Enhancing M Currents: A Way Out for Neuropathic Pain?

Almost three decades ago, the M current was identified and characterized in frog sympathetic neurons (Brown and Adams, 1980). The years following this discovery have seen a huge progress in the understanding of the function and the pharmacology of this current as well as on the structure of the underlying ion channels. Therapies for a number of syndromes involving abnormal levels of excitability in neurons are benefiting from research on M currents. At present, the potential of M current openers as analgesics for neuropathic pain is under discussion. Here we offer a critical view of existing data on the involvement of M currents in pain processing. We believe that enhancement of M currents at the site of injury may become a powerful strategy to alleviate pain in some peripheral neuropathies

Fosfoetanolamina sintética: a judicialização da saúde na busca por milagres, inconsequência jurídica ou prestação do dever estatal?

Trabalho de Conclusão de Curso (Graduação)A partir da distribuição da Fosfoetanolamina Sintética por um pesquisador do Instituto de Química da Universidade de São Paulo para pessoas com câncer - sob a alegação de que esta seria capaz de auxiliar no tratamento podendo ocasionar, inclusive, a cura - o judiciário foi abarrotado com demandas requerendo a produção e concessão da seguinte pílula. Diante de inúmeras súplicas materializadas em petições, numerosas decisões foram articuladas em sentido favorável à concessão da Fosfoetanolamina Sintética. No entanto, a substância referida faz-se totalmente experimental, isenta de qualquer estudo austero e comprovação científica que ao menos venha a indicar provável eficácia. Sendo assim, tais circunstâncias em que o judiciário vem a sobrepujar diretrizes terapêuticas determinadas pelo ordenamento jurídico, em prol da vontade da parte autora legitimada pelo seu direito subjetivo à saúde, geram a problematização se consistiriam em uma tentativa de prestação do dever de saúde do Estado ou em mera inconsequência jurídica. A fim de desvendar e discorrer acerca de tal problemática serão analisadas na pesquisa ações nas quais foi requerida a concessão da substância Fosfoetanolamina Sintética, ajuizadas no período referente aos meses de novembro e dezembro do ano de 2015 e de janeiro e fevereiro do ano de 2016, todas interpostas contra o Estado de Santa Catarina

Associação de padrões alimentares com a inflamação e desfechos cardiovasculares em adultos: uma revisão sistemática

TCC(graduação)- Universidade Federal de Santa Catarina. Centro de Ciências da Saúde. Nutrição.Introdução: A alimentação tem se mostrado um importante fator influenciador na inflamação, que por sua vez, possui relação direta com as doenças cardiovasculares. Estudos recentes demonstram as vantagens de se utilizar padrões alimentares para avaliar o efeito da dieta na saúde. Objetivo: Investigar se padrões alimentares estão associados com marcadores de inflamação e desfechos cardiovasculares em adultos. Metodologia: A revisão sistemática foi realizada nas bases de dados PubMed, Scopus, Scielo e Google Acadêmico, na data de 08 de Março de 2019. Foram incluídos estudos observacionais e ensaios clínicos (EC) com adultos descrevendo padrões alimentares a priori ou a posteriori e que analisassem a associação entre marcadores de inflamação e desfechos cardiovasculares. Resultados: 20 artigos apresentaram todos os critérios de inclusão e exclusão e foram selecionados para esta revisão. O principal padrão alimentar encontrado a priori foi a Dieta Mediterrânea (DM), avaliada em 10 artigos por meio do escore de aderência ou como intervenções nos EC. A DM foi associada com a diminuição de marcadores de inflamação, principalmente da proteína C reativa (PCR), e dos desfechos cardiovasculares. Padrões alimentares a posteriori caracterizados pelo consumo de cereais refinados, carnes e processados, foram associados positivamente em sete estudos com marcadores de inflamação, como a PCR. Similarmente, desfechos cardiovasculares, tais como risco cardiovascular ou moléculas de adesão elevadas, foram associados positivamente em sete estudos com padrões alimentares caracterizados pelo consumo de gorduras hidrogenadas, cereais refinados, carnes vermelhas, álcool e doces. Por outro lado, padrões alimentares caracterizados pelo consumo de frutas, legumes, azeite de oliva e cereais integrais apresentaram associação inversa com marcadores de inflamação em cinco estudos. Conclusão: A adesão à DM e padrões alimentares caracterizados pelo consumo de frutas, legumes, azeite de oliva e cereais integrais foram associados à redução dos marcadores de inflamação e desfechos cardiovasculares. Por outro lado, padrões alimentares com alto índice inflamatório da dieta e caracterizados pelo alto consumo de cereais refinados, carnes e processados, gorduras hidrogenadas, álcool e doces foram associados ao aumento dos marcadores de inflamação e desfechos cardiovasculares. A adesão a DM e aos padrões alimentares benéficos deve ser estimulada para promoção da saúde cardiovascular

Identification of Potential Visceral Pain Biomarkers in Colon Exudates from Mice with Experimental Colitis: An Exploratory In Vitro Study

Chronic visceral pain (CVP) is extremely difficult to diagnose, and available analgesic treatment options are quite limited. Identifying the proteins secreted from the colonic nociceptors, or their neighbor cells within the tube walls, in the context of disorders that course with visceral pain, might be useful to decipher the mechanism involved in the establishment of CVP. Addressing this question in human with gastrointestinal disorders entails multiple difficulties, as there is not a clear classification of disease severity, and colonic secretion is not easy to manage. We propose using of a murine model of colitis to identify new algesic molecules and pathways that could be explored as pain biomarkers or analgesia targets. Descending colons from naïve and colitis mice with visceral hyperalgesia were excised and maintained ex vivo. The proteins secreted in the perfusion fluid before and during acute noxious distension were evaluated using high-resolution mass spectrometry (MS). Haptoglobin (Hp), PZD and LIM domain protein 3 (Pdlim3), NADP-dependent malic enzyme (Me1), and Apolipoprotein A-I (Apoa1) were increased during visceral insult, whilst Triosephosphate isomerase (Tpi1), Glucose-6-phosphate isomerase (Gpi1), Alpha-enolase (Eno1), and Isoform 2 of Tropomyosin alpha-1 chain (Tpm1) were decreased. Most identified proteins have been described in the context of different chronic pain conditions and, according to gene ontology analysis, they are also involved in diverse biological processes of relevance. Thus, animal models that mimic human conditions in combination with unbiased omics approaches will ultimately help to identify new pathophysiological mechanisms underlying pain that might be useful in diagnosing and treating pain. Perspective: Our study utilizes an unbiased proteomic approach to determine, first, the clinical relevance of a murine model of colitis and, second, to identify novel molecules/pathways involved in nociception that would be potential biomarkers or targets for chronic visceral pain

Origin and classification of spontaneous discharges in mouse superficial dorsal horn neurons

Superfcial laminae of the spinal cord possess a considerable number of neurons with spontaneous activity as reported in vivo and in vitro preparations of several species. Such neurons may play a role in the development of the nociceptive system and/or in the spinal coding of somatosensory signals. We have used electrophysiological techniques in a horizontal spinal cord slice preparation from adult mice to investigate how this activity is generated and what are the main patterns of activity that can be found. The results show the existence of neurons that fre regularly and irregularly. Within each of these main types, it was possible to distinguish patterns of spontaneous activity formed by single action potentials and diferent types of bursts according to intra-burst fring frequency. Activity in neurons with irregular patterns was blocked by a mixture of antagonists of the main neurotransmitter receptors present in the cord. Approximately 82% of neurons with a regular fring pattern were insensitive to synaptic antagonists but their activity was inhibited by specifc ion channel blockers. It is suggested that these neurons generate endogenous activity due to the functional expression of hyperpolarisation activated and persistent sodium currents driving the activity of irregular neuronsMinisterio de Economía y Competitivida

Pyrethroids inhibit K2P channels and activate sensory neurons: basis of insecticide-induced paraesthesias

Pyrethroid insecticides are widely used for pest control in agriculture or in human public health commonly as a topical treatment for scabies and head lice. Exposure to pyrethroids such as permethrin or tetramethrin (TM) causes sensory alterations such as transient pain, burning, stinging sensations, and paraesthesias. Despite the well-known effects of pyrethroids on sodium channels, actions on other channels that control sensory neuron excitability are less studied. Given the role of 2-pore domain potassium (K2P) channels in modulating sensory neuron excitability and firing, both in physiological and pathological conditions, we examined the effect of pyrethroids on K2P channels mainly expressed in sensory neurons. Through electrophysiological and calcium imaging experiments, we show that a high percentage of TM-responding neurons were nociceptors, which were also activated by TRPA1 and/or TRPV1 agonists. This pyrethroid also activated and enhanced the excitability of peripheral saphenous nerve fibers. Pyrethroids produced a significant inhibition of native TRESK, TRAAK, TREK-1, and TREK-2 currents. Similar effects were found in transfected HEK293 cells. At the behavioral level, intradermal TM injection in the mouse paw produced nocifensive responses and caused mechanical allodynia, demonstrating that the effects seen on nociceptors in culture lead to pain-associated behaviors in vivo. In TRESK knockout mice, pain-associated behaviors elicited by TM were enhanced, providing further evidence for a role of this channel in preventing excessive neuronal activation. Our results indicate that inhibition of K2P channels facilitates sensory neuron activation and increases their excitability. These effects contribute to the generation of paraesthesias and pain after pyrethroid exposure

Lysophosphatidic Acid and Glutamatergic Transmission

Signaling through bioactive lipids regulates nervous system development and functions. Lysophosphatidic acid (LPA), a membrane-derived lipid mediator particularly enriched in brain, is able to induce many responses in neurons and glial cells by affecting key processes like synaptic plasticity, neurogenesis, differentiation and proliferation. Early studies noted sustained elevations of neuronal intracellular calcium, a primary response to LPA exposure, suggesting functional modifications of NMDA and AMPA glutamate receptors. However, the crosstalk between LPA signaling and glutamatergic transmission has only recently been shown. For example, stimulation of presynaptic LPA receptors in hippocampal neurons regulates glutamate release from the presynaptic terminal, and excess of LPA induce seizures. Further evidence indicating a role of LPA in the modulation of neuronal transmission has been inferred from animal models with deficits on LPA receptors, mainly LPA1 which is the most prevalent receptor in human and mouse brain tissue. LPA1 null-mice exhibit cognitive and attention deficits characteristic of schizophrenia which are related with altered glutamatergic transmission and reduced neuropathic pain. Furthermore, silencing of LPA1 receptor in mice induced a severe down-regulation of the main glutaminase isoform (GLS) in cerebral cortex and hippocampus, along with a parallel sharp decrease on active matrix-metalloproteinase 9. The downregulation of both enzymes correlated with an altered morphology of glutamatergic pyramidal cells dendritic spines towards a less mature phenotype, indicating important implications of LPA in synaptic excitatory plasticity which may contribute to the cognitive and memory deficits shown by LPA1-deficient mice. In this review, we present an updated account of current evidence pointing to important implications of LPA in the modulation of synaptic excitatory transmission

Pharmacological activation of dopamine D4 receptor prevents morphine-induced impairment of the subventricular adult neurogenesis: functional implications in odor discrimination learning.

Morphine reduces adult neurogenesis in the subventricular zone (SVZ) and therefore the integration of newly generated neurons in the local olfactory bulb (OB) circuit. However, the effects of opioids drugs on the olfactory perception have been scarce studied, although some data suggests that they interfere with olfactory function. We have previously shown that the activation of the dopamine D4 receptor (D4R) prevents both morphine addiction -by modulating dopamine signaling from nigral dopamine cells- and the development of morphine-induced analgesic tolerance -by regulating the primary circuit of pain and GABA/glutamate balance within the dorsal horn. Here, we hypothesize that the D4R could also counteract the impairment of olfaction associated with morphine. We investigated the effect of chronic paradigm of combined treatment of morphine with the D4R agonist PD168,077 on SVZ neurogenesis in adult rats using immunohistochemistry and its functional implications by an olfactory discrimination test. Results showed that, in the SVZ, D4R activation counteracted morphine-induced depletion of newly generated glial cells (astrocytes and oligodendrocytes) and neuroblasts as well as the increase of tyrosine hydroxylase expression. Besides, three weeks of chronic administration of morphine impaired olfactory discrimination between a pair of odorants, which was completely prevented by the co-administration with PD168,077. The present results give support for the existence of antagonistic functional D4R-MOR interaction in olfactory bulb and SVZ that could help to the development of new pharmacology strategies for the treatment of pain reducing side-effects of morphine.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. CTS161, Junta de Andalucía UMA20-FEDERJA-122, Junta de Andalucí

Seleção de genótipos de aveia-branca para condições contrastantes de manejo de fungicida

The objective of this work was to select white oat (Avena sativa) genotypes for environments with and without fungicide application, as well as to identify relationships between meteorological variables and agronomic traits. Two experiments were carried out: one without and the other with the use of the tebuconazole fungicide. In each experiment, 26 genotypes were evaluated, conducted during ten years in the same experimental area; cultivation years were considered as one environment. The methodologies of genotype and of the genotypes x environments interaction were used to define the ideal genotype. 'URS Corona' is considered an ideal genotype due to its excellent responses in the environment with tebuconazole. The 'Brisasul', 'IPR Aphrodite', and 'URS Taura' genotypes respond better in the environment without the fungicide. However, based on multitraits, the 'URS Taura' and 'IPR Afrodite' genotypes can be positioned in environments with or without the use of tebuconazole. Genotypes with a rust incidence lower than 15% and a height higher than 93 cm in an environment with a relative humidity lower than 70.75% have a higher grain yield regardless of fungicide use. Greater magnitudes of air temperature and solar radiation result in a higher grain yield of white oat, regardless of fungicide use.O objetivo deste trabalho foi selecionar genótipos de aveia-branca (Avena sativa) para ambientes com e sem aplicação de fungicidas, bem como identificar relações entre variáveis meteorológicas e características agronômicas. Dois experimentos foram conduzidos: um sem e outro com o uso do fungicida tebuconazole. Em cada experimento, foram avaliados 26 genótipos, conduzidos durante dez anos na mesma área experimental; os anos de cultivo foram considerados como um ambiente. As metodologias de genótipos e da interação genótipos x ambientes foram utilizadas para definir o genótipo ideal. 'URS Corona' é considerado um genótipo ideal devida às suas ótimas respostas em ambiente com uso de tebuconazole. Já os genótipos 'Brisasul', 'IPR Afrodite' e 'URS Taura'  respondem melhor em ambiente sem o fungicida. Contudo, com base em multicaracterísticas, os genótipos 'URS Taura' e 'IPR Afrodite' podem ser posicionados em ambientes com ou sem o uso de tebuconazole. Genótipos com incidência de ferrugem menor que 15% e altura maior que 93 cm, em ambiente com umidade relativa menor que 70,75%, apresentam maior produtividade de grãos independentemente do uso de fungicida. Maiores magnitudes de temperatura do ar e radiação solar resultam em maior produtividade de grãos de aveia-branca, independentemente do uso de fungicida