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Background: Pain plays roles in both the nervous system and immune system. Changes in the neuroendocrine pathway under pain conditions give rise to sympathetic outflow with increased plasma catecholamines and activate immune reactions. Dexmedetomidine exerts sedative, analgesic, and anesthetic-sparing effects and is known to diminish pro-inflammatory processes by central sympatholytic effects. To investigate the influence of the analgesic effect of dexmedetomidine on immunomodulation under pain conditions, splenic natural killer (NK) tumoricidal cytotoxic activity, proliferative ability of T lymphocytes, and cytokine changes were assessed. Methods: After evaluation of the analgesic efficacy of dexmedetomidine in C57BL mice that were subjected to formalin-induced pain, dexmedetomidine (30 µg/kg) or saline was injected intraperitoneally (ip) 30 min before formalin (20 µL of 2% formalin in 0.9% saline) injection. NK cell activity against NK-sensitive YAC-1 lymphoma cells was evaluated by the percentage of specific lactate dehydrogenase (LDH) release. Various numbers of effector cells (NK cells) were added to the wells of a microtiter plate containing 2 × 104 target YAC-1 cells in 100 μL, to achieve final effector-to-target cell ratios of 80:1, 40:1, and 20:1. The level of lymphocyte proliferation in response to phytohemagglutinin (PHA) was detected by bromodeoxyuridine (BrdU) incorporation assay. TNF-α, IL-1β, and IL-10 levels were determined in blood samples and supernatants of splenocyte preparations. Results: IP administration of dexmedetomidine significantly decreased the time of licking and biting during the first and second phases of the formalin test (p

Background. The increase of NSAIDs safety is current direction of modern pharmacology, because of so-called "class-specific" adverse reactions, which are common to this class, and the leading place among them is occupied by gastro-intestinal toxicity. In previous studies we have proved the ability of vinboron to neutralize ulcerogenic effect of ibuprofen (Hladkykh F.V. and al., 2014). The presence of the proven analgesic activity in the domestic antispasmodics (Stepaniuk H.I. and al., 2007) serves as the basis for research of vinboron action on analgesic aspect of ibuprofen pharmacotherapeutic effec.Aim is to conduct research in silico of the relation «molecular structure – anelgetic activity» of vinboron and to prove experimentally in vivo the practicability of vinboron using with the aim to increase the analgesic activity of ibuprofen on the model of adjuvant arthritis in rats.Materials and methods. The study of the relation «molecular structure – activity anelgetic» of vinboron was conducted in silico by PASS- analysis of biological activity spectrum. The analysis was set online with direct insertion of structural formula of vinboron in browser using Marvin JS web-resource «PASS Online» (http://www.way2drug.com/passonline). Analgesic activity in vivo was studied on the model of acute thermal pain, which was simulated in the conventional behavioral test of nociception «Hot plate». The lag of pain reaction was determined at the beginning («0» day), on 7, 14, 21 and 28 days of experiment.Results and discussion. According to the PASS-forecast the mechanisms of vinboron analgesic activity is caused by agonism towards the vanilloid (TRPV1) receptors (Pa=0,490; Pi=0,008), agonism to the μ (mu) – receptor (Pa=0,323; Pi=0,036), inhibition of GABA (Pa=0,329; Pi=0,089) and others. Experimental studies have shown that the combined administration of ibuprofen and vinboron analgesic activity was higher than the results by ibuprofen monotherapy at a dose of 73 mg/kg up by 15.3%, and at a dose of 218 mg/kg up by 20.4%. Besides, it is worthwhile to note that analgesic activity during the integrated administration of ibuprofen at a dose of 218 mg/kg and vinboron (+39.8%) was higher than the total analgesic activity of ibuprofen monotherapy at the same dose (+19.4%) and monotherapy of vinboron (+10.9%), that points at potentiation of analgesic effect of both drugs during their integrated administration.Conclusions. According to the PASS-analysis, the leading mechanism in analgesic component implementation of vinboron is its agonism to TRPV1. The results of our in vivo studies point at the ability of vinboron to intensify the antinociceptive activity of ibuprofen., Актуальным направлением современной фармакологии является повышение безопасности нестероидных противовоспалительных препаратов, поскольку для них характерны так называемые «класс-специфические» побочные реакции, ведущее место среди которых занимает гастротоксичность. В предыдущих исследованиях нами была доказана способность винборона нивелировать ульцерогенный эффект ибупрофена (Гладких Ф. В. и соавт., 2014), а наличие у отечественного спазмолитика доказанной собственной болеутоляющей активности (Степанюк Г. И. и соавт., 2007) служат основой исследования влияния винборона на анальгетический компонент фармакотерапевтического эффекта ибупрофена.Цель работы – провести in silico исследование взаимосвязи «молекулярная структура – анальгетическая активность» винборона и экспериментально in vivo обосновать целесообразность применения винборона с целью повышения анальгезирующей активности ибупрофена на модели адъювантного артрита у крыс.Материалы и методы. Исследование взаимосвязи «молекулярная структура – анальгетическая активность» винборона выполнено in silico с помощью PASS-анализа спектра биологической активности, который проводили в режиме online при непосредственном введении структурной формулы винборона в браузере, используя Marvin JS web-ресурса «PASS Online» (http://www.way2drug.com/passonline). Анальгезирующую активность in vivo исследовали на модели острой термической боли, которую моделировали в общепринятом поведенческом тесте ноцицепции «Горячая пластинка» (Hot plate). Латентный период болевой реакции определяли в начале («0» день), на 7, 14, 21 и 28 день эксперимента.Результаты. По данным PASS-прогноза, механизмами реализации болеутоляющей активности винборона выступают: его агонизм по отношению к ванилоидным (TRPV1) рецепторам. (Pa=0,490; Pi=0,008), агонизм к μ (mu) рецепторам (Pa=0,323; Pi=0,036), ингибирование GABA (Pa=0,329; Pi=0,089) и другие. Экспериментальные исследования показали, что при комбинированном применении и ибупрофена, и винборона анальгетическая активность превышала аналогичные показатели при монотерапии ибупрофеном в дозе 73 мг/кг – на 15,3%, а в дозе 218 мг/кг – на 20,4%. Кроме того, стоит отметить, что анальгетическая активность при комбинированном применении ибупрофена в дозе 218 мг/кг и винборона (+39,8%) превышала суммарную анальгезирующую активность монотерапии ибупрофеном в той же дозе (+19,4%) и монотерапии винбороном (+10,9%), что указывает на потенцирование анальгетического эффекта обоих препаратов при их одновременном применении.Выводы. Ведущим механизмом в реализации анальгетического компонента винборона, по данным PASS-прогноза, выступает его агонизм к TRPV1. Результаты проведённых нами исследований in vivo указывают на способность винборона усиливать антиноцицептивную активность ибупрофена., Актуальним напрямом сучасної фармакології є підвищення безпечності нестероїдних протизапальних засобів, оскільки для них притаманні так звані «клас-специфічні» побічні реакції, провідне місце серед них посідає гастротоксичність. У попередніх дослідженнях довели здатність вінборону нівелювати ульцерогенний ефект ібупрофену (Гладких Ф. В. та співав., 2014), а наявність у вітчизняного спазмолітика доведеної власної болезаспокійливої активності (Степанюк Г. І. та співів., 2007) слугує підґрунтям дослідження впливу вінборону на анальгетичний компонент фармакотерапевтичного ефекту ібупрофену.Мета роботи – здійснити in silico дослідження взаємозв’язку «молекулярна структура – аналгетична активність» вінборону та експериментально in vivo обґрунтувати доцільність застосування вінборону з метою підвищення анальгетичної активності ібупрофену на моделі ад’ювантного артриту в щурів.Матеріали та методи. Дослідження взаємозв’язку «молекулярна структура – анальгетична активність» вінборону здійснили in silico за допомогою PASS-аналізу спектра біологічної активності, котрий виконали в режимі online за безпосереднього введення структурної формули вінборону в браузері, використовуючи Marvin JS web-ресурсу «PASS Online» (http://www.way2drug.com/passonline). Анальгетичну активність іn vivo досліджували на моделі гострого термічного болю, який моделювали в загальноприйнятому поведінковому тесті ноцицепції «Гаряча пластинка» (Hot plate). Результати. За даними PASS-прогнозу, механізмами реалізації болезаспокійливої активності вінборону є: аґонізм щодо ванілоїдних (TRPV1) рецепторів (Pa=0,490; Pi=0,008), аґонізм до μ (mu) рецепторів (Pa=0,323; Pi=0,036), інгібування GABA (Pa=0,329; Pi=0,089) тощо. Експериментальні дослідження показали, що при комбінованому застосуванні ібупрофену та вінборону анальгетична активність перевищувала аналогічні показники при монотерапії ібупрофеном у дозі 73 мг/кг – на 15,3%, а в дозі 218 мг/кг – на 20,4%. Крім того, варто відзначити, що анальгетична активність під час комбінованого застосування ібупрофену в дозі 218 мг/кг і вінборону (+39,8%) перевищувала сумарну анальгетичну активність монотерапії ібупрофеном у тій самій дозі (+19,4%) та монотерапії вінбороном (+10,9%), що вказує на потенціювання анальгетичного ефекту обох препаратів при їхньому комбінованому застосуванні.Висновки. Провідним механізмом у реалізації анальгетичного компонента вінборону, за даними PASS-прогнозу, є його аґонізм до TRPV1. Результати досліджень вказують на здатність вінборону потенціювати антиноцицептивну активність ібупрофену.

Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq Indole-3carbinol (I3C) is a phytochemical that has several therapeutic properties. However, it is unstable against acid and light conditions. In this sense, polymeric nanocapsules are interesting alternatives for the encapsulation of this compound. Thus, this study aimed the nanocapsule suspensions development from poly(ε-caprolactone) or Eudragit® RS 100 and from medium chain triglycerides or rose hip oil. All the formulations showed adequate physicochemical characteristics with encapsulation efficiency around 40 % regardless of the used constituents. Furthermore, it was found that the nanocapsules increased about fourfold the compound photostability against UVC radiation, which was 10 % more effective for rose hip oil nanocapsules. The in vitro release profile studies demonstrated a biphasic release profile of I3C from nanocapsules, which is driven by Fickian diffusion. In biological evaluations of the formulations, they were divided in two groups: The first group consisted of nanocapsule suspensions prepared with poly(ε-caprolactone), intending to intravenous administration of I3C. In hemolysis test the formulations demonstrated hemocompatibility at 10 μg/ml. The DPPH scavenging activity assay showed that medium chain triglycerides nanocapsules and rose hip oil nanocapsules increased the I3C activity from 50 % to 72 and 81 %, respectively, demonstrating that rose hip oil nanocapsules are promising formulations. Thus, the antitumor activity of these suspensions was evaluated against breast tumor and glioma cells. The results demonstrated that nanoencapsulated I3C presented an antitumor effect two times higher than free I3C without causing cytotoxicity on astrocyte cells. The second group, which consisted of nanocapsule formulations prepared with Eudragit® RS 100 and rose hip oil, was evaluated in vivo concerning its antinociceptive action. The results showed that free I3C and nanocapsules had an onset of action at 30 min. However, free I3C has rapidly lost its effect, whereas nanocapsules prolonged the antinociceptive action of this compound until 6h. This way, the developed nanocapsules are promising alternatives for I3C administration in the control of cancer and pain treatment. O indol-3carbinol (I3C) é um fitoquímico que possui diversas propriedades terapêuticas. Entretanto, é instável frente a ambientes ácidos e à luz. Neste sentido, as nanocápsulas poliméricas são alternativas interessantes para a veiculação deste composto. Assim, este trabalho objetivou o desenvolvimento de suspensões de nanocápsulas a partir da poli(ε-caprolactona) ou do Eudragit® RS 100 e dos triglicerídeos de cadeia média ou do óleo de rosa mosqueta. Todas as formulações apresentaram características físicoquímicas satisfatórias, com eficiência de encapsulação de 40 %, independentemente dos constituintes. Ademais, verificou-se que as nanocápsulas aumentaram em cerca de 4 vezes a fotoestabilidade do composto frente à radiação UVC, sendo esta fotoproteção 10 % mais efetiva para as nanocápsulas preparadas com óleo de rosa mosqueta. Os estudos de liberação in vitro demonstraram um perfil de liberação bifásico do I3C a partir das nanocápsulas, sendo esta governada por difusão fickiana. Na avaliação biológica das formulações, as mesmas foram divididas em dois grupos: O primeiro grupo consistiu de suspensões de nanocápsulas preparadas com poli(ε-caprolactona), pretendendo-se a administração intravenosa do I3C. No teste de hemólise, as formulações demostraram hemocompatibilidade até a concentração de 10 g/mL. O ensaio de atividade sequestradora do radical DPPH demonstrou que as nanocápsulas com triglicerídeos de cadeia média e óleo de rosa mosqueta aumentaram a atividade do I3C de 50% para 72 e 81 %, respectivamente, demonstrando que as nanocápsulas de óleo de rosa mosqueta são formulações mais promissoras. Dessa forma, a atividade antitumoral destas suspensões foi avaliada frente a células de câncer de mama e de glioma. Os resultados demonstraram que o I3C nanoencapsulado apresentou um efeito antitumoral 2 vezes superior que o I3C na sua forma livre, sem causar citotoxicidade para astrócitos. O segundo grupo de formulações, que consistiu nas nanocápsulas de Eudragit® RS 100 e óleo de rosa mosqueta, foi avaliado in vivo quanto à ação antinociceptiva. Os resultados demonstraram que, da mesma forma que o I3C livre, as nanocápsulas tiveram início de ação em 30 minutos. No entanto, o I3C livre teve seu efeito perdido rapidamente, enquanto que as nanocápsulas prolongaram a ação antinociceptiva deste composto por 6 horas. Considerando os resultados obtidos, as nanocápsulas contendo I3C desenvolvidas são uma alternativa promissora para a administração deste composto no controle do câncer e no tratamento da dor.

Orientador: Julio Cezar Pastre Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química Resumo: O espilantol é uma N-alquilamida presente na Spilanthes acmella, considerado o principal responsável por diversas atividades biológicas, tais como antinociceptiva, anti-inflamatória, antioxidante, diurética, antifúngica, antimalarial, bacteriostática e atividade larvicida contra mosquitos, como o Aedes aegypti. Esse produto natural foi descoberto em 1903, e em 1963 foi descrita a primeira rota sintética para sua obtenção. Em trabalhos subsequentes, outras sínteses foram descritas, porém apresentaram baixos rendimentos globais ou grande número de etapas, além de não descreverem a pureza do composto formado e se há presença de isômeros. O objetivo desse trabalho foi desenvolver uma nova uma rota sintética para o espilantol e alguns análogos, avaliando a etapa chave (reação de Sonogashira) em fluxo contínuo, a fim de obter uma rota potencialmente mais curta, barata e eficiente, levando a um produto final de maior pureza quando comparado com as rotas presentes na literatura. As atividades biológicas dos compostos preparados também foram estudadas, uma vez que a maioria dos trabalhos relatam as atividades do extrato bruto que o contém. A etapa mais desafiadora para a obtenção do espilantol é a síntese do dieno com geometria E/Z desejada para as ligações duplas. Três abordagens foram utilizadas para a obtenção desse sistema. Primeiramente foi realizada uma rota baseada na reação de Wittig entre o crotonaldeído e o sal de fosfônio derivado do 4-bromo-1-butanol. Essa proposta levou a baixos rendimentos, que foram atribuídos a presença da hidroxila livre no sal de fosfônio. Foi então proposta uma segunda abordagem com a proteção prévia dessa hidroxila. Essa abordagem levou a melhores rendimentos porém conta com duas etapas adicionais, a proteção e desproteção da hidroxila. Por fim, uma terceira abordagem foi avaliada, que se baseia na reação de Sonogashira entre 1-bromoprop-2-ene e o pent-4-in-1-ol seguida de uma semi-redução Z-seletiva para obtenção do dieno, em condições ótima, essa rota leva a formação apenas do dieno com a geometria desejada para as ligações duplas e com um rendimento global de 30%. Essa rota foi escolhida para seguir com a síntese do espilantol, que em seguida conta com uma etapa da oxidação de Swern e uma reação de HWE com o éster fosfonato previamente preparado. Dessa forma, foi possível desenvolver uma rota sintética para o espilantol em 5 etapas, com 25% de rendimento global, obtendo um produto de alta pureza (>98% HPLC) e sem a presença de outros isômeros (RMN de 1H). A rota desenvolvida possibilita a síntese em grande escala, permitindo a obtenção de material para diversos ensaios biológicos. Com pequenas alterações na rota inicialmente proposta, foi possível sintetizar 5 análogos naturais e não-naturais do espilantol. A reação de Sonogashira foi avaliada em fluxo contínuo, porém, não apresentou até o momento, vantagens em relação a reação em batelada. O potencial antitumoral e anti-HIV dos compostos sintetizados foi avaliado, a fim de obter-se informações sobre a relação estrutura atividade desta série de análogos. No entanto, até o momento não foi observado nenhum efeito biológico significativo. Estudou-se também a atividade antinociceptiva do espilantol utilizando o modelo tail flick em camundongos. O espilantol e outros dois análogos mostram atividade superior ao controle positivo EMLA®, principal anestésico de uso tópico utilizado atualmente. Esses resultados abrem possibilidades para estudos futuros e aplicações dos análogos sintetizados Abstract: Spilanthol is an N-alkylamide found in the Spilanthes acmella, it is considered the be the main responsible for many biological activities, such as antinociceptive, anti-inflammatory, antioxidant, diuretic, antifungal, bacteriostatic and larvicide activity against mosquitoes, such as Aedes aegypti. This natural product was discovered in 1903 and in 1963 it was described its first synthesis. In the following publications new approaches were reported, but they presented low global yields or an elevated number of reaction steps and did not determine the purity of the synthetized compound or the presence of other isomers. The objective of this project was to develop a new synthetic route for the spilanthol and some analogues, evaluating the key step (Sonogashira reaction) in continuous flow to obtain a shorter, less expensive and efficient route that would afford the desired product with an elevated purity. The biological activity of the synthesized spilanthol was also evaluated since there are only studies in the literature with the crude extract of the Spilanthes acmella. The most challenging step is the synthesis of the diene with the desired E/Z geometry for the double bonds. Three different approaches were explored for the synthesis of this portion. The first route explored was based on the Wittig reaction between crotonaldehyde and phosphonium salt obtained from the 4-bromo-1-butanol. This strategy afforded the desired product in low yields in virtue of the free hydroxyl group. Based in these results a second approach was explored, where the hydroxyl group was first protected. Due to this, better yields were obtained at the cost of two additional steps: protection and deprotection. Finally, a third strategy was evaluated. This new route was based on the Sonogashira reaction between 1-bromoprop-2-ene and pent-4-yn-1-ol followed by a semi-reduction Z-selective to obtain the diene. The optimal conditions of this route led to the exclusively formation of the product of the desired double bond configuration and global yield of 30%. This route was chosen to conclude the synthesis of the spilanthol. The alcohol obtained was oxidized via a Swern protocol and the final product was obtained by a HWE reaction with phosphonate ester previously prepared. This final route afforded the spilanthol in 5 steps with 25% global yield, in high purity (>98% HPLC) and without the presence of the other isomers (1H-RMN). This synthetic route gives access to the spilanthol in a larger scale, which allowed the synthesis of enough material for several biological tests. Minor modifications in the original route allowed the synthesis of 5 different natural and non-natural analogs of the spilanthol. The Sonogashira reaction was evaluated in continuous flow, but so far, it did not prove better than the batch protocol. The antitumor and anti-HIV activity of the synthesized products was evaluated to elucidate the structure-activity relationship of the analogues produced but no significant activity was observed. The antinociceptive activity of the spilanthol and its analogues was evaluated utilizing the tail flick model in mice. The spilanthol and two other analogues presented better activity than the positive control EMLA®, major anesthetic for topical use nowadays. These results led to new possibilities for future studies and applications of the synthesized analogues Mestrado Química Orgânica Mestra em Química CAPES

Context: Euphorbia pulcherrima (EP) belongs to the family: Euphorbiaceae and Genus: Euphorbia. Many species of Euphorbia have been reported as having beneficial properties like anticonvulsive effect, central analgesic properties, antipyretic action, central depressant action and strong sedative effect. However, little study has been done and published on EP. Aims: To observe and evaluate various neuropharmacological effects like antinociceptive effect, anticonvulsant effect, motor in-coordination, pentobarbital induced sleeping time and behavioral responses of EP in mice and rats. Setting and Design: Quantitative experimental study in mice and rats by various experimental models. Materials and Methods: Different experimental models were used to assess the antinociceptive effect (hotplate, tail flick and acetic acid induced writhing test), anticonvulsant effect (Maximal Electroshock Seizure test [MES] and Pentylenetetrazole induced seizures [PTZ]), motor in-coordination effect (Rota rod test), pentobarbital induced sleeping time and behavioral responses of EP in mice and rats after oral administration of EP crude dried extracts in three different doses (250, 500 and 1000 mg/kg). Statistical Analysis Used: The significance of difference with respect to control was evaluated using the Mann-Whitney U test. A probability (P-value) level less than 0.05 was considered as significant. Results: In MES test model, duration of tonic hind limb extension in mice treated with EP was significantly less as compared to vehicle treated group. EP was most effective in a dose of 1000 mg/kg. There was also significant increase in the latency and decrease in the incidence of convulsions with the use of EP in three different doses in PTZ induced seizure model. Conclusions: This study showed EP (crude dried) extracts to possess anticonvulsant properties but no effect on motor co-ordination and anxiety.

The ethanol extract from Vernonia polyanthes leaves (EEVP) was investigated for antinociceptive and anti-inflammatory effects at the doses (p.o.) of 100, 200 and 400 mg/kg in animal models. The extract reduced the number of abdominal contortions by 16.75% and 31.44% at a dose of 200 and 400 mg/kg, respectively. The results obtained showed that EEVP exerted a significant antinociceptive effect in the two phases of formalin. The EEVP increased the reaction time on a hot plate at the doses of 100, 200 and 400 mg/kg after 90 min of treatment. The paw edema was reduced by EEVP at the doses of 100, 200 and 400 mg/kg after 4 h of application of carrageenan. Doses of 200 and 400 mg/kg, administered 4 h before the carrageenan injection, significantly reduced the exudate volume (29.25 and 45.74%, respectively) and leukocyte migration (18.19 and 27.95%, respectively). These results suggest that V. polyanthes can be an active source of substances with antinociceptive and anti-inflammatory activities.

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8 per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg−1·day−1, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5% (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7%), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9%, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8/per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg-1·day-1, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5% (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7%), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9%, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.

Visseral ağrı en sık rastlanılan ağrı tipi olup, mekanizması tam olarak anlaşılamamıştır. Doku hasarına bağlı olarak salgılanan prostaglandinler ağrı reseptörlerinin eşiğini düşürmektedir. Dolayısıyla, sitokinlerin ve diğer proinflamatuvar faktörlerin ekspresyonunu kontrol eden c-Raf kinaz sinyal yolağının farmakolojik olarak inhibe edilmesi bu eşiğin yükselmesine sebep olabilir. Bu araştırma selektif c-Raf inhibitörü olan GW5074'ün kimyasal ağrı modelinde antinosiseptif etkisinin olup olmadığını test etmek amacıyla gerçekleştirilmiştir. Metamizol (250 mg/kg), GW5074 0.5 ve 2 mg/kg dozlarında asetik asitle indüklenen abdominal kontraksiyon testinde antinosiseptif aktivite gösterdi. GW5074 her iki dozda da kıvranma sayılarını önemli derecede azalttı. Bu bulgular ışığında, GW5074'ün kimyasal ağrı modelinde farelerde periferik antinosiseptif özellik gösterdiği düşünülebilir. Buna göre, c-Raf sinyalizasyonunun inhibe edilmesinin ağrı yönetiminde olası yararı olabilir., Visceral pain is the most common type of pain, and its mechanism isn't understood exactly. Prostaglandins which are released depending on tissue damage reduce the pain receptors threshold. Thus, pharmacological inhibition of c-Raf kinase signaling which controls expressions of cytokines and other proinflammatory factors, may increase mentioned threshold. The present investigation was performed to assess if there is any possible antinociceptive effect of GW5074, a selective c-Raf inhibitor, in chemical pain model. Metamizole (250 mg/kg), GW5074 0.5 and 2 mg/kg showed antinociceptive activity in the abdominal constrictor test induced by acetic acid. Both doses of GW5074 significantly reduced the number of stretches in the abdominal constrictor test. Therefore it is possible to conclude that GW5074 has a peripheral antinociceptive effect in mice evaluated from chemical pain model. The analgesic effect of GW5074 suggests that inhibition of c-Raf signaling may be potentially useful for managing pain.

Bu çalışma, Verbascum exuberans ekstresi (Vex)'nin antinosiseptif etkinliğini, bu etkide serotonerjik, nitrerjik ve opiyoderjik yolaklar üzerindeki rolünü ve antiinflamatuvar aktivitesini belirlemek üzere dizayn edilmiştir. Ekstrenin santral antinosiseptif etkinliği tail clip, tail flick ve hot plate testleriyle, periferal antinosiseptif etkinliği ise asetik asit ile oluşturulan writhing testiyle araştırılmıştır. Bu duruma ek olarak, Vex (250 mg/kg) L-NAME (100 mg/kg), siproheptadin (50 µg/kg) ve nalokson (1 mg/kg) ile kombine edilmiştir. Karragenan ile oluşturulan arka ayak pençe ödem modeli Vex (250 mg/kg)'nin antiinflamatuvar aktivitesinin belirlenmesinde kullanılmıştır. 250 mg/kg Vex % MPE değerlerini sadece tail clip testinde arttırırken (p˂0,05), 500 mg/kg Vex % MPE değerlerini tail clip, tail flick ve hot plate testlerinde arttırmamıştır (p˃0,05). Ekstrenin her iki dozu asetik asit ile oluşturulan writhing testinde kıvranma sayılarını azaltmıştır (p˂0,001). Vex ile kombine verilen L-NAME santral antinosiseptif testlerdeki % MPE değerini sadece tail clip testinde arttırdığı görülmüştür (p0,05). Çalışmamızda, Vex'nin santral spinal düzeyde antinosiseptif etkili olduğu, santral supraspinal düzeyde antinosiseptif etkili olmadığı ve Vex'nin periferal antinosiseptif etkili olduğu bulunmuştur. Vex'nin periferal antinosiseptif etkide hem nitrerjik hem de opiyoderjik yolaklara aracılık ettiği, serotonerjik yolağın aracılık etmediği görülmüştür. Ayrıca, Vex'nin santral spinal düzeyde nitrerjik yolak üzerinden antinosiseptif etkiye aracılık ettiği belirlenmiştir. Vex, karragenan ile oluşturulan inflamasyona karşı ödem miktarını TNF-α ve IL-1β düzeylerini azaltarak inhibitör etki göstermiştir. This study was designed to investigate the antinociceptive effects of Verbascum exuberans extract (Vex) and the contribution of nitrergic, serotonergic and opioidergic pathways of Vex, and the antiinflammatory activity of Vex. Tail clip, tail flick, and hot plate tests were used to investigate the central antinociceptive effect and acetic acid-induced writhing test was used to assess the pheripheral antinociceptive effect of Vex. In addition, Vex (250 mg/kg) was combined with L-NAME (100 mg/kg), cyproheptadine (50 µg/kg), and naloxone (1 mg/kg). Carrageenan-induced hind paw edema model was used for the assessment of antiinflammatory activity of Vex (250 mg/kg). Vex 250 mg/kg increased MPE % solely in tail clip test (p0.05). The combined use of Vex with L-NAME reduced the MPE % solely in tail clip test (p

The pain is a serious public health problem, affects the quality of life of their patients, he brings harm to society. The science continues to seek new more potent analgesic drugs and with fewer side effects. Bornyl salicylate (BS) is a salicylic acid derivative obtained by esterification of salicylic acid with the monoterpene (-)-borneol, both with analgesic effects described in the literature. The aim of this study was to evaluate the antinociceptive effect of BS and its possible mechanisms in models of acute nociception in mice. For this purpose, we performed a behavioral pharmacological screening, test of acetic acid-induced writhing and formalin test. We used blockers pathways involved in pain in the formalin test to elucidate the possible mechanisms of action. BS (200 mg/kg, i.p.) showed behavioral changes indicative of CNS depressant drugs, no effect was observed on oral administration. Doses of 100 and 200 mg/kg (i.p.) reduced the number of writhings and increased the latency time to the first writhing. BS (100 and 200 mg/kg, i.p.) decreased paw licking time of animals only during the inflammatory phase of the formalin test. Pretreatment of animals with the precursor of nitric oxide (L-arginine, 600 mg/kg, i.p.), inhibitor of soluble guanylyl cyclase (methylene blue, 20 mg/kg, i.p.), non-selective muscarinic antagonist (atropine, 1 mg/kg, i.p.) and GABAA receptors antagonist (bicuculline, 1 mg/kg, i.p.), do not reverted the antinociceptive effect of BS (200 mg/kg, i.p.) in the second phase of the formalin test. These data suggest that BS exerts peripheral antinociceptive effect (anti-inflammatory), which mechanism seems in principle not involve nitric oxide, cGMP, muscarinic cholinergic receptors or GABAA receptors. Further studies are required to clarify the effect produced by bornyl salicylate. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES A dor é um grave problema de saúde pública, afeta a qualidade de vida de seus portadores e traz inúmeros prejuízos para a sociedade. A ciência continua buscando novos fármacos analgésicos mais potentes e com menos efeitos colaterais. O salicilato de bornila (SB) é um derivado salicílico obtido pela esterificação do ácido salicílico com o monoterpeno (-)-borneol, ambos com efeitos analgésicos já descritos na literatura. O objetivo deste estudo foi avaliar o efeito antinociceptivo do SB e seus possíveis mecanismos em modelos de nocicepção aguda em camundongos. Para tanto, realizou-se uma triagem farmacológica comportamental, teste das contorções abdominais induzidas por ácido acético e teste da formalina. Utilizou-se bloqueadores de vias envolvidas na dor no teste da formalina para evidenciar os possíveis mecanismos de ação. O SB (200 mg/kg, i.p.) promoveu alterações comportamentais indicativas de droga depressora do SNC, efeito não observado na administração por via oral. As doses de 100 e 200 mg/kg (i.p.) reduziram o número de contorções abdominais e aumentaram o tempo de latência para a primeira contorção. O SB (100 e 200 mg/kg, i.p.) diminuiu o tempo de lambida da pata dos animais somente na fase inflamatória do teste da formalina. O pré-tratamento dos animais com o precursor do óxido nítrico (L-arginina, 600 mg/kg, i.p.), inibidor da ciclase de guanilil solúvel (azul de metileno, 20 mg/kg, i.p.), antagonista muscarínico não-seletivo (atropina, 1 mg/kg, i.p.) e antagonista de receptores GABAA (bicuculina, 1 mg/kg, i.p.), não reverteram o efeito antinociceptivo do SB (200 mg/kg, i.p.) na segunda fase do teste da formalina. Estes dados sugerem que o SB apresenta efeito antinociceptivo periférico (anti-inflamatório), cujo mecanismo parece em princípio não envolver óxido nítrico, GMPc, receptores colinérgicos muscarínicos nem receptores GABAA. Novos estudos são necessários para melhor esclarecer o efeito produzido pelo salicilato de bornila.

Chrysopogon zizanioides (L.) Roberty, Poaceae, is a plant widely used in northeast Brazil in folk medicine for the treatment of various pathological conditions, including infl ammatory pain. The present study evaluated the antinociceptive and antiinfl ammatory effects of C. zizanioides essential oil (EO) in rodents. EO was further characterized by GC/MS. The major components of EO were identifi ed as khusimol (19.57%), E-isovalencenol (13.24%), α-vetivone (5.25%), β-vetivone (4.87%) and hydroxy-valencene (4.64%). Following intraperitoneal injection (i.p.), EO at 50 and 100 mg/kg signifi cantly reduced the number of writhes (51.9 and 64.9%, respectively) and the number of paw licks during phase 2 (56.7 and 86.2%, respectively) of a formalin model when compared to control group animals. However, EO-treated mice were ineffective at all doses in hot-plate and rota-rod tests. The EO inhibited the carrageenan-induced leukocyte migration to the peritoneal cavity in a dose-dependent manner (34.7, 35.4, and 62.5% at doses of 25, 50 and 100 mg/kg, respectively). In the paw edema test, the EO (100 mg/kg) inhibited all three phases of the edema equally well, suggesting that the EO has a non-selective inhibitory effect on the release or actions of these mediators. Our results suggest possible antinociceptive and antiinfl ammatory effects of the EO.

Chrysopogon zizanioides (L.) Roberty, Poaceae, is a plant widely used in northeast Brazil in folk medicine for the treatment of various pathological conditions, including inflammatory pain. The present study evaluated the antinociceptive and anti-inflammatory effects of C. zizanioides essential oil (EO) in rodents. EO was further characterized by GC/MS. The major components of EO were identified as khusimol (19.57%), E-isovalencenol (13.24%), α-vetivone (5.25%), β-vetivone (4.87%) and hydroxy-valencene (4.64%). Following intraperitoneal injection (i.p.), EO at 50 and 100 mg/kg significantly reduced the number of writhes (51.9 and 64.9%, respectively) and the number of paw licks during phase 2 (56.7 and 86.2%, respectively) of a formalin model when compared to control group animals. However, EO-treated mice were ineffective at all doses in hot-plate and rota-rod tests. The EO inhibited the carrageenan-induced leukocyte migration to the peritoneal cavity in a dose-dependent manner (34.7, 35.4, and 62.5% at doses of 25, 50 and 100 mg/kg, respectively). In the paw edema test, the EO (100 mg/kg) inhibited all three phases of the edema equally well, suggesting that the EO has a non-selective inhibitory effect on the release or actions of these mediators. Our results suggest possible antinociceptive and anti-inflammatory effects of the EO.

Hybrids of amino-poly(ethylene glycol) (a PEG) and [D-Ala2, (N-Me)Phe4]enkephalin analogs, H-Tyr-D-Ala-Gly-(Me)Phe-aPEG, H-Tyr-D-Ala-Gly-(Me)Phe-Leu-aPEG and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-aPEG, were prepared by the solution method and their antinociceptive properties were examined in comparison with those of the peptides. H-Tyr-D-Ala-Gly-(Me)Phe-OH and H-Tyr-D-Ala-Gly-(Me)Phe-Leu-OH themselves at intracerebroventricular (i.c.v.) doses of 10-30nmol/animal produced an antinociceptive effect which was less potent than that of i.c.v. morphine, 3μg/animal, and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-OH did not have any marked effect. However, the antinociceptive effects of H-Tyr-D-Ala-Gly-(Me)Phe-Leu-OH and H-Tyr-D-Ale-Gly-(Me)Phe-D-Leu-OH were remarkably potentiated by hybrid formation with aPEG to levels higher than that of 3μg/mouse of morphine, and the effect lasted at least 120min. In contrast, the effect of H-Tyr-D-Ala-Gly-(Me)Phe-OH was rather diminished by hybrid formation. In view of the low toxicity and weak immunogeic properties of aPEG, the hybrids could be useful in therapy of patients for relieving chronic and severe pain.

The purpose of this study was to investigate if botulinum neurotoxin type-A (BoNT/A) had a preemptive antinociceptive effect in a formalin-induced orofacial pain model (FT). To test this hypothesis, male Rattus norvegicus were injected with isotonic saline solution 0.9% or BoNT/A administered as a 40 μl bolus, lateral to their nose, at 24 hours, 8, 15, 22, 29 or 36 days pre-FT. The procedures were repeated 42 days later. Influence on motor activity was assessed through the open-field test. Pain scores corresponded to the time spent rubbing and flicking the injected area. Animals pre-treated with BoNT/A at the first protocol (8 days subgroup) showed reduced inflammatory scores (p=0.011). For the other groups no significant results were observed at any phase. Motor activity was similar in both groups. BoNT/A showed to be effective preventing inflammatory pain up to eight days after the first treatment, an effect not reproduced on the second dose administration. O objetivo deste estudo foi investigar o efeito preemptivo da neurotoxina botulínica do tipo/A (NTBo/A) através de um modelo de dor orofacial induzida pelo teste da formalina (TF). Rattus norvegicus machos foram injetados no lábio superior com solução salina isotônica 0,9% (SSI) ou NTBo/A (subgrupos 24 horas, 8, 15, 22, 29 ou 36 dias) antes do TF, em dois tratamentos farmacológicos e respectivas avaliações intercalados por 42 dias. Os escores da dor corresponderam ao tempo de fricção da região injetada. Após o primeiro pré-tratamento com NTBo/A no subgrupo 8 dias os escores da fase inflamatória foram menores do que no grupo SSI (p=0,011). Todas as outras comparações não foram significativas. Nos testes de atividade motora não ocorreram diferenças entre SSI e NTBo/A. A NTBo/A pode ser considerada como tratamento preemptivo das dores orofaciais quando utilizada até oito dias antes do estímulo álgico, não havendo consistência terapêutica após um segundo tratamento.

Cladonia clathrata (Cladoniaceae) is a lichen specie and several Cladonia species extracts have been used in folk medicine. In order to evaluate the actions of this lichen extract, studies were performed on antinociceptive, anti-inflammatory, and antioxidant activities. The hydroalcoholic extract of C. clathrata (HECc) was used in the following experiments and elicited inhibitory activity (p < 0.001) on acetic acid effect at 100 (47.2%), 200 (47.2%), and 400 mg/Kg (86.4%), and reduced the formalin effect on both the first- (400 mg/Kg, p < 0.01) and second-phases (200 and 400 mg/Kg, p < 0.01). Carrageenan-induced neutrophil migration into the peritoneal cavity was inhibited with the HECc (p < 0.001) at the dose of 400 mg/Kg. The HECc react with the DPPH radical and reduce the same by 25.76%, and exhibited IC50 value of 77.39 ± 5.03 mg/mL DPPH. The HECc shows antinociceptive and anti-inflammatory activities, with antioxidant potential. Cladonia clathrata (Cladoniaceae) é uma espécie liquenica e vários extratos de espécies de Cladonia são utilizados como remédios na medicina popular. Para avaliar as ações do extrato desse líquen, estudos foram realizados sobre as atividades antinociceptiva, anti-inflamatória e antioxidante. O extrato hidroalcoólico da C. clathrata (EHCc) foi utilizado nos experimentos e produziu atividade inibitória (p < 0,001) sobre o efeito do ácido acético no modelo de contorções abdominais nas doses de 100 (47,2%), 200 (47,2%) e 400 mg/Kg (86,4%), além de reduzir o efeito da formalina na primeira (400 mg/Kg, p < 0,01) e segunda (200 e 400 mg/Kg, p < 0,01) fases da nocicepção. A migração de neutrófilos para a cavidade peritoneal induzida pela carragenina foi inibida pelo pré-tratamento dos animais com o EHCc na dose de 400 mg/Kg (p < 0,001). O EHCc reagiu com o radical DPPH e reduziu o mesmo em 25,76%, com um valor de CI50 de 77,39 ± 5,03 mg/mL de DPPH. O EHCc mostrou atividades antinociceptiva e anti-inflamatória, com potencial antioxidante.

Submitted by Elisangela Pires (emotapires@gmail.com) on 2011-03-22T20:58:40Z No. of bitstreams: 1 Antinociceptive Effects of the Aqueous Extract of Brugmansia suaveolens Flowers in Mice..pdf: 90005 bytes, checksum: 2481c8df039af0288151c7efd32b2997 (MD5) Approved for entry into archive by Barbara Milbrath(barbaramilbrath@yahoo.com.br) on 2011-03-23T17:28:55Z (GMT) No. of bitstreams: 1 Antinociceptive Effects of the Aqueous Extract of Brugmansia suaveolens Flowers in Mice..pdf: 90005 bytes, checksum: 2481c8df039af0288151c7efd32b2997 (MD5) Made available in DSpace on 2011-03-23T17:28:55Z (GMT). No. of bitstreams: 1 Antinociceptive Effects of the Aqueous Extract of Brugmansia suaveolens Flowers in Mice..pdf: 90005 bytes, checksum: 2481c8df039af0288151c7efd32b2997 (MD5) Previous issue date: 2007 The infusion of Brugmansia suaveolens, popularly known as trombeteira or cartucheira, has been used to treat pain in Brazil. The present study was conducted to test for its antinociceptive effects using the abdominal-writhing, formalin, tail-flick, and hotplate tests in mice. The aqueous extract from B. suaveolens flowers administered intraperitoneally at doses of 100 and 300 mg/kg body weight significantly inhibited acetic acid–induced abdominal constrictions. An increase in hot-plate latency was also observed in animals receiving both doses (100 and 300 mg/kg). In the formalin test, both doses from the aqueous extract inhibited the first (0-5 min) and second phase (20-25 min). Tail-flick assays demonstrated that treatment of animals with plant extract induced attenuation of the response. These results suggest that the aqueous extract from B. suaveolens flowers produced antinociceptive effects, as demonstrated in the experimental models of nociception in mice. This supports popular medicinal uses of this plant as an analgesic.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior This present study is about the phytotherapic effects of the hydroalchoholic extracted from the Hyptis fruticosa leaves. Typical plant from the northeast of Brazil used as an aromatyzer and discongestyzer. Probably, de Araújo et. al., 1974, were the first ones to study and discribe the studies of the metanolic extracts from the roots of this plant, that contains antimicroorganism and antineoplasic activity. Pain, insomnia and epilepsy are disturbs that attack people in our society, specially pain, causing personal and socialeconomic problems. The main objective of this study is to describe partialy the effects of the hydroalchoholic extracted from the Hyptis fruticosa Salzm. (ex) Benth. leaves in the nervours central system of mice. Having as specifics objectives: to determinate the acute toxicity (DL50); to evidence the anticonvulsant and sedative/hypnotic effects; to mensure the antinociceptive effects in mice. This is an experimental search using acute toxicity test in the doses 1, 2, 3, 4 and 5 grams; pentylenetetrazole-induced convulsion, 60mg/Kg i.p.; pentobarbital-induced sleep, 60mg/Kg i.p.; writhing-induced by acetic acid 6% and tail-flick test. The animals used were the swiss type mice. The data obtained were analysed by ANOVA, the p

UVOD. Klinička opažanja ukazuju na moguće antinociceptivno djelovanje BT-A u različitih bolnih stanja. Hipoteza ove disertacije je da botulinum toksin tip A (BT-A) ima antinociceptivno djelovanje koje uključuje procese središnje senzitizacije. MATERIJALI I METODE. Na mužjacima štakora soja Wistar, BT-A je primijenjen subkutano (s.c.) u šapu, intratekalno i intraneuronalno (u n. ishiadicus). Djelovanje je ispitivano na modelima nociceptivne, upalne i neuropatske boli, a mjerena je bolnost na pritisak, toplinu, te na injiciranje formalina. Istraživano je djelovanje BT-A na upalu, i to mjerenjem povećanja obujma i mase šapa nakon s.c. primjene karagenana, te mjerenjem ektravazacije proteina vezanih uz Evansovo modrilo nakon injiciranja kapsaicina. Pri kroničnoj mišićnoj hiperalgeziji, uzrokovanoj ponovljenim intramuskularnim injiciranjem kisele otopine 0,9 % NaCl-a, ispitivano je djelovanje BT-A na sekundarnu bilateralnu hiperalgeziju. Istraživan je utjecaj inhibicije aksonalnog transporta kolhicinom i distalnom transekcijom n. ishiadicusa na djelovanje BT-A. Western blot metoda i imunohistokemija korištene su s ciljem detekcije BT-A u n.ishiadicusu i senzornim ganglijima. REZULTATI. BT-A je smanjio upalnu i neuropatsku, dok na nonciceptivnu bol nije utjecao. BT-A nije utjecao na edem, niti na ekstravazaciju proteina pri upali. BT-A je spriječio nastanak i smanjio sekundarnu bilateralnu mehaničku hiperalgeziju. Inhibicija aksonalnog transporta kolhicinom spriječila je djelovanje s.c. primijenjenog BT-A, dok transekcija n.ishiadicusa distalno od mjesta intraneuronalnog injiciranja BT-A nije utjecala na njegovo djelovanje na kontralateralnu bol. Preliminarni rezultati imunohistokemije i Western blota ukazuju na moguću nazzočnost kratkog lanca BT-A u n. ishiadicusu i senzornim ganglijima. ZAKLJUČAK. BT-A je djelotvoran pri uklananju upalne boli i pri smanjenju simptoma neuroptske boli. Antinociceptvno djelovanje BT-A vjerojatno uključuje promjene središnje senzitizacije., OBJECTIVE. The hypothesis of this dissertaion is that botulinum toxin type A (BT-A) has antinociceptive effect, which might include interference with mechanisms of central sensitization. MATERIALS AND METHODS. Male Wistar rats were injected with BT-A subcutaneously, intrathecally and intraneuronally. Antinociceptive effect of BT-A was investigated in nociceptive, inflammatory and neuropathic pain. The influence of BT-A on secondary bilateral hyperalgesia was explored, too. Effect of BT-A on carrageenan-induced paw edema and capsaicin-induced extravasation of proteins coupled to Evans blue was investigated. Colchicine and transection of n. ishiadicus were used as tools to prevent the axonal transport of BT-A. Western blot and immunohistochemistry were employed in order to detect the toxin in n.ishiadicus and sensory ganglia. RESULTS. BT-A decreased inflammatory and neuropathic pain, while it did not affect nociceptive pain. It did not show antiinflammatory effect. BT-A reduced bilateral secondary hyperlgesia. Colchine prevented the effectiveness of subcutaneous BT-A, while distal transection of n.ishiadicus did not affect the influence of intraneuronal BT-A on contralateral pain. CONLUSION. BT-A reduces inflammatory pain and symptoms of neuropathic pain. Antinociceptive effect of BT-A probably involves interference with central sensitization.