G Protein-Coupled Receptors and Ion Channels Involvement in Cisplatin-Induced Peripheral Neuropathy: A Review of Preclinical Studies.

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.

Involvement of peripheral mast cells in a fibromyalgia model in mice.

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.

TRPV4 Activation and its Intracellular Modulation Mediated by Kinin Receptors Contribute to Painful Symptoms Induced by Anastrozole.

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.

Ocorrência de indicações farmacológicas não recomendadas por estágios na endometriose e impacto no quadro de ansiedade por persistência de sintomas / Occurrence of pharmacological indications not recommended by stages in endometriosis and impact on anxiety due to persistence of symptoms / Presencia de indicaciones farmacológicas no recomendadas por etapas en la endometriosis e impacto en la ansiedad por la persistencia de los síntomas

Introdução: Endometriose é uma patologia pélvica crônica de caráter inflamatório e estrogênio-dependente. Manifesta-se em quatro tipos de estágio (EI, EII, EIII e EIV), caracterizados pelos números de lesões. Tem indicações farmacológicas recomendadas se baseadas nos estágios, sendo EI/EII sintomático com AINES e/ou uso de anticonceptivos de uso contínuo; e EIII/EIV com fármacos análogos de GnRH. O estilo de vida dessas mulheres é impactado pela dor, que altera a rotina e vida afetivo/sexual contribuindo para quadros de ansiedade. O presente estudo se norteia pela questão "qual impacto na ansiedade de mulheres com endometriose, quando não ocorrem indicações farmacológicas recomendadas para os estágios que se encontra? Logo, o objetivo deste estudo é avaliar os efeitos do tratamento medicamentoso não recomendado e risco de ansiedade. Metodologia: Levantamento de pacientes com diagnóstico de Endometriose, cadastradas no Banco de Dados do Projeto agrupadas em estágios de tratamentos farmacológicos similares (EI/EII e EIII/EIV). O relato de ansiedade, com diagnóstico médico e pós endometriose foi a variável dependente em estudo. As variáveis independentes (ou influenciadoras) foram [1] Estágio da doença, [2] Farmacoterapia recomendada (FR) ou não (FNR) e [3] esquema medicamentoso empregado (classes e combinações). Estatística feitas por chi quadrado e Fischer. Resultados: Do total de 375 mulheres, 274 apresentavam ansiedade. Destas, 170 estavam no grupo IFR; sendo 141 no agrupamento EI/EII, e 29 mulheres no EIII/EIV. No que se refere ao grupo IFNR, teve se um n=104 mulheres, sendo apenas 1 nos EI/EII e 103 nos EIII/EIV. Os casos de FNR estão mais presentes em EIII/EIV, com 90% dos casos (IC 95%, p<0,05). O esquema terapêutico mais presente foi AINEs em monoterapia, sendo 65% (IC 95%, p<0,05) em Estágio inadequado. Notou-se uma correlação positiva entre FNR e quadros de ansiedade, principalmente quando se empregava a monoterapia com AINEs (IC 95%, p<0,05). Conclusão: Dificuldades de acesso a especialistas para diagnóstico e aos medicamentos do EIII/EIV podem ser as causas, que serão investigadas em estudos futuros.

Introduction: Endometriosis is a chronic pelvic pathology with an inflammatory and estrogen-dependent nature. It manifests itself in four types of stages (EI, EII, EIII and EIV), characterized by the number of lesions. It has recommended pharmacological indications based on the stages, being symptomatic EI/EII with NSAIDs and/or use of continuous contraceptives; and EIII/EIV with GnRH analogue drugs. The lifestyle of these women is impacted by pain, which alters their routine and emotional/sexual life, contributing to anxiety. The present study is guided by the question "what impact on the anxiety of women with endometriosis, when there are no recommended pharmacological indications for the stage they are in?" Therefore, the objective of this study is to evaluate the effects of non-recommended drug treatment and the risk of anxiety. Methodology: Survey of patients diagnosed with Endometriosis, registered in the Project Database grouped into stages of similar pharmacological treatments (EI/EII and EIII/EIV). The report of anxiety, with medical diagnosis and post-endometriosis was the dependent variable under study. The independent (or influencing) variables were [1] Stage of the disease, [2] Pharmacotherapy recommended (FR) or not (FNR) and [3] medication regimen used (classes and combinations). Statistics made by chi square and Fischer. Results: Of the total of 375 women, 274 had anxiety. Of these, 170 were in the IFR group; 141 in the EI/EII group, and 29 women in the EIII/EIV group. Regarding the IFNR group, there were n=104 women, with only 1 in EI/EII and 103 in EIII/EIV. FNR cases are more present in EIII/EIV, with 90% of cases (95% CI, p<0.05). The most common therapeutic regimen was NSAIDs as monotherapy, with 65% (95% CI, p<0.05) in an inadequate stage. A positive correlation was noted between FNR and anxiety, especially when using monotherapy with NSAIDs (95% CI, p<0.05). Conclusion: Difficulties in accessing specialists for diagnosis and EIII/EIV medications may be the causes, which will be investigated in future studies.

Introducción: La endometriosis es una patología pélvica crónica de naturaleza inflamatoria y estrógeno-dependiente. Se manifiesta en cuatro tipos de estadios (EI, EII, EIII y EIV), caracterizados por el número de lesiones. Tiene indicaciones farmacológicas recomendadas según los estadios, siendo EI/EII sintomática con AINE y/o uso de anticonceptivos continuos; y EIII/EIV con fármacos análogos de GnRH. El estilo de vida de estas mujeres se ve impactado por el dolor, lo que altera su rutina y su vida emocional/sexual, contribuyendo a la ansiedad. El presente estudio se guía por la pregunta "¿qué impacto tiene en la ansiedad de las mujeres con endometriosis, cuando no existen indicaciones farmacológicas recomendadas para las etapas en las que se encuentra? Por tanto, el objetivo de este estudio es evaluar los efectos del tratamiento farmacológico no recomendado y el riesgo de ansiedad. Metodología: Encuesta a pacientes diagnosticadas de Endometriosis, registradas en la Base de Datos del Proyecto agrupadas en etapas de tratamientos farmacológicos similares (EI/EII y EIII/EIV). El reporte de ansiedad, con diagnóstico médico y post-endometriosis fue la variable dependiente en estudio. Las variables independientes (o influyentes) fueron [1] Estadio de la enfermedad, [2] Farmacoterapia recomendada (FR) o no (FNR) y [3] régimen de medicación utilizado (clases y combinaciones). Estadística realizada por chi cuadrado y Fischer. Resultados: Del total de 375 mujeres, 274 presentaron ansiedad. De ellos, 170 estaban en el grupo IFR; 141 en el grupo EI/EII y 29 mujeres en el grupo EIII/EIV. En cuanto al grupo IFNR, hubo n=104 mujeres, siendo sólo 1 en EI/EII y 103 en EIII/EIV. Los casos de FNR están más presentes en EIII/EIV, con un 90% de los casos (IC 95%, p<0,05). El régimen terapéutico más común fue el de AINE en monoterapia, con un 65% (IC 95%, p<0,05) en estadio inadecuado. Se observó una correlación positiva entre la FNR y la ansiedad, especialmente cuando se utilizaba monoterapia con AINE (IC del 95%, p<0,05). Conclusión: Las dificultades para acceder a especialistas para el diagnóstico y a los medicamentos EIII/EIV pueden ser las causas, que serán investigadas en futuros estudios.

Kinin B2 Receptor Mediates Cisplatin-Induced Painful Peripheral Neuropathy by Intracellular Kinase Pathways and TRPA1 Channel Sensitisation.

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.

Kinin B2 and B1 Receptors Activation Sensitize the TRPA1 Channel Contributing to Anastrozole-Induced Pain Symptoms.

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.

Kinin B1 and B2 Receptors Contribute to Cisplatin-Induced Painful Peripheral Neuropathy in Male Mice.

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.

Kinin B1 and B2 receptors mediate cancer pain associated with both the tumor and oncology therapy using aromatase inhibitors.

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.

Kinins and their B1 and B2 receptors as potential therapeutic targets for pain relief.

Kinins are endogenous peptides that belong to the kallikrein-kinin system, which has been extensively studied for over a century. Their essential role in multiple physiological and pathological processes is demonstrated by activating two transmembrane G-protein-coupled receptors, the kinin B1 and B2 receptors. The attention is mainly given to the pathological role of kinins in pain transduction mechanisms. In the past years, a wide range of preclinical studies has amounted to the literature reinforcing the need for an updated review about the participation of kinins and their receptors in pain disorders. Here, we performed an extensive literature search since 2004, describing the historical progress and the current understanding of the kinin receptors' participation and its potential therapeutic in several acute and chronic painful conditions. These include inflammatory (mainly arthritis), neuropathic (caused by different aetiologies, such as cancer, multiple sclerosis, antineoplastic toxicity and diabetes) and nociplastic (mainly fibromyalgia) pain. Moreover, we highlighted the pharmacological actions and possible clinical applications of the kinin B1 and B2 receptor antagonists, kallikrein inhibitors or kallikrein-kinin system signalling pathways-target molecules in these different painful conditions. Notably, recent findings sought to elucidate mechanisms for guiding new and better drug design targeting kinin B1 and B2 receptors to treat a disease diversity. Since the kinin B2 receptor antagonist, Icatibant, is clinically used and well-tolerated by patients with hereditary angioedema gives us hope kinin receptors antagonists could be more robustly tested for a possible clinical application in the treatment of pathological pains, which present limited pharmacology management.

TRPA1 participation in behavioral impairment induced by chronic corticosterone administration.

RATIONALE: Major depressive disorder (MDD) is one of the most diagnosed mental disorders. Despite this, its pathophysiology remains poorly understood. In this context, basic research aims to unravel the pathophysiological mechanisms of MDD as well as investigate new targets and substances with therapeutic potential. Transient receptor potential ankyrin 1 (TRPA1) is a transmembrane channel considered a sensor for inflammation and oxidative stress. Importantly, both inflammation and oxidative stress have been suggested as participants in the pathophysiology of MDD. However, the potential participation of TRPA1 in depressive disorder remains poorly investigated. OBJECTIVE: To investigate the involvement of the TRPA1 channel in the behavioral changes induced by chronic corticosterone administration (CCA) in male mice. METHODS: Swiss male mice were exposed to 21 days of CCA protocol and then treated with HC-030031 or A-967079, TRPA1 antagonists. Behavioral tests, analyzes of oxidative parameters and TRPA1 immunocontent were performed in the prefrontal cortex (PFC) and hippocampus (HIP). RESULTS: CCA induced despair-like behavior in mice accompanied by an increase in the levels of hydrogen peroxide (H2O2), a TRPA1 agonist, which was reversed by TRPA1 antagonists and ketamine (positive control). In addition, CCA protocol reduced the immunocontent of this channel in the HIP and showed a tendency to increase the TRPA1 protein expression in the PFC. CONCLUSION: Our work suggests that TRPA1 channel appears crucial to mediate the behavioral impairment induced by CCA in male Swiss mice.

Lower antidepressant response to fluoxetine is associated with anxiety-like behavior, hippocampal oxidative imbalance, and increase on peripheral IL-17 and IFN-γ levels.

Major depression is a leading contributor to the global burden of disease. This is mainly related to the disorder chronic and recurrent nature, and to high rates of refractoriness to treatment. Limited efficacy with currently available antidepressants highlights the need for more effective options for treating drug-resistant patients and emphasizes the importance of developing specific preclinical models for treatment-resistant populations. Treatment-resistant depression (TRD) is commonly defined as failure to respond to two or more trials of antidepressants. In this study, we investigated the effect of fluoxetine treatment for fourteen days on the depressive-like behavior and the oxidative and inflammatory parameters of mice submitted to chronic corticosterone administration. After 21 days of subcutaneous corticosterone administration (20 mg/kg/day) and 14 days of oral fluoxetine treatment (10 mg/kg/day, started on day 7 of induction protocol), we separated animals into two groups according to the tail suspension test (TST) results: antidepressant responders (good response to antidepressant, GRA) and non-responders (resistance to antidepressant, AR). Forced swimming test (FST), elevated plus maze test (EPMT), and open field test (OFT) were performed. We found that animals classified as AR (i.e., those with higher immobility values in the TST) demonstrated anxiety-like behavior in the EPMT, increased H2O2 levels, and decreased catalase activity in the hippocampus, as well as increased serum levels of IL-17 and IFN-γ. Our findings suggest that a redox imbalance in the hippocampus, combined with increased levels of peripheral IL-17 and INF-γ, may be involved with an impaired response to fluoxetine.

Animal models of fibromyalgia: What is the best choice?

Fibromyalgia (FM) is a complex syndrome, with an indefinite aetiology and intricate pathophysiology that affects 2 - 3% of the world population. From the beginning of the 2000s, experimental animal models have been developed to mimic clinical FM and help obtain a better understanding of the relevant neurobiology. These animal models have enabled a broad study of FM symptoms and mechanisms, as well as new treatment strategies. Current experimental FM models include the reserpine-induced systemic depletion of biogenic amines, muscle application of acid saline, and stress-based (cold, sound, or swim) approaches, among other emerging models. FM models should: (i) mimic the cardinal symptoms and complaints reported by FM patients (e.g., spontaneous nociception, muscle pain, hypersensitivity); (ii) mimic primary comorbidities that can aggravate quality of life and lead to worse outcomes (e.g., fatigue, sleep disturbance, depression, anxiety); (iii) mimic the prevalent pathological mechanisms (e.g., peripheral and central sensitization, inflammation/neuroinflammation, change in the levels of the excitatory and inhibitory neurotransmitters); and (iv) demonstrate a pharmacological profile similar to the clinical treatment of FM. However, it is difficult for any one of these models to include the entire spectrum of clinical FM features once even FM patients are highly heterogeneous. In the past six years (2015 - 2020), a wide range of experimental FM studies has amounted to the literature reinforcing the need for an updated review. Here we have described, in detail, several approaches used to experimentally study FM, with a focus on recent studies in the field and in previously less discussed mechanisms. We highlight each model's challenges, limitations, and future directions, intending to help preclinical researchers establish the correct experimental FM model to use depending on their goals.

Copaiba oleoresin has topical antinociceptive activity in a UVB radiation-induced skin-burn model in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Copaiba oleoresin, extracted from Copaifera L., is used as a wound healing, analgesic, antimicrobial and, mainly, anti-inflammatory agent. Thus, in this study we investigated the antinociceptive and anti-inflammatory effects of a topical formulation containing Copaiba oleoresin (3%) in a UVB radiation-induced skin burn model (0.75 J/cm2) in mice and performed a cream-formulation stability study. MATERIALS AND METHODS: The chemical composition of Copaiba oleoresin was analyzed using gas chromatography (GC-MS). The topical antinociceptive (evaluated through mechanical allodynia and thermal hyperalgesia) and the anti-inflammatory (dermal thickness and inflammatory cell infiltration) effects of treatments were assessed. The cream-formulation stability study was performed after two months, and organoleptic characteristics, pH, spreadability and rheological characteristics were analyzed. RESULTS: Copaiba oleoresin cream was able to prevent UVB radiation-induced mechanical allodynia on the 2nd, 3rd and 4th day after UVB radiation exposure with a maximum inhibition (Imax) of 64.6 ± 7% observed on the 2nd day; it also reduced the thermal hyperalgesia on the 1st and 2nd days post UVB radiation, with a Imax of 100% observed on the 2nd day. Moreover, topical treatment with Copaiba oleoresin cream inhibited the inflammatory cell infiltration, but did not reduce the dermal thickness. Such effects can be attributed, at least in part, to the presence of biological components, such as ß-caryophyllene and other sesquiterpenes identified by GC-MS. CONCLUSION: Our results demonstrate that the topical formulation containing Copaiba oleoresin presented antinociceptive and anti-inflammatory effects in mice subjected to a UVB radiation and that the cream-formulation was stable for two months. Thus, use of Copaiba oleoresin is a promising strategy for the treatment of inflammatory pain associated with sunburn.

TRPA1 involvement in analgesia induced by Tabernaemontana catharinensis ethyl acetate fraction in mice.

BACKGROUND: Ionic channels such as the transient receptor potential ankyrin 1 (TRPA1) are essential for the detection and transmission of painful stimuli. In this sense, new TRPA1 antagonists have been searched as analgesics. PURPOSE: Preclinical studies support the antinociceptive activity of Tabernaemontana catharinensis ethyl acetate fraction (Eta), which has constituents previously identified as TRPA1 antagonists (gallic acid). It was verified for the first time the involvement of the TRPA1 on Eta's antinociceptive and anti-inflammatory effects in mice pain models. STUDY DESIGN: It was evaluated the Eta's effect (0.01-100 mg/kg, oral route) on nociceptive (spontaneous nociception, mechanical and cold allodynia) and inflammatory (paw edema) parameters in pain models involved with TRPA1 activation. METHODS: Firstly, it was investigated the ability of Eta to act on TRPA1 or TRPV1 channels (Ca2+influx and binding assays in mice spinal cords). Next, it was evaluated the Eta's antinociceptive and anti-inflammatory effects after intraplantar injection of TRPA1 agonists (hydrogen peroxide, cinnamaldehyde or allyl isothiocyanate) in male Swiss mice (30-35 g). Moreover, the Eta's antinociceptive effects were evaluated on complete Freund's adjuvant (CFA)-induced chronic inflammatory pain (CIP), postoperative pain and on paclitaxel-induced peripheral neuropathy (PIPN). Oxidative parameters were evaluated in mice paw utilized for CFA induced-CIP model. RESULTS: Eta inhibited the TRPA1 agonist-induced Ca2+ influx [Imax = 72.4 ±â€¯1.5%; IC50 = 0.023(0.004-0.125)µg/ml], but not TRPV1 agonist-induced, nor was able to displace [3H]-resiniferatoxin (TRPV1 agonist) binding. Eta (0.1-100 mg/kg) inhibited the spontaneous nociception [ID50 = 0.043(0.002-0.723)mg/kg], mechanical [ID50 = 7.417(1.426-38.570)mg/kg] and cold allodynia, and edema development caused by TRPA1 agonists. Moreover, Eta (100 mg/kg) prevented and reversed the CFA-induced CIP (Imax = 55.8 ±â€¯13.7%, Imax = 80.4 ±â€¯5.1%, respectively) and postoperative pain (Imax = 88.0 ±â€¯11.6%, Imax = 51.3 ±â€¯14.9%, respectively), been also effective in reversing the acute (Imax = 94.4 ±â€¯12.4%) and chronic (Imax = 86.8 ±â€¯8.6%) PIPN. These effects seem to occur by TRPA1 channels pathway, and independently of TRPV1 or oxidative mechanisms. CONCLUSION: Our results demonstrate that Eta-induced antinociception and anti-inflammatory effects occur by TRPA1 inhibition making possible the use of this preparation as a potential therapeutic agent to treat pathological pains.

Citrus essential oils inhalation by mice: Behavioral testing, GCMS plasma analysis, corticosterone, and melatonin levels evaluation.

The use of orange essential oils (EOs) as a complementary treatment is very common in Brazilian popular culture. The levels of melatonin (MEL) and corticosterone (CORT) hormones were investigated simultaneously, by the Luminex™ immunoassay system in mice plasma, after Citrus aurantium and Citrus sinensis EOs inhalation for 30 min. The plasma was analyzed by headspace through gas chromatography coupled to mass spectrometry for investigation of the EO components. Mice were submitted to behavioral testing to research anxiolytic-like, sedative, and antidepressant-like effects. The inhalation of atmosphere obtained from vaporization of 10% solution of this Citrus EO separately did not affect MEL or CORT plasma levels; that is, the MEL and CORT levels did not present variation in function of the EO in the schedule used. On the other hand, the imipramine positive control used altered the level of MEL as expected. The EO constituents were detected in plasma at different ratios that is present in inhaled EO. Behavioral tests showed that the inhalation of 10% C. sinensis EO presents an anxiolytic-like and sedative effect. Thus, C. sinensis EO can be a valuable tool for treatment of the anxiety disturbs, apparently without interference with MEL and CORT physiological levels.

Intervenções farmacêuticas em prescrições pediátricas: uma revisão narrativa / Pharmaceutical interventions in pediatric prescriptions: a narrative review

As intervenções farmacêuticas (IFs) são um componente importante no papel do farmacêutico clínico na prevenção de eventos adversos relacionados a medicamentos. A maioria dos estudos aborda as IFs em pacientes adultos e ainda há uma lacuna de informações sobre essas intervenções na população pediátrica. Trata-se de uma revisão narrativa sobre as IFs em prescrições de medicamentos de pacientes pediátricos internados em hospitais. A coleta de dados foi realizada entre julho e agosto de 2018 em três bases de dados e foram selecionados artigos publicados entre janeiro de 2010 a julho de 2018. As IFs apresentaram resultados positivos para os pacientes pediátricos. No total, foram descritos 35700 IFs realizadas com uma taxa de aceitação média de 92% por parte dos prescritores nos estudos que quantificaram a aceitação. A classe de medicamentos mais envolvidas nas IFs foi a de anti-infecciosos. Através dos estudos é possível concluir que as IFs podem beneficiar a segurança do paciente e levar à identificação de potenciais erros, além da prevenção de eventos adversos relacionados a terapia medicamentosa. São necessárias pesquisas contínuas que utilizem métodos padronizados para avaliar desfechos e eventos, permitindo assim a comparação entre resultados. (AU)

Pharmaceutical interventions (PIs) are an important component of the role of the clinical pharmacist in preventing drug-related adverse events. Most studies have addressed PIs in adult patients and there is still a lack of information on these interventions in the pediatric population. This narrative review focuses on PIs in prescriptions of pediatric patients admitted to hospitals. Data collection was performed from July to August 2018 in three databases, and articles published from January 2010 to July 2018 were selected. The reported PIs showed positive results for pediatric patients. In total, 35,700 PIs were performed with an average acceptance rate of 92% by prescribers in the studies that measured acceptance. The most common class of drugs used in PIs was anti-infective drugs. Based on the studies, a possible conclusion is that PIs may contribute to patient safety and lead to identification of potential errors as well as prevention of drug-related adverse events. Further research using standardized methods is required to evaluate outcomes and events, thus allowing a comparison between results. (AU)

Metodologias ativas de ensino-aprendizagem no processo de ensino em saúde no Brasil: uma revisão narrativa / Active teaching-learning methodologies in the teaching health process in Brazil: a narrative review

Nas últimas décadas, a formação dos profissionais de saúde tornou-se um ponto importante a ser discutido. O novo profissional desejado pelas últimas reformas curriculares dos cursos da área da saúde tem perfil humanista, crítico e reflexivo, para atuar em todos os níveis de atenção à saúde. Apesar disso, a educação dos profissionais de saúde ainda é, na maioria das vezes, baseada em um modelo fragmentado do saber, desconsiderando as necessidades de atuação na prática. Neste contexto, surgem as metodologias ativas de ensino-aprendizagem (MAEA), que propõem desafios a serem superados pelos estudantes, possibilitando-lhes ocupar o lugar de sujeitos na construção do conhecimento. O objetivo deste estudo foi revisar artigos disponíveis em periódicos científicos que exemplificassem o uso de MAEA no processo de ensino nos cursos de graduação da área da saúde, com ênfase na realidade brasileira. A busca foi realizada através das bases de dados PubMed, SciELO e BVS, nas quais foram selecionados artigos científicos de relatos de experiência em português. Os resultados relatados nos artigos foram positivos em relação ao uso das MAEA no processo de ensino em saúde durante a graduação (AU)

In the last decades, the training of health professionals has become an important point to be discussed. The new professional required by the latest curricular reforms in health courses has a humanist, critical and reflective profile, to work at all levels of health care. In spite of this, the education of health professionals is still mostly based on a fragmented model of knowledge, disregarding the needs of action in practice. In this context, active teaching-learning methodologies (ATLM) propose challenges to be overcome by students, enabling them to act as subjects in the construction of knowledge. The aim of this study was to select and categorize articles available in scientific journals that exemplify the use of ATLM in the teaching process in undergraduate courses in the health area, with focus on the Brazilian reality. The search was carried out through PubMed, SciELO and BVS databases, from which scientific papers presenting experience reports in Portuguese were selected. The results reported in the articles were positive regarding the use of ATLM in the health teaching process during undergraduate studies (AU)

Subchronic oral administration of Benzo[a]pyrene impairs motor and cognitive behavior and modulates S100B levels and MAPKs in rats.

Benzo[a]pyrene (BaP) is an environmental contaminant produced during incomplete combustion of organic material that is well known as a mutagenic and carcinogenic toxin. There are few studies addressing the molecular and cellular basis of behavioural alterations related to BaP exposure. The aim of this study was to evaluate the effect of subchronic oral administration of BaP on behavioral and neurochemical parameters. Wistar male rats received BaP (2 mg/kg) or corn oil (control), once a day for 28 days (n = 12/group). Spontaneous locomotor activity and short- and long-term memories were evaluated. Glial fibrillary acid protein and S100B content in the hippocampus, serum and CSF were measured using ELISA and total and phosphorylated forms of mitogen activated protein kinases (MAPKs) named extracellular signal-regulated kinases 1 and 2, p38(MAPK) and c-Jun amino-terminal kinases 1 and 2, in the hippocampus, were evaluated by western blotting. BaP induced a significant increase on locomotor activity and a decrease in short-term memory. S100B content was increased significantly in cerebrospinal fluid. BaP induced a decrease on ERK2 phosphorylation in the hippocampus. Thus, BaP subchronic treatment induces an astroglial response and impairs both motor and cognitive behavior, with parallel inhibition of ERK2, a signaling enzyme involved in the hippocampal neuroplasticity. All these effects suggest that BaP neurotoxicity is a concern for environmental pollution.