g., PLC, PKC and PKCε pathways downstream from B2R and B1R activation. Thus, the TRPV4 channels act as sensors of extracellular and intracellular changes, making them potential therapeutic targets for alleviating pain related to aromatase inhibitors use, such as anastrozole.

Assuntos

Antineoplásicos , Canais de Cátion TRPV , Humanos , Camundongos , Animais , Anastrozol , Hiperalgesia/induzido quimicamente , Qualidade de Vida , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Dor/tratamento farmacológico , Bradicinina/farmacologia

RESUMO

Abstract Cleaning and shaping the root canal system are essential steps for performing successful endodontic therapy, and are challenging procedures in the apical region. This study aimed to conduct an ex vivo assessment of the debridement ability of the WaveOne Gold (Medium 35/.06) and TruNatomy (Medium 36/.03) systems in the apical third of round root canals of mandibular premolars. Forty-eight teeth, extracted for orthodontic or periodontal reasons, were divided into three groups (n=16), as follows: Group C, control (without instrumentation or irrigation); Group WOG, instrumentation with WaveOne Gold; Group TN, instrumentation with TruNatomy. A total of 40 mL of 2.5% sodium hypochlorite and 5 mL of 17% ethylenediamine tetraacetic acid were used per root canal in all the groups. Ten 0.5-μm serial cross-sections per specimen were obtained every 0.2 mm from a 2-mm segment of the apical region, extending from 1 to 3 mm short of the root apex. The sections were stained with hematoxylin-eosin and analyzed under a digital microscope (100x). The percentages of unprepared walls and remaining debris were quantified using ImageJ software. Generalized linear models were used to analyze the results (α=5%). Groups WOG and TN had significantly lower percentages of unprepared walls and remaining debris than Group C (p<0.05). There was no significant difference between groups WOG and TN for either of the variables studied (p>0.05). Instrumentation with the WaveOne Gold Medium and TruNatomy Medium instruments was associated with equivalent percentages of unprepared walls and remaining debris in the apical third of round canals of mandibular premolars.

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Resumo A limpeza e modelagem do sistema de canais radiculares são etapas fundamentais para o sucesso da terapia endodôntica e são procedimentos desafiadores na região apical. O objetivo deste trabalho foi realizar uma avaliação ex vivo da capacidade de debridamento dos sistemas WaveOne Gold (Medium 35/.06) e TruNatomy (Medium 36/.03) no terço apical de canais radiculares circulares de pré-molares inferiores. Quarenta e oito dentes que haviam sido extraídos por razões ortodônticas ou periodontais foram divididos em três grupos (n=16),da seguinte forma: Grupo C, Controle (sem instrumentação nem irrigação); Grupo WOG, instrumentação com WaveOne Gold; Grupo TN, instrumentação com TruNatomy. Um total de 40 mL de hipoclorito de sódio a 2,5% e 5 mL de ácido etilenodiamino tetraacético a 17% foi utilizado por canal radicular em todos os grupos. Dez secções transversais em série de 0,5 μm por espécime foram obtidas a cada 0,2 mm de um segmento de 2 mm da região apical, estendendo-se desde 1 até 3 mm aquém do ápice radicular. As seções foram coradas com hematoxilina-eosina e analisadas sob um microscópio digital (100x). As porcentagens de paredes não tocadas e detritos remanescentes foram quantificadas utilizando-se o software ImageJ. Modelos lineares generalizados foram utilizados para analisar os resultados (α=5%). Os grupos WOG e TN apresentaram porcentagens significativamente menores de paredes intocadas e detritos remanescentes do que o grupo C (p<0,05). Não houve diferença significativa entre os grupos WOG e TN quanto a nenhuma das variáveis estudadas (p>0,05). A instrumentação com os instrumentos WaveOne Gold Medium e TruNatomy Medium foi associada a porcentagens equivalentes de paredes intocadas e detritos remanescentes no terço apical de canais circulares de pré-molares inferiores.

RESUMO

The current study describes a new species of nematode, Orientatractis matosi n. sp. (Atractidae), from the stomach and large intestine of Podocnemis unifilis Troschel, 1848 (Testudinidae), collected in the Tocantins and Xingu rivers in the Brazilian state of Pará. The new species was described using light and scanning electron microscopy and differs from its congeners mainly in the number and distribution of the male caudal papillae and by having a shorter right spicule. Orientatracits matosi n. sp. is the eleventh species of the genus Orientatractis Petter, 1966, the third reported from the Amazon, and the second described from P. unifilis.

RESUMO

Musculoskeletal pain is a widely experienced public healthcare issue, especially after traumatic muscle injury. Besides, it is a common cause of disability, but this pain remains poorly managed. However, the pathophysiology of traumatic muscle injury-associated pain and inflammation has not been fully elucidated. In this regard, the transient receptor potential ankyrin 1 (TRPA1) has been studied in inflammatory and painful conditions. Thus, this study aimed to evaluate the antinociceptive and anti-inflammatory effect of the topical application of a TRPA1 antagonist in a model of traumatic muscle injury in rats. The mechanical trauma model was developed by a single blunt trauma impact on the right gastrocnemius muscle of Wistar male rats (250-350 g). The animals were divided into four groups (Sham/Vehicle; Sham/HC-030031 0.05%; Injury/Vehicle, and Injury/HC-030031 0.05%) and topically treated with a Lanette® N cream base containing a TRPA1 antagonist (HC-030031, 0.05%; 200 mg/muscle) or vehicle (Lanette® N cream base; 200 mg/muscle), which was applied at 2, 6, 12, 24, and 46 h after muscle injury. Furthermore, we evaluated the contribution of the TRPA1 channel on nociceptive, inflammatory, and oxidative parameters. The topical application of TRPA1 antagonist reduced biomarkers of muscle injury (lactate/glucose ratio), spontaneous nociception (rat grimace scale), inflammatory (inflammatory cell infiltration, cytokine levels, myeloperoxidase, and N-acetyl-ß-D-glucosaminidase activities) and oxidative (nitrite levels and dichlorofluorescein fluorescence) parameters, and mRNA Trpa1 levels in the muscle tissue. Thus, these results demonstrate that TRPA1 may be a promising anti-inflammatory and antinociceptive target in treating muscle pain after traumatic muscle injury.

Assuntos

Inflamação , Nociceptividade , Ratos , Masculino , Animais , Ratos Wistar , Canal de Cátion TRPA1 , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Analgésicos/farmacologia , Músculos

RESUMO

Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B2 and B1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin.

RESUMO

Postoperative pain causes discomfort and disability, besides high medical costs. The search for better treatments for this pain is essential to improve recovery and reduce morbidity and risk of chronic postoperative pain. Kinins and their receptors contribute to different painful conditions and are among the main painful inflammatory mediators. We investigated the kinin's role in a postoperative pain model in mice and reviewed data associating kinins with this painful condition. The postoperative pain model was induced by an incision in the mice's paw's skin and fascia with the underlying muscle's elevation. Kinin levels were evaluated by enzyme immunoassays in sham or operated animals. Kinin's role in surgical procedure-associated mechanical allodynia was investigated using systemic or local administration of antagonists of the kinin B1 receptor (DALBk or SSR240612) or B2 receptor (Icatibant or FR173657) and a kallikrein inhibitor (aprotinin). Kinin levels increased in mice's serum and plantar tissue after the surgical procedure. All kinin B1 or B2 receptor antagonists and aprotinin reduced incision-induced mechanical allodynia. Although controversial, kinins contribute mainly to the initial phase of postoperative pain. The kallikrein-kinin system can be targeted to relieve this pain, but more investigations are necessary, especially associations with other pharmacologic targets.

RESUMO

Aromatase inhibitors (AIs) cause symptoms of musculoskeletal pain, and some mechanisms have been proposed to explain them. However, signaling pathways downstream from kinin B2 (B2R) and B1 (B1R) receptor activation and their possible sensitizing of the Transient Receptor Potential Ankyrin 1 (TRPA1) remain unknown. The interaction between the kinin receptor and the TRPA1 channel in male C57BL/6 mice treated with anastrozole (an AI) was evaluated. PLC/PKC and PKA inhibitors were used to evaluate the signaling pathways downstream from B2R and B1R activation and their effect on TRPA1 sensitization. Anastrozole caused mechanical allodynia and muscle strength loss in mice. B2R (Bradykinin), B1R (DABk), or TRPA1 (AITC) agonists induced overt nociceptive behavior and enhanced and prolonged the painful parameters in anastrozole-treated mice. All painful symptoms were reduced by B2R (Icatibant), B1R (DALBk), or TRPA1 (A967079) antagonists. We observed the interaction between B2R, B1R, and the TRPA1 channel in anastrozole-induced musculoskeletal pain, which was dependent on the activation of the PLC/PKC and PKA signaling pathways. TRPA1 seems to be sensitized by mechanisms dependent on the activation of PLC/PKC, and PKA due to kinin receptors stimulation in anastrozole-treated animals. Thus, regulating this signaling pathway could contribute to alleviating AIs-related pain symptoms, patients' adherence to therapy, and disease control.

RESUMO

Cisplatin is the preferential chemotherapeutic drug for highly prevalent solid tumours. However, its clinical efficacy is frequently limited due to neurotoxic effects such as peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-dependent adverse condition that negatively impacts quality of life, and it may determine dosage limitations or even cancer treatment cessation. Thus, it is urgently necessary to identify pathophysiological mechanisms underlying these painful symptoms. As kinins and their B1 and B2 receptors contribute to the development of chronic painful conditions, including those induced by chemotherapy, the contribution of these receptors to cisplatin-induced peripheral neuropathy was evaluated via pharmacological antagonism and genetic manipulation in male Swiss mice. Cisplatin causes painful symptoms and impaired working and spatial memory. Kinin B1 (DALBK) and B2 (Icatibant) receptor antagonists attenuated some painful parameters. Local administration of kinin B1 and B2 receptor agonists (in sub-nociceptive doses) intensified the cisplatin-induced mechanical nociception attenuated by DALBK and Icatibant, respectively. In addition, antisense oligonucleotides to kinin B1 and B2 receptors reduced cisplatin-induced mechanical allodynia. Thus, kinin B1 and B2 receptors appear to be potential targets for the treatment of cisplatin-induced painful symptoms and may improve patients' adherence to treatment and their quality of life.

RESUMO

Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B1 and B2 receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B1 and B2 receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors' role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B1 (DALBk) and B2 (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B1 or B2 receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.

Assuntos

Antineoplásicos , Dor do Câncer , Neoplasias , Camundongos , Animais , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Receptor B2 da Bradicinina/metabolismo , Receptor B1 da Bradicinina/metabolismo , Bradicinina/farmacologia , Dor , Paclitaxel

RESUMO

Fibromyalgia (FM) is a complex disease with an uncertain aetiology and intricate pathophysiology. Although its genesis is not fully explained, potential environmental factors, such as viral infections might trigger FM or worsen patients' clinical outcomes. The SARS-CoV-2 virus may affect central and peripheral nervous systems, leading to musculoskeletal, neurological, and psychological disturbances. These symptoms might persist at least 12 months beyond the recovery, often referred to as post-COVID syndrome, which resembles FM syndrome. In this sense, we argued the potential consequences of COVID-19 exclusively on FM syndrome. First, we have described post-COVID syndrome and its painful symptoms. Afterwards, we argued whether FM syndrome could be triggered or enhanced by COVID-19 infection or by numerous and persistent stressors imposed daily by the pandemic setting (isolation, uncertainty, depression, mental stress, generalized anxiety, and fear of the virus). In addition, we have demonstrated similarities between pathophysiological mechanisms and cardinal symptoms of FM and COVID-19, speculating that SARS-CoV-2 might represent a critical mediator of FM or an exacerbator of its symptoms once both syndromes share similar mechanisms and complaints. Therefore, pharmacologic and non-pharmacological approaches commonly used to treat FM could serve as strategic therapies to attenuate painful and neurological manifestations of post-COVID syndrome. Although it is still theoretical, clinicians and researchers should be alert of patients who develop symptoms similar to FM or those who had their FM symptoms increased post-COVID to manage them better.

Assuntos

COVID-19 , Fibromialgia , Humanos , COVID-19/complicações , SARS-CoV-2 , Dor , Síndrome