Activation of beta2-adrenergic receptors alleviates neuropathic pain hypersensitivity in mice: focus on spinal glial cells

Chronic pain affects roughly one-fifth of the world’s population, and many patients do not respond to current therapies or conventional analgesics. Thus, studying the molecular mechanisms underlying neuropathic pain is crucial in identifying novel molecular targets that can be used to develop effective pain relief therapies. Previous studies have thus far focused on α2-adrenergic receptors (α2-ARs) and neuronal excitability, among others. However, recent research suggests that astrocytes and microglia, which express adrenergic receptors, contribute significantly to neuropathic pain. In particular, microglia have been found to express elevated levels of Gs-coupled β2-AR and they are responsive to norepinephrine application. Additionally, systemic administration of β2-AR agonists, such as Formoterol, has anti-inflammatory and anti-nociceptive properties in neuropathic pain, but the underlying processes are poorly understood. Therefore, this thesis work focuses on investigating glial noradrenergic signaling via β2-AR, specifically on microglia and its contribution to the modulation of neuropathic pain in mice. In the present study, activation of the β2-ARs through Formoterol induced a decrease of anti-inflammatory cytokine levels in primary isolated microglia and reversed nerve injury-induced morphological alterations in spinal dorsal horn microglia. Systemic administration of Formoterol inhibited evoked behaviors as well as aversive components related to neuropathic pain and reduced chronically-established neuropathic pain. The analgesic effects of Formoterol were mainly mediated by microglia, as demonstrated by employing the conditional knock-out mouse line lacking the β2-AR specifically in microglia. Remarkably, the effect of Formoterol on neuropathic pain-related behavior and microgliosis was lost in mice with the microglia-specific deletion of β2-ARs. In addition, microglia phenotype showed a sex-dependency in the late phase of neuropathic pain, which was not observed in response to β2-AR stimulation. Notably, Formoterol also reduced astrogliosis in the late stage of neuropathic pain independently of β2-AR signaling in microglia. Collectively, this work highlights the impact of microglial β2-AR stimulation in mediating the inhibition of pro-inflammatory signaling in the spinal cord during the initial phase of neuropathic pain. These results emphasize the importance of exploring microglial β2-AR agonists in alleviating neuropathic pain and elucidating the underlying mechanisms

Astrocytes and Microglia Exhibit Cell-Specific Ca2+ Signaling Dynamics in the Murine Spinal Cord

The spinal cord is the main pathway connecting brain and peripheral nervous system. Its functionality relies on the orchestrated activity of both neurons and glial cells. To date, most advancement in understanding the spinal cord inner mechanisms has been made either by in vivo exposure of its dorsal surface through laminectomy or by acute ex vivo slice preparation, likely affecting spinal cord physiology in virtue of the necessary extensive manipulation of the spinal cord tissue. This is especially true of cells immediately responding to alterations of the surrounding environment, such as microglia and astrocytes, reacting within seconds or minutes and for up to several days after the original insult. Ca2+ signaling is considered one of the most immediate, versatile, and yet elusive cellular responses of glia. Here, we induced the cell-specific expression of the genetically encoded Ca2+ indicator GCaMP3 to evaluate spontaneous intracellular Ca2+ signaling in astrocytes and microglia. Ca2+ signals were then characterized in acute ex vivo (both gray and white matter) as well as in chronic in vivo (white matter) preparations using MSparkles, a MATLAB-based software for automatic detection and analysis of fluorescence events. As a result, we were able to segregate distinct astroglial and microglial Ca2+ signaling patterns along with method-specific Ca2+ signaling alterations, which must be taken into consideration in the reliable evaluation of any result obtained in physiological as well as pathological conditions. Our study revealed a high degree of Ca2+ signaling diversity in glial cells of the murine spinal cord, thus adding to the current knowledge of the astonishing glial heterogeneity and cell-specific Ca2+ dynamics in non-neuronal networks

MÚSCULO ADUTOR DO POLEGAR: PREDITOR DE DESNUTRIÇÃO EM PACIENTES COM CÂNCER DE CABEÇA E PESCOÇO

Este estudo teve como objetivo descrever a medida da espessura do músculo adutor do polegar (MAP) como preditor de desnutrição em pacientes oncológicos. Trata-se de um estudo quantitativo de delineamento transversal com pacientes em tratamento oncológico com diagnóstico de câncer de cabeça e pescoço. Os dados foram coletados através de uma ficha de anamnese nutricional que aborda dados demográficos, clínicos e antropométricos. Para a avaliação antropométrica, utilizou-se os seguintes parâmetros: índice de massa corporal (IMC), circunferência do braço (CB), prega cutânea tricipital (PCT), circunferência muscular do braço (CMB), área muscular do braço corrigida (AMBc), músculo adutor do polegar da mão dominante (MAPD), músculo adutor do polegar da mão não dominante (MAPND) e percentual de perda de peso (%PP). Os resultados indicaram maior prevalência do sexo masculino (82,1%) com média de idade de 64,57±12,52 anos. Quanto à localização do tumor, constatamos maior prevalência de câncer de laringe (28,6%), seguido de câncer de cavidade oral (25%) e câncer de orofaringe (17,9%). Segundo o IMC, a maioria dos pacientes encontravam-se eutróficos (46,4%). A desnutrição esteve mais prevalente através das medidas de CB, PCT, AMBc, MAPD e MAPND. Foi diagnosticado que 78,6% dos pacientes estavam desnutridos segundo a medida do MAP das mãos dominante e não dominante. Os resultados sugerem que a medida do MAP pode ser um método sensível para identificação da desnutrição, contudo, se fazem necessários mais estudos com o objetivo de verificar a eficácia desta medida, proporcionando assim, uma maior compreensão da utilização da mesma para esses pacientes

Axon Guidance Molecules and Pain

Chronic pain is a debilitating condition that influences the social, economic, and psychological aspects of patients’ lives. Hence, the need for better treatment is drawing extensive interest from the research community. Developmental molecules such as Wnt, ephrins, and semaphorins are acknowledged as central players in the proper growth of a biological system. Their receptors and ligands are expressed in a wide variety in both neurons and glial cells, which are implicated in pain development, maintenance, and resolution. Thereby, it is not surprising that the impairment of those pathways affects the activities and functions of the entire cell. Evidence indicates aberrant activation of their pathways in the nervous system in rodent models of chronic pain. In those conditions, Wnt, ephrin, and semaphorin signaling participate in enhancing neuronal excitability, peripheral sensitization, synaptic plasticity, and the production and release of inflammatory cytokines. This review summarizes the current knowledge on three main developmental pathways and their mechanisms linked with the pathogenesis and progression of pain, considering their impacts on neuronal and glial cells in experimental animal models. Elucidations of the downstream pathways may provide a new mechanism for the involvement of Wnt, ephrin, and semaphorin pathways in pain chronicity

Activation of β2-Adrenergic Receptors in Microglia Alleviates Neuropathic Hypersensitivity in Mice

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings

Assessment of nutritional status in oncological elderly patients admitted to a high complexity hospital of the North of Rio Grande do Sul

Aims: To assess the nutritional risk in hospitalized oncological elderly patients. Methods: Retrospective study conducted with oncological elderly patients hospitalized at the São Vicente de Paulo Hospital, in Passo Fundo, Rio Grande do Sul, Brazil. Patients with cancer who underwent anthropometric and subjective evaluation by the Mini Nutritional Assessment Reduced Forms were selected. Data were collected from the research form used by the National Cancer Institute, including clinical evaluation, type of cancer, reason for hospital admission and length of stay. Results: A total of 70 elderly patients with cancer, of both genders, with a mean age of 72.94±6.93 years, were evaluated. All patients with pancreatic cancer had weight loss. Patients with lung cancer and pancreatic cancer had the highest percentage of severe weight loss (greater than 10% of usual weight in the last six months), 57.1% and 40% respectively, while the majority of breast cancer cases had no weight loss. Body mass index and calf circumference diagnosed greater proportion of normal weight (55.7% and 65.7%, respectively), unlike the Mini Nutritional Assessment Reduced Forms, that identified higher rates of malnutrition or nutritional risk (84.4%). Conclusions: Most hospitalized oncological elderly were found to be eutrophic by the anthropometric indicators body mass index and calf circumference, while a higher proportion of these patients were classified as malnourished or at nutritional risk by the Mini Nutritional Assessment Reduced Forms, as well as by the percentage of weight loss. Patients with lung and pancreas cancer had the most severe weight loss. These results confirm the importance of using different parameters to assess the nutritional status of elderly with cancer

Avaliação do estado nutricional em pacientes idosos oncológicos internados em um hospital de alta complexidade do Norte do Rio Grande do Sul = Assessment of nutritional status in oncological elderly patients admitted to a high complexity hospital of the North of Rio Grande do Sul

Objetivos: Avaliar o risco nutricional em pacientes idosos oncológicos hospitalizados. Métodos: Estudo retrospectivo transversal realizado com pacientes idosos oncológicos internados no Hospital São Vicente de Paulo, em Passo Fundo, Rio Grande do Sul. Foram selecionados os pacientes com câncer que passaram pela avaliação antropométrica e subjetiva por meio da Mini Avaliação Nutricional Reduzida. Os dados foram coletados do formulário de investigação utilizado pelo Instituto Nacional de Câncer, incluindo avaliação de dados clínicos, tipo de câncer, motivo e tempo de internação. Resultados: Foram avaliados 70 idosos com câncer, de ambos os sexos, com média de idade de 72,94±6,93 anos. Todos os pacientes com câncer de pâncreas apresentaram perda de peso. Os pacientes com câncer de pulmão e de pâncreas foram os que apresentaram maior porcentagem de perda de peso grave (maior que 10% do peso habitual nos últimos seis meses), 57,1% e 40% respectivamente, enquanto a maioria dos casos de câncer de mama não tinham perda de peso. O índice de massa corporal e a circunferência da panturrilha diagnosticaram maior proporção de eutrofia (55,7% e 65,7%, respectivamente), diferentemente da Mini Avaliação Nutricional Reduzida, que identificou maiores percentuais de desnutrição ou risco nutricional (84,4%) Conclusões: A maioria dos idosos oncológicos hospitalizados encontravam-se eutróficos pelos indicadores antropométricos índice de massa corporal e circunferência da panturrilha, enquanto uma proporção maior desses pacientes foram classificados como desnutridos ou em risco nutricional pela Mini Avaliação Nutricional Reduzida, assim como pela porcentagem de perda de peso. Os pacientes com câncer de pulmão e pâncreas foram os que mais apresentaram perda de peso grave. Os presentes resultados confirmam a importância de usar diferentes parâmetros para avaliar o estado nutricional de idosos oncológico