CaMKIIα mediates spermidine-induced memory enhancement in rats: A potential involvement of PKA/CREB pathway.

Memory consolidation is associated with the regulation of protein kinases, which impact synaptic functions and promote synaptogenesis. The administration of spermidine (SPD) has been shown to modulate major protein kinases associated with memory improvement, including the Ca2+-dependent protein kinase (PKC) and cAMP-dependent protein kinase (PKA), key players in the cAMP response element-binding protein (CREB) activation. Nevertheless, the initial mechanism underlying SPD-mediated memory consolidation remains unknown, as we hypothesize a potential involvement of the memory consolidation precursor, Ca2+/calmodulin-dependent protein kinase II-α (CaMKIIα), in this process. Based on this, our study aimed to investigate potential interactions among PKC, PKA, and CREB activation, mediated by CaMKIIα activation, in order to elucidate the SPD memory consolidation pathway. Our findings suggest that the post-training administration of the CaMKII inhibitor, KN-62 (0.25 nmol, intrahippocampal), prevented the memory enhancement induced by SPD (0.2 nmol, intrahippocampal) in the inhibitory avoidance task. Through western immunoblotting, we observed that phosphorylation of CaMKIIα in the hippocampus was facilitated 15 min after intrahippocampal SPD administration, resulting in the activation of PKA and CREB, 180 min after infusion, suggesting a possible sequential mechanism, since SPD with KN-62 infusion leads to a downregulation in CaMKIIα/PKA/CREB pathway. However, KN-62 does not alter the memory-facilitating effect of SPD on PKC, possibly demonstrating a parallel cascade in memory acquisition via PKA, without modulating CAMKIIα. These results suggest that memory enhancement induced by SPD administration involves crosstalk between CaMKIIα and PKA/CREB, with no PKC interaction.

Intravenous administration of recombinant Phα1ß: Antinociceptive properties and morphine tolerance reversal in a cancer-associated pain model.

Cancer-related pain is considered one of the most prevalent symptoms for those affected by cancer, significantly influencing quality of life and treatment outcomes. Morphine is currently employed for analgesic treatment in this case, however, chronic use of this opioid is limited by the development of analgesic tolerance and adverse effects, such as digestive and neurological disorders. Alternative therapies, such as ion channel blockade, are explored. The toxin Phα1ß has demonstrated efficacy in blocking calcium channels, making it a potential candidate for alleviating cancer-related pain. This study aims to assess the antinociceptive effects resulting from intravenous administration of the recombinant form of Phα1ß (r-Phα1ß) in an experimental model of cancer-related pain in mice, tolerant or not to morphine. The model of cancer-induced pain was used to evaluate these effects, with the injection of B16F10 cells, followed by the administration of the r-Phα1ß, and evaluation of the mechanical threshold by the von Frey test. Also, adverse effects were assessed using a score scale, the rotarod, and open field tests. Results indicate that the administration of r-Phα1ß provoked antinociception in animals with cancer-induced mechanical hyperalgesia, with or without morphine tolerance. Previous administration of r-Phα1ß was able to recover the analgesic activity of morphine in animals tolerant to this opioid. r-Phα1ß was proved safe for these parameters, as no adverse effects related to motor and behavioral activity were observed following intravenous administration. This study suggests that the concomitant use of morphine and r-Phα1ß could be a viable strategy for pain modulation in cancer patients.

Topical application of a TRPA1 antagonist reduced nociception and inflammation in a model of traumatic muscle injury in rats.

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.

Role of Cav2.3 (R-type) Calcium Channel in Pain and Analgesia: A Scoping Review.

BACKGROUND: Voltage-gated calcium channels (VGCCs) play an important role in pain development and maintenance. As Cav2.2 and Cav3.2 channels have been identified as potential drug targets for analgesics, the participation of Cav2.3 (that gives rise to R-type calcium currents) in pain and analgesia remains incompletely understood. OBJECTIVE: Identify the participation of Cav2.3 in pain and analgesia. METHODS: To map research in this area as well as to identify any existing gaps in knowledge on the potential role of Cav2.3 in pain signalling, we conducted this scoping review. We searched PubMed and SCOPUS databases, and 40 articles were included in this study. Besides, we organized the studies into 5 types of categories within the broader context of the role of Cav2.3 in pain and analgesia. RESULTS: Some studies revealed the expression of Cav2.3 in pain pathways, especially in nociceptive neurons at the sensory ganglia. Other studies demonstrated that Cav2.3-mediated currents could be in-hibited by analgesic/antinociceptive drugs either indirectly or directly. Some articles indicated that Cav2.3 modulates nociceptive transmission, especially at the pre-synaptic level at spinal sites. There are studies using different rodent pain models and approaches to reduce Cav2.3 activity or expression and mostly demonstrated a pro-nociceptive role of Cav2.3, despite some contradictory findings and deficiencies in the description of study design quality. There are three studies that reported the association of single-nucleotide polymorphisms in the Cav2.3 gene (CACNA1E) with postoperative pain and opioid consumption as well as with the prevalence of migraine in patients. CONCLUSION: Cav2.3 is a target for some analgesic drugs and has a pro-nociceptive role in pain.

Characterization of Depression- and Anxiety-Like Behaviours in a Mouse Model of Relapsing-Remitting Multiple Sclerosis.

Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune neurological disease and is the most common subtype of MS. In addition, it is associated with the development of depression and anxiety. To date, depressive- and anxiety-like behaviours were only studied using models of progressive MS, which causes severe motor alterations. Thus, we sought to standardise the depressive and anxiety-like behaviours in an RRMS model induced by experimental autoimmune encephalomyelitis (RR-EAE) in mice. The RR-EAE model was induced in C57BL/6 female mice using myelin oligodendrocyte glycoprotein (MOG35-55) antigen and Quillaja saponin (Quil A) as an adjuvant. The immunisation of RR-EAE did not induce locomotor alteration but caused relapsing-remitting induction of clinical scores in mice until 35 post-immunization (p.i.). Also, increased levels of tumour necrosis factor alpha (TNF-α), astrocyte marker (GFAP), and microglial markers (IBA-1) were detected in the prefrontal cortex at 35 p.i. of RR-EAE. In the open field test, RR-EAE mice showed decreased time spent at the centre and sniffing behaviour (at days 21 and 34 p.i.). Also, on day 35 p.i. the RR-EAE group spent less time in the open arms and had decreased open-arm entries compared to control mice in the elevated plus maze (EPM) test, confirming the anxiety-like behaviour. At day 36° p.i. in the tail suspension test, mice showed depression-like behaviour with decreased latency time and increased immobility time. Thus, the RR-EAE model mimics the neuroinflammatory and behavioural features of the RRMS, including depression- and anxiety-like symptoms.

Kinins' Contribution to Postoperative Pain in an Experimental Animal Model and Its Implications.

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.

Advance directives in the perspective of the elderly population : Advance directives / Diretivas antecipadas na perspectiva da população idosa: Advance directives

Objective: To analyze the knowledge and acceptance of the elderly person regarding the elaboration of the Advance Directives, their preference in relation to the filling models and the choice of the representative who will replace them in the decision-making process. Methodology: Cross-sectional study carried out by providing participants with two models  of Advance Directives were made available to the participants for completion and applied a questionnaire on knowledge, acceptance, and evaluation of the device. Results: There were 85.63% of the participants who were unaware of the Advance Directives, 98.13% who were unaware of document models, 100% who considered model 1, more complete, to be good or acceptable, and 66.88% who indicated a son as its representative. When asked about the importance of preparing, making available to the population, and passing a law that regulates this right, the participants were assertive respectively by 91.88%, 91.25% and 91.25%. Conclusion: Although lack of knowledge was general among the participants, after clarification there was a high rate of evaluation and acceptance of the Advance Directives, as well as a recommendation for their legalization and availability to the population as a device that contributes to the guarantee of autonomy and human dignity, especially during the end-of-life health care.

Objetivo: Analisar o conhecimento e a aceitação da pessoa idosa acerca da elaboração das Diretivas Antecipadas de Vontade, a sua preferência em relação aos modelos de preenchimento e a escolha do representante que irá substitui-la na tomada de decisão. Metodologia: Estudo transversal realizado por meio da disponibilização aos participantes de dois modelos de Diretivas Antecipadas de Vontade para preenchimento e aplicação de um questionário sobre conhecimento, aceitação e avaliação do dispositivo. Resultados: A grande maioria dos participantes (85,63%) desconhecia as Diretivas Antecipadas de Vontade; 98,13% desconheciam os modelos do documento; 100% consideraram bom ou aceitável o modelo 1, mais completo; e 66,88% indicaram um filho como o seu representante legal. Quando questionados sobre a importância da elaboração, disponibilização à população e aprovação de lei que regulamente esse direito, as respostas foram afirmativas, respectivamente, para 91,88%, 91,25% e 91,25% dos participantes. Conclusão: Embora o desconhecimento fosse geral entre os participantes, após esclarecimento houve elevado índice de avaliação e aceitação das Diretivas Antecipadas de Vontade, bem como recomendação para sua legalização e disponibilização à população como um dispositivo que contribui para a garantia da autonomia e dignidade humana, sobretudo durante a assistência à saúde no final da vida.

Critical Pronociceptive Role of Family 2 Voltage-Gated Calcium Channels in a Novel Mouse Model of HIV-Associated Sensory Neuropathy.

Some people living with HIV present painful sensory neuropathy (HIV-SN) that is pharmacoresistant, sex-associated, and a major source of morbidity. Since the specific mechanisms underlying HIV-SN are not well understood, the aim of our study was to characterize a novel model of painful HIV-SN by combining the HIV-1 gp120 protein and the antiretroviral stavudine (d4T) in mice and to investigate the pronociceptive role of the family 2 voltage-gated calcium channel (VGCC) α1 subunit (Cav2.X channels) in such a model. HIV-SN was induced in male and female C57BL/6 mice by administration of gp120 and/or d4T and detected by a battery of behavior tests and by immunohistochemistry. The role of Cav2.X channels was assessed by the treatment with selective blockers and agonists as well as by mRNA detection. Repeated administration with gp120 and/or d4T produced long-lasting touch-evoked painful-like behaviors (starting at 6 days, reaching a maximum on day 13, and lasting up to 28 days after treatment started), with a greater intensity in female mice treated with the combination of gp120 + d4T. Moreover, gp120 + d4T treatment reduced the intraepidermal nerve fibers and well-being of female mice, without altering other behaviors. Mechanistically, gp120 + d4T treatment induced Cav2.1, 2.2, and 2.3 transcriptional increases in the dorsal root ganglion and the Cav2.X agonist-induced nociception. Accordingly, intrathecal selective Cav2.2 blockade presented longer and better efficacy in reversing the hyperalgesia induced by gp120 + d4T treatment compared with Cav2.1 or Cav2.3, but also presented the worst safety (inducing side effects at effective doses). We conclude that the family 2 calcium channels (Cav2.X) exert a critical pronociceptive role in a novel mouse model of HIV-SN.

Emerging MIMO Technologies for 6G Networks.

The demand for wireless connectivity has grown exponentially over the last years. By 2030 there should be around 17 billion of mobile-connected devices, with monthly data traffic in the order of thousands of exabytes. Although the Fifth Generation (5G) communications systems present far more features than Fourth Generation (4G) systems, they will not be able to serve this growing demand and the requirements of innovative use cases. Therefore, Sixth Generation (6G) Networks are expected to support such massive connectivity and guarantee an increase in performance and quality of service for all users. To deal with such requirements, several technical issues need to be addressed, including novel multiple-antenna technologies. Then, this survey gives a concise review of the main emerging Multiple-Input Multiple-Output (MIMO) technologies for 6G Networks such as massive MIMO (mMIMO), extremely large MIMO (XL-MIMO), Intelligent Reflecting Surfaces (IRS), and Cell-Free mMIMO (CF-mMIMO). Moreover, we present a discussion on how some of the expected key performance indicators (KPIs) of some novel 6G Network use cases can be met with the development of each MIMO technology.

Diretivas antecipadas de vontade na perspectiva da população idosa de um município do meio oeste catarinense / Advance directives in the perspective of the older adults of a municipality in the Midwest of Santa Catarina

Resumo Objetivo Analisar o conhecimento da pessoa idosa em um município do meio oeste catarinense acerca da elaboração das Diretivas Antecipadas de Vontade (DAV), a sua preferência em relação aos modelos de preenchimento e a escolha do representante que irá substitui-la na tomada de decisão. Método Estudo transversal realizado por meio da disponibilização aos participantes de dois modelos de DAV para preenchimento e aplicação de um questionário sobre conhecimento, aceitação e avaliação do dispositivo. Resultados A maioria dos participantes (85,63%) desconhecia as DAV; 98,13% desconheciam os modelos do documento; 100% consideraram bom ou aceitável o modelo 1, mais completo; 66,88% indicaram um filho como representante legal. Questionados sobre a importância da elaboração, disponibilização à população e aprovação de lei que regulamente esse direito, as respostas foram afirmativas, respectivamente, para 91,88%, 91,25% e 91,25% dos participantes. Apenas 5% dos respondentes apontaram dificuldades no entendimento dos modelos, sendo a "linguagem" o item de maior dificuldade. Conclusão A maioria das pessoas idosas desconhecia os modelos de DAV, mas referiram o modelo 1, considerando-o bom ou aceitável. A maioria não teve dificuldades no entendimento e reconheceu a importância da elaboração e disponibilização das DAV à população, assim como a necessidade de uma lei para regulamentar esse direito. Observou-se uma alta proporção de participantes indicando um filho como representante legal, enfatizando a importância de envolver a família nesse processo. Esses resultados ressaltam a necessidade de conscientizar as pessoas idosas sobre as DAV e disponibilizar modelos claros e abrangentes.

Abstract Objective To analyze the knowledge of older individuals in a municipality in the Midwestern region of Santa Catarina regarding the development of Advance Directives, their preferences regarding the available models, and the selection of a representative to make decisions on their behalf. Method Cross-sectional study carried out by providing participants with two models of Advance Directives were made available to the participants for completion and applied a questionnaire on knowledge, acceptance, and evaluation of the device. Results There were 85.63% of the participants who were unaware of the Advance Directives, 98.13% who were unaware of document models, 100% who considered model 1, more complete, to be good or acceptable, and 66.88% who indicated an adult child as its representative. When asked about the importance of preparing, making available to the population, and passing a law that regulates this right, the participants were assertive respectively by 91.88%, 91.25% and 91.25%. Conclusion Most older people were unaware of the AD models, but mentioned model 1, considering it good or acceptable. Most had no difficulties in understanding and recognized the importance of preparing and making AD available to the population, as well as the need for a law to regulate this right. There was a high proportion of participants indicating an adult child as a legal representative, emphasizing the importance of involving the family in this process. These results highlight the need to make older people aware of AD and provide clear and comprehensive models.

Angiotensin type 2 receptor antagonism as a new target to manage gout.

BACKGROUND: There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS: Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1ß release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS: AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1ß levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1ß levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION: Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism.

Migraine represents one of the major causes of disability worldwide and is more prevalent in women; it is also related to anxiety symptoms. Stress, such as sound stress, is a frequently reported trigger in migraine patients, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized nociception and anxiety-related symptoms after the induction of sound stress in mice. C57BL/6 mice (20-30 g) were exposed to unpredictable sound stress for 3 days, nonconsecutive days. We observed enhanced plasma corticosterone levels on day 1 after stress induction. First, 7 days after the last stress session, mice developed hind paw and periorbital mechanical allodynia, grimacing pain behavior, anxiety-like symptoms, and reduced exploratory behavior. The nociceptive and behavioral alterations detected in this model were mostly shown in female stressed mice at day 7 post-stress. In addition, on day 7 post-stress nociception, these behaviors were consistently abolished by the CGRP receptor antagonist olcegepant (BIBN4096BS, 100 mg/kg by intraperitoneal route) in female and male stressed mice. We also demonstrated an increase in interleukine-6 (IL-6), tumor necrosis factor (TNF-α), and CGRP levels in stressed mice plasma, with female mice showing higher levels compared to male mice. This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine-inducing pain.

K-mer applied in Mycobacterium tuberculosis genome cluster analysis.

According to studies carried out, approximately 10 million people developed tuberculosis in 2018. Of this total, 1.5 million people died from the disease. To study the behavior of the genome sequences of Mycobacterium tuberculosis (MTB), the bacterium responsible for the development of tuberculosis (TB), an analysis was performed using k-mers (DNA word frequency). The k values ranged from 1 to 10, because the analysis was performed on the full length of the sequences, where each sequence is composed of approximately 4 million base pairs, k values above 10, the analysis is interrupted, as consequence of the program's capacity. The aim of this work was to verify the formation of the phylogenetic tree in each k-mer analyzed. The results showed the formation of distinct groups in some k-mers analyzed, taking into account the threshold line. However, in all groups, the multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains remained together and separated from the other strains.

Dificuldade de comunicar a morte do paciente aos familiares / Difficulty communicating the patient's death to family members / Dificultad para comunicar la muerte del paciente a los familiares

Resumo Considerando que comunicar a morte de paciente a familiares é tarefa difícil para profissionais de saúde, o objetivo desta pesquisa foi identificar na literatura recomendações para reduzir os malefícios dessa situação. Trata-se de estudo qualitativo realizado por meio de revisão bibliográfica nas bases de dados do Portal Capes com a utilização dos termos "morte" e "comunicação". Os resultados, obtidos em 18 artigos selecionados, foram divididos em três categorias: formação profissional, preparo familiar e prática profissional. Quanto à formação profissional, indicou-se, sobretudo, treinamento por role playing precedido de fundamentação teórica; para o preparo dos familiares, recomendou-se promover diálogo enquanto o paciente vive; em relação à prática profissional, aconselhou-se compartilhar informações entre colegas e adotar medidas para controle emocional. Constatou-se que práticas simuladas, troca de informações entre profissionais, controle emocional dos profissionais e diálogo com e entre familiares contribuem para reduzir o malefício da comunicação de morte.

Abstract Considering that informing family members of a patient's death is an arduous task for health professionals, the objective of this research was to identify in the literature recommendations to reduce the distress caused by this situation. This is a qualitative study carried out by means of a literature review on the Capes Portal database using the terms "death" and "communication." The results, obtained from 18 selected articles, were divided into three categories: professional training, family preparation, and professional practice. Regarding professional training, it was indicated, above all, training by role playing preceded by theoretical foundations; for family members' preparation, the recommendation was to engage in dialogue while the patient is alive; in relation to professional practice, the advice given was information sharing between colleagues and adoption of measures for emotional control. It was found that simulated practices, information sharing between professionals, emotional control of professionals and dialogue with and between family members contribute to reducing the distress when communicating death.

Resumen Teniendo en cuenta que comunicar la muerte de un paciente a familiares es tarea difícil para los profesionales de la salud, el objetivo de esta investigación fue identificar en la literatura recomendaciones para reducir los daños de esa situación. Se trata de un estudio cualitativo realizado por medio de revisión bibliográfica en las bases de datos del portal Capes con la utilización de los Términos "muerte" y "comunicación". Los resultados, obtenidos a partir de 18 artículos seleccionados, fueron divididos en tres categorías: formación profesional, preparación familiar y práctica profesional. En cuanto a la formación profesional, se indicó, sobre todo, entrenamiento por role playing precedido de fundamentación teórica; para la preparación de los familiares, se recomendó promover el diálogo mientras el paciente vive; en relación con la práctica profesional, se aconsejó compartir informaciones entre compañeros y adoptar medidas de control emocional. Se comprobó que prácticas simuladas, intercambio de informaciones entre profesionales, control emocional de los profesionales y diálogo con y entre familiares contribuyen a reducir el daño de la comunicación de muerte.

Analgesic effects of Phα1ß toxin: a review of mechanisms of action involving pain pathways.

Phα1ß is a neurotoxin purified from spider venom that acts as a high-voltage-activated (HVA) calcium channel blocker. This spider peptide has shown a high selectivity for N-type HVA calcium channels (NVACC) and an analgesic effect in several animal models of pain. Its activity was associated with a reduction in calcium transients, glutamate release, and reactive oxygen species production from the spinal cord tissue and dorsal ganglia root (DRG) in rats and mice. It has been reported that intrathecal (i.t.) administration of Phα1ß to treat chronic pain reverted opioid tolerance with a safer profile than ω-conotoxin MVIIA, a highly selective NVACC blocker. Following a recent development of recombinant Phα1ß (CTK 01512-2), a new molecular target, TRPA1, the structural arrangement of disulphide bridges, and an effect on glial plasticity have been identified. CTK 01512-2 reproduced the antinociceptive effects of the native toxin not only after the intrathecal but also after the intravenous administration. Herein, we review the Phα1ß antinociceptive activity in the most relevant pain models and its mechanisms of action, highlighting the impact of CTK 01512-2 synthesis and its potential for multimodal analgesia.

Suicide cases in developed and emerging countries: an analysis using wavelets / Casos de suicídio em países desenvolvidos e emergentes: uma análise usando ondaletas

OBJECTIVE: The aim of this study was to use a wavelet technique to determine whether the number of suicides is similar between developed and emerging countries. METHODS: Annual data were obtained from World Health Organization (WHO) reports from 1986 to 2015. Discrete nondecimated wavelet transform was used for the analysis, and the Daubechies wavelet function was applied with five-level decomposition. Regarding clustering, energy (variance) was used to analyze the clusters and visualize the clustering process. We constructed a dendrogram using the Mahalanobis distance. The number of groups was set using a specific function in the R program. RESULTS: The cluster analysis verified the formation of four groups as follows: Japan, the United States and Brazil were distinct and isolated groups, and other countries (Austria, Belgium, Chile, Israel, Mexico, Italy and the Netherlands) constituted a single group. CONCLUSION: The methods utilized in this paper enabled a detailed verification of countries with similar behaviors despite very distinct socioeconomic, geographic and climate characteristics.

OBJETIVO: Verificar se existe relação de similaridade entre o número de suicídio em países desenvolvidos e emergentes usando a técnica de ondaletas. MÉTODOS: Os dados anuais foram obtidos a partir do relatório da Organização Mundial da Saúde (OMS), no período de 1986 a 2015. Para análise, foi empregada a transformada discreta não decimada de ondaleta (NDWT), a função ondaleta aplicada foi a Daubechies com cinco níveis de decomposição. Com relação ao agrupamento, utilizou-se a energia (variância) para analisar os clusters e, para a visualização do processo de clusterização, trabalhamos com o dendograma, no qual se empregou a distância de Mahalanobis. A quantidade de grupos foi definida por meio da função NbCluster. RESULTADOS: A partir da análise de cluster, verificou-se a formação de quatros grupos. No qual, Japão e Estados Unidos e Brasil localizam-se em grupos distintos e isolados. E os demais países (Áustria, Bélgica, Chile, Israel, México, Itália e Holanda) em um único grupo. CONCLUSÃO: Utilizando esse método, foi possível verificar com mais detalhes quais países apresentaram comportamentos semelhantes, mesmo apresentando características bem distintas entre si, tanto socioeconômica, geográfica e climática.

Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation.

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

TRPA1 involvement in depression- and anxiety-like behaviors in a progressive multiple sclerosis model in mice.

Progressive multiple sclerosis (PMS) is a neurological disease associated with the development of depression and anxiety, but treatments available are unsatisfactory. The transient receptor potential ankyrin 1 (TRPA1) is a cationic channel activated by reactive compounds, and the blockage of this receptor can reduce depression- and anxiety-like behaviors in naive mice. Thus, we investigated the role of TRPA1 in depression- and anxiety-like behaviors in a PMS model in mice. PMS model was induced in C57BL/6 female mice by the experimental autoimmune encephalomyelitis (EAE). Nine days after the PMS-EAE induction, behavioral tests (tail suspension and elevated plus maze tests) were performed to verify the effects of sertraline (positive control), selective TRPA1 antagonist (A-967,079), and antioxidants (α-lipoic acid and apocynin). The prefrontal cortex and hippocampus were collected to evaluate biochemical and inflammatory markers. PMS-EAE induction did not cause locomotor changes but triggered depression- and anxiety-like behaviors, which were reversed by sertraline, A-967,079, α-lipoic acid, or apocynin treatments. The neuroinflammatory markers (AIF1, GFAP, IL-1ß, IL-17, and TNF-α) were increased in mice's hippocampus. Moreover, this model did not alter TRPA1 RNA expression levels in the hippocampus but decrease TRPA1 levels in the prefrontal cortex. Moreover, PMS-EAE induced an increase in NADPH oxidase and superoxide dismutase activities and TRPA1 endogenous agonist levels (hydrogen peroxide and 4-hydroxynonenal). TRPA1 plays a fundamental role in depression- and anxiety-like behaviors in a PMS-EAE model; thus, it could be a possible pharmacological target for treating these symptoms in PMS.

Antinociceptive synergism upon the joint use of methadone and Phα1ß in a model of cancer-related pain in C57BL/6J mice.

Opioids are the first-line treatment for cancer pain. Incomplete pain relief and the high rate of adverse effects of these compounds bring a need to combine them with other drugs acting on different targets. AIMS: We here evaluate the antinociceptive interaction and adverse events of methadone combined with recombinant Phα1ß, an analgesic toxin from Phoneutria nigriventer. MAIN METHODS: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw. von Frey filaments measured the paw-withdrawal threshold after administration of methadone, Phα1ß, and their combination. The degree of interaction was evaluated using isobolographic analysis. Spontaneous performance and forced motor performance were assessed with the open-field and rotarod tests, respectively. Intestinal function was evaluated by the distance traveled by charcoal and opioid tolerance was induced by daily morphine injections. KEY FINDINGS: Co-administration of Phα1ß with methadone synergistically reverses the melanoma-induced mechanical hypersensitivity. No motor alterations were observed but mild alterations on intestinal function after treatment with the combination that was also capable of restoring morphine analgesia in the tail-flick test after an opioid-induced tolerance. SIGNIFICANCE: Combinatorial treatment with Phα1ß and methadone produces synergistic analgesic potentiation with potential implications to pain treatment even under opioid tolerance conditions.

Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1ß and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.