¡iAbstract¡j Neurogenic inflammation is an acute inflammatory tissue response, that is mediated by sensory axon reflex. Accompanied with neurogenic inflammation, plasma extravasation, occurs in the eyes, esophagus, bladder, joints, the tip of tongue, and the respiratory tract of the mammal. Recently, many studies have investigated the neurogenic inflammation by electrical stimulation of nerves and intravascular injection of irritants. Upon stimulation, the sensory nerve endings in mucosa can release neuropeptides such as substance P, that causes formation of the venular endothelial gaps, plasma extravasation and tissue edema in various organs. Substance P also cause smooth muscle contraction and mucus secretion in the respiratory tract. Neurogenic plasma extravasation has been studied extensively in the trachea, and bronchi, but rarely in the esophagus. It is known that a plexus of substance P-immunoreactive axons exists in the mucosal and submucosal layers. They play an important role in releasing substance P to act on the receptors of the venular endothelium through diffusion. Based on plasma extravasation and other studies related to the respiratory tract, the purpose of the present study was to investigate neurogenic inflammatory response in the esophagus of the digestive tract. In this study, capsaicin (90 µg/ml/kg) and substance P (3 µg/ml/kg) were used as the irritant and inflammatory mediator, respectively to reduce neurogenic inflammation in the esophagus. India ink was used to label the affected venules. The magnitude of the neurogenic inflammation was expressed as area density of India ink-labeled leaky venules. Histopathological changes in the esophageal tissue were studied under the light microscope. The result of this study indicated that capsaicin at the dose of (90 µg/ml/kg) and substance P at the dose of (3 µg/ml/kg) caused similar magnitude of inflammation in the esophagus. India ink-labeled venules distributed like a network in the mucosal tissue and in connective tissue of the submucosal layer. The upper, middle and lower parts of esophagus exhibited the same degree of inflammatory response, that was similar to that in the lower respiratory tract as the previous studies reported. These results suggest that nerve branches from the vagal trunk send sensory axons to innervate both the esophagus and airways.

In searching for new human pain models that more closely resemble clinical pain states, the capsaicin pain model has emerged as a viable model for both inflammatory and neuropathic pain states. A principal benefit of the capsaicin model is that it allows study of two different pain processes, primary and secondary hyperalgesia. Primary hyperalgesia is characterized by spontaneous pain and both heat and mechanical hyperalgesia. In addition, it is likely the result of activation and sensitization of both peripheral and central nociceptors. In contrast, secondary hyperalgesia is characterized by only mechanical hyperalgesia and is caused by the sensitization of central nociceptive neurons. Previous research utilizing the capsaicin pain model has primarily focused on the neural properties with little focus on the impact of affective states on capsaicin-related pain processes. The present study examined the impact of a noise stressor on both primary and secondary hyperalgesia. Results indicated that the effects of the noise stressor impacted secondary hyperalgesia, but not primary hyperalgesia.

Darbo tikslas Ištirti kosulio reflekso jautrumo pokyčius metus rūkyti sveikiems asmenims ir sergantiems lėtine obstrukcine plaučių liga. Darbo uždaviniai 1. Ištirti ir įvertinti rūkymo metimo poveikį sveikų asmenų kosulio reflekso jautrumui. 2. Ištirti ir įvertinti metusių ir vėl pradėjusių rūkyti sveikų asmenų kosulio reflekso jautrumą. 3. Ištirti ir palyginti sergančių lėtine obstrukcine plaučių liga rūkorių ir sergančių lėtine obstrukcine plaučių liga buvusių rūkorių kosulio reflekso jautrumą. 4. Palyginti sergančių lėtine obstrukcine plaučių liga rūkorių ir sergančių lėtine obstrukcine plaučių liga buvusių rūkorių bei sveikų rūkorių ir sveikų nerūkančiųjų kosulio reflekso jautrumą 5. Ištirti bronchoalveolinio lavažo skysčio ląstelių sudėtį ir uždegimo žymenų (interleukino-8, leukotrieno B4, leukotrieno E4) koncentraciją sergantiems lėtine obstrukcine plaučių liga rūkoriams, sergantiems lėtine obstrukcine plaučių liga buvusiems rūkoriams ir sveikiems rūkoriams. 6. Įvertinti galimas kosulio reflekso jautrumo sąsajas su uždegimo ląstelių kiekiu ir uždegimo žymenų (interleukino-8, leukotrieno B4, leukotrieno E4) koncentracija bronchoalveolinio lavažo skystyje sergantiems lėtine obstrukcine plaučių liga rūkoriams, sergantiems lėtine obstrukcine plaučių liga buvusiems rūkoriams ir sveikiems rūkoriams. Šiame darbe pirmą kartą ištirtas rūkymo metimo poveikis sveikų asmenų kosulio reflekso jautrumui ir sveikų asmenų kosulio reflekso jautrumas jiems metus ir vėl... [toliau žr. visą tekstą] / The aim of the study To evaluate changes of cough reflex sensitivity after smoking cessation in healthy subjects and patients with chronic obstructive pulmonary disease (COPD). Objectives of the study 1. To evaluate the effect of smoking cessation on cough reflex sensitivity changes in healthy subjects. 2. To investigate cough reflex sensitivity changes after cessation and resumption of smoking in healthy subjects. 3. To evaluate and compare cough reflex sensitivity in COPD smokers and COPD ex-smokers. 4. To compare cough reflex sensitivity in COPD smokers and COPD ex-smokers with the cough reflex sensitivity in healthy smokers and healthy never smokers. 5. To evaluate the inflammatory cells count and the concentration of inflammatory mediators (IL-8, LTB4, LTE4) in bronchoalveolar lavage (BAL) fluid from COPD smokers, COPD ex-smokers and healthy smokers. 6. To investigate probable association between cough reflex sensitivity and inflammatory cells count and concentration of inflammatory mediators (IL-8, LTB4, LTE4) in BAL fluid in COPD smokers, COPD ex-smokers and healthy smokers. This is the first study, where the effect of smoking cessation on cough reflex sensitivity in healthy subjects was evaluated and this is the first time, when cough reflex sensitivity in COPD smokers and COPD ex-smokers was evaluated and compared.

This thesis is an investigation of the neurophysiologic mechanism, central sensitization, underlying pain and dysfunction in osteoarthritis. Central sensitization is an important mechanism in the pathophysiology of osteoarthritis but, to our knowledge, its influence on motoneurone excitability is unknown. Our primary hypothesis states that increasing central sensitization within a spinal segment will cause a greater increase in the excitability of motoneurones in subjects with osteoarthritis when compared to healthy controls. To test this hypothesis, we experimentally induced central sensitization in individuals and monitored the recruitment threshold force of the motor units in the first dorsal interosseous muscle using indwelling electromyography. Findings from this study suggest that central sensitization lowers the motor unit recruitment threshold in osteoarthritis compared to healthy individuals. Motoneurone excitability might be inhibited in healthy individuals with persistent sensitization as well. Thus, central sensitization is an important consideration in the biomechanical dysfunction seen in osteoarthritis. / Canadian Arthritis Network

Orientador: Luís Fernando Barbisan / Resumo: A capsaicina (8-metil-N-vanilil-trans-6-nonamida) é uma substância alcaloide de natureza lipofílica, responsável pela pungência de pimentas e pimentões. Apresenta propriedades anti-inflamatória, antimicrobiana e antioxidante bem descritas na literatura científica. Assim, este projeto teve como objetivo investigar se a capsaicina apresenta efeito quimioprotetor quando administrada na etapa de promoção/progressão da carcinogênese de cólon induzida pela 1,2-dimetilhidrazina (DMH). Ratos Wistar machos foram alocados em seis grupos experimentais com 10 a 15 animais cada. Os animais dos grupos 1-3 receberam quatro injeções subcutâneas (s.c) do carcinógeno DMH (40mg/kg, duas doses/semana) e os animais do grupo 4-6 receberam quatro injeções s.c de solução de EDTA .Os grupos 2 e 4 receberam por gavagem 5mg/kg p.c e os grupos 3 e 5 receberam 50mg/kg p.c de capsaicina diluída em óleo de milho até o final da 24ª semana do experimento. Após a eutanásia dos animais, os cólons distal, medial e proximal foram corados com azul de metileno a 2% para detecção de focos de criptas aberrantes (FCA). Após a análise de FCAs, os cólons foram processados para análise histológica e classificação de tumores. As amostras congeladas foram utilizadas para análise de expressão de gênica pela técnica Taqman® Low Density Array (TLDA). Os níveis séricos de ALT (p=0,346) e creatinina (p=0,854) foram semelhantes entre os grupos, mostrando que as doses de capsaicina utilizadas não apresentaram ação citotóxica par... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Capsaicin (8-Methyl-N-vanillyl-(trans)-6-nonenamide) is a lipophilic alkaloid, responsible for the pungency in pepper. Its antiinflamatory, antimicrobial and antioxidant properties are well described in the scientific literature. Thus, the objective of this study was to investigate whether capsaicin exerts a chemoprotective effect when administered during 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis promotion/progression in rates. Male Wistar rats were allocated into six groups of 10-15 animals each. Groups 1-3 received 4 subcutaneous injections of DMH (40 mg/kg bw, 2 doses/week), while groups 4-6 received EDTA solution (DMH vehicle, 2 doses/week), followed by intragastric 5mg/kg bw capsaicin diluted in corn oil (G2, G4) or 50mg/kg bw (G3, G5) for 24 weeks (3 doses/week). After sacrifice, blood samples were drawn by heart puncture for the assessment of serum alanine aminotransferase (ALT) and creatinine levels, and the colon was removed. A segment of distal colon and colon tumor samples were frozen in liquid nitrogen at -80ºC. Distal, medial and proximal colon samples were stained with 2% methylene blue for the detection of aberrant crypt foci (ACF).After ACF analysis, colon tumors were processed for histological analysis and tumor classification. The frozen samples were used for the analysis of gene expression by Taqman® Low Density Array (TLDA). Serum ALT (p=0.346) and creatinine (p=0.854) levels were similar among groups, indicating that the capsaicin doses use... (Complete abstract click electronic access below) / Doutor

Pica, nos hace ponernos rojos, pero también alivia el dolor. La capsaicina es el componente principal del ají, ingrediente de tantas comidas en nuestro país. / It is spicy, it makes us blush, but it also relieves pain. Capsaicin is the main component of chili pepper, an ingredient in so many dishes in our country.

Neste trabalho, avaliou-se a eficácia do uso da oleoresina de capsaicina, extraído das pimentas Malagueta, Red Savina e Bhut Jolokia, no tratamento da superfície de madeiras do gênero Pinus sp. com teores de umidade de equilíbrio de 12% e 0%. Os corpos de prova foram submetidos ao ataque de fungos Paecilomyces variotti e Pycnoporus sanguineus. Foi utilizado um preservante sintético conhecido comercialmente como stain para se comparar com a eficiência de preservantes naturais à base de oleoresina de capsaicina. A partir de medidas de ângulo de contato das superfícies das madeiras tratadas com o óleo de capsaicina, observou-se que a pimenta Bhut Jolokia e o preservante stain proporcionavam menor molhabilidade para a espécie de madeira estudada em ambos teores de umidade. O tratamento preservante fez com que a energia de superfície diminuísse se comparada aos valores de amostras de madeiras sem o tratamento preservante devido às contribuições polares e dispersivas. A análise estatística dos resultados, pelo método de Tukey, mostrou que não existe um grupo de resultados estatisticamente equivalente aos obtidos com a amostra testemunha (sem tratamento). As amostras de Pinus sp. a um teor de umidade 0% mostrou-se mais protegida superficialmente quando modificada com a oleoresina extraída da pimenta Bhut Jolokia e o mesmo efeito foi observado estatisticamente para o preservante stain. A técnica de Langmuir foi utilizada para melhor compreender as interações capsaicina/ergosterol, capsaicina/DPPG (dipalmitoil fosfatidil glicerol) e capsaicina/DPPG/ergosterol. A isotermas de pressão de superfície vs área por molécula se mostraram mais expandidas quando a subfase continha oleoresina de capsacina e quando comparada com as de lipídio puro (DPPG), indicando assim, a inserção da capsaicina na monocamada. Em linhas gerais, oleoresina de capsaicina extraída da pimenta Bhut Jolokia mostrou-se mais eficiente em todos os aspectos se comparada com as pimentas Red Savina e Malagueta, marcando, assim, uma potencialidade para uso como preservante natural de madeiras. / The present study evaluated the effectiveness of capsaicin oleoresin extracted from Malagueta, Red Savina and Bhut Jolokia peppers in the surface treatment of Pinus sp. with moisture contents of 12% and 0%. The samples were submitted to the attack of Paecilomyces variotti and Pycnoporus sanguineus fungus. A synthetic wood preservative, that is commercially known as stain, was used to compare the effectiveness of natural preservatives based on capsaicin oleoresin. From contact angle measurements for wood surfaces treated with capsaicin oleoresin, it was obtained that Bhut Jolokia pepper and stain preservatives have provided worse wettability for wood samples at both moisture contents. The preservative treatment caused a decrease in the surface energy when compared to the samples without preservative treatment due to polar and dispersive contributions. Statistical analysis for the results by using the Tukey method showed that there is not a group of results that are statistically equivalent to those obtained for the control samples (without treatment). Pinus sp. samples at a moisture content of 0% showed to be more surface protected after being modified with the oleoresin extracted from Bhut Jolokia; the same effect was observed statistically for stain. The Langmuir technique was used to better understand interactions among capsaicin/ergosterol, capsaicin/DPPG (dipalmitoyl phosphatidyl glycerol) and capsaicin/DPPG/ergosterol. Surface pressure vs. area per molecule isotherms appeared to be even more extended when the subphase contained capsaicin oleoresin instead of pure lipid (DPPG), thus indicating the inclusion of capsaicin into the monolayer. In general, the capsaicin oleoresin extracted from Bhut Jolokia proved to be more efficient in all the aspects of characterization when compared to Red Savina and Malagueta highlighting its potential for use as a natural wood preservative.

Nesse estudo, utilizamos a oleoresina de capsaicina, extraído da pimenta Malagueta (Capsicum frutensens) e da pimenta Dedo-de-moça (Capsicum baccatum), para a preservação de amostras de madeira contra o ataque do fungo Paecilomyces variotti. Os preservantes naturais foram aplicados em corpos de prova de madeiras do gênero Pinus sp. e Hymenae sp. (Jatobá) com as dimensões 5,0 x 3,0 x 1,0 (cm). A seguir, esses corpos de prova foram expostos ao fungo para o acompanhamento do seu desenvolvimento. As análises mostraram que o preservante natural retardou o crescimento do fungo, sendo a oleoresina de capsaicina extraído da pimenta Malagueta a mais eficiente se comparada à oleoresina extraída da pimenta Dedo-de-moça e ao óleo de linhaça. A partir da medida de ângulo de contato observou-se que o preservante de oleoresina da pimenta Malagueta proporcionava uma maior molhabilidade para as duas espécies de madeiras. A técnica de FTIR-ATR indicou que os preservantes não modificaram a estrutura das madeiras e a análise de raios X revelou que o desenvolvimento do fungo provocou uma perda de estabilidade e periodicidade nas estruturas das madeiras. Através do teste de proporção utilizado para a análise do desenvolvimento do fungo, comprovou-se estatisticamente que o seu crescimento foi menor para as amostras com os preservantes das pimentas. Pelo MEV foi possível visualizar as estrutura de hifas do fungo sobre a madeira. E a perda de massa para ambas as espécies de madeiras foram menores quando foram utilizados os preservantes, sendo o Pinus a espécie que sofreu maior degradação. / In this study, were used the oleoresin capsaicin, extracted from Capsicum frutensens and Capsicum baccatum, for the preservation of wood samples against the attack of the Paecilomyces variotti fungus. The natural preservatives were applied to Pinus sp. and Hymenaea sp. (Jatobá) specimens with the dimensions 5.0 x 3.0 x 1.0 (cm). Subsequently, these specimens were exposed to fungus and their development was monitored. . Analyses showed that the natural preservative slowed the growth of the fungus. Action of the oleoresin capsaicin extracted from Chilli pepper is the most efficient when compared to pepper oleoresin extracted from Capsicum frutensens and Capsicum baccatum and also with the linseed oil. The contact angle measured showed that the preservative of Oleoresin Chilli Pepper offered a higher wettability for both wood species. FTIR-ATR technique indicated that the preservatives did not change wood structure and X-ray analysis revealed that the development of the fungus caused a loss of stability and periodicity in the wood structures. At proportion test to analyze the development of the fungus, it was shown statistically that their growth was lower for the samples with preservatives peppers. It was possible to visualize the hyphae structure by scanning electronic microscopy technique. Mass loss of both wood specie was lower when preservative was used, and Pine species was more degraded.

abstract: Transient receptor potential vanilloid member 1 (TRPV1) is a membrane protein ion channel that functions as a heat and capsaicin receptor. In addition to activation by hot temperature and vanilloid compounds such as capsaicin, TRPV1 is modulated by various stimuli including acidic pH, endogenous lipids, diverse biological and synthetic chemical ligands, and modulatory proteins. Due to its sensitivity to noxious stimuli such as high temperature and pungent chemicals, there has been significant evidence that TRPV1 participates in a variety of human physiological and pathophysiological pathways, raising the potential of TRPV1 as an attractive therapeutic target. However, the polymodal nature of TRPV1 function has complicated clinical application because the TRPV1 activation mechanisms from different modes have generally been enigmatic. Consequently, tremendous efforts have put into dissecting the mechanisms of different activation modes, but numerous questions remain to be answered. The studies conducted in this dissertation probed the role of the S1-S4 membrane domain in temperature and ligand activation of human TRPV1. Temperature-dependent solution nuclear magnetic resonance (NMR) spectroscopy for thermodynamic and mechanistic studies of the S1-S4 domain. From these results, a potential temperature sensing mechanism of TRPV1, initiated from the S1-S4 domain, was proposed. Additionally, direct binding of various ligands to the S1-S4 domain were used to ascertain the interaction site and the affinities (Kd) of various ligands to this domain. These results are the first to study the isolated S1-S4 domain of human TRPV1 and many results indicate that the S1-S4 domain is crucial for both temperature-sensing and is the general receptor binding site central to chemical activation. / Dissertation/Thesis / Doctoral Dissertation Biochemistry 2019

Background: Patients with nonallergic irritant rhinitis (NAIR) have symptoms of nasal congestion, nasal irritation, rhinorrhea, and sneezing in response to nasal irritants. We currently have no reliable objective means to quantify these patients' subjective symptoms. In this study, we used the transient receptor potential vanilloid receptor (TRPV1) receptor agonist, capsaicin, as an intranasal challenge while comparing the changes in blood flow with optical rhinometry between subjects with NAIR and healthy controls (HCs). Methods: Six HCs and 6 NAIR subjects were challenged intranasally with saline solution followed by increasing concentrations of capsaicin (0.005 mM, 0.05 mM, and 0.5 mM) at 15-minute intervals. We recorded maximum optical density (OD) and numeric analog scores (NAS) for nasal congestion, nasal irritation, rhinorrhea, and sneezing for each subject after each challenge. Correlations between NAS and maximum OD were calculated. Results: Maximum OD increased with increasing concentrations of intranasal capsaicin in NAIR subjects. There were significant differences in maximum OD obtained for 0.05 mM and 0.5 mM capsaicin between NAIR subjects and HCs. Significant differences were found in the NAS for nasal irritation at 0.005 mM, 0.05 mM, and 0.5 mM, and nasal congestion at 0.5 mM. Correlation between maximum OD and mean NAS was most significant for 0.05 mM capsaicin. Conclusion: Optical rhinometry with intranasal capsaicin challenge could prove a viable option in the diagnosis of NAIR. Further studies will investigate its use to monitor a patient's response to pharmacologic therapy and provide further information about the underlying mechanisms of NAIR.