Acute pancreatitis (AP) is an inflammatory condition of the pancreas, which causes high mortality in the severe forms. Although the incidence of AP is increasing in the last years, there is no specific treatment for this condition. Preclinical evidence suggests that medicinal plants (MP) may be a viable alternative for the treatment of AP. The standardized extract of Vaccinium macrocarpon (SeVm) possesses antioxidant activity and may be useful in the treatment of this disease. The objetives of this study were to carry out a systematic review regarding the use of MP in preclinical models of AP and to investigate the anti-inflammatory, antioxidant and antinociceptive properties of SeVm in a model of AP in mice. Therefore, pre-clinical studies of AP in which a MP was administered and outcomes were compared to a control group (placebo treatment) were selected. Electronic searches were conducted using MEDLINE via PubMed, SCOPUS, Web of Science and Embase, and gray literature (Google Scholar) and hand search by using specific keywords. Two independent reviewers identified the relevant studies, extracted data and evaluated the risk of bias following the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) risk of bias tool. Data from eligible studies were qualitatively extracted and synthesized. Thirty-one studies were selected, analyzed, and from these studies we concluded that the treatment with MP can be effective to treat experimental AP. For the experimental study, AP was induced in male Swiss mice (30-35 g, n=6 per group) by two successive injections of L-arginine (4 g/kg, i.p.), and euthanized 72 h after induction. Animals were treated with SeVm (50, 100 and 200 mg/kg, p.o.), dexamethasone (5 mg/kg, s.c.), morphine (5 mg/kg, i.p.), or vehicle (NaCl, 0,9%) every 24 h, starting from 1 h after the induction of AP. After euthanasia, inflammatory parameters (myeloperoxidase activity and concentration of tumoral necrosis factor [TNF]-α, interleukin [IL]-1β and IL-6 in pancreas and lung tissues, leucocyte counts in blood and edema index in pancreas), oxidative stress markers (thiobarbituric acid reactive substances [TBARS], non-protein sulfhydryl groups content [NPSH], carbonyl radicals content and ferric reducing/antioxidant power [FRAP] assay in lung and pancreas), antioxidant enzyme activities (catalase [CAT], superoxide dismutase [SOD] and glutathione peroxidase [GSH-Px] in pancreas and lung), biochemical parameters (concentration of amylase, lipase, alanine aminotransferase, aspartate aminotransferase, urea and creatinine in serum) and abdominal hyperalgesia were measured. The induction of AP by L-arginine significantly altered inflammatory parameters and oxidative stress markers, as well as abdominal hyperalgesia induced by AP. Treatment with SeVm inhibited the abdominal hyperalgesia caused by AP. All inflammatory parameters were reduced in animals treated with SeVm. Treatment with SeVm partially decreased the alterations in biochemical parameters in serum. The reduction of SOD and CAT activities in pancreas and lung of animals with AP, were reverted by the treatment with SeVm, but the activity of GSH-Px was not changed. The formation of TBARS and carbonil radicals were reduced after treatment with SeVm and the NPSH was increased after this treatment, as well as did total antioxidant potential. In summary, these results demonstrate that MP have potential in the treatment of experimental AP and that SeVm decreases inflammation, oxidative stress and hyperalgesia in AP, making it of interest in future approaches to treat this condition. / A pancreatite aguda (PA) é uma condição inflamatória do pâncreas que pode causar elevada mortalidade nas suas formas graves. Evidências pré-clínicas sugerem que as plantas medicinais (PM) podem ser uma alternativa viável para o tratamento da PA. O extrato padronizado da Vaccinium macrocarpon (EpVm) possui atividade antioxidante e pode ser útil no tratamento desta doença. Os objetivos deste estudo foram realizar uma revisão sistemática sobre o uso de PM em modelos pré-clínicos de PA e investigar as propriedades anti-inflamatória, antioxidante e antinociceptiva do EpVm em modelo de PA em camundongos. Para tanto, foram selecionados estudos pré-clínicos de PA em que PM foram utilizados e os desfechos foram comparados ao grupo controle (tratamento placebo). As buscas eletrônicas foram realizadas utilizando-se das bases MEDLINE, LILACS, BVS, SCIELO, SCOPUS, Web of Science e Embase, além da “gray literature” (Google Scholar) pela inserção de descritores e por “hand search”. Dois revisores independentes identificaram os estudos relevantes, fizeram a extração dos dados e avaliaram o risco de viés dos estudos selecionados, por meio da ferramenta de risco de viés do “Systematic Review Protocol for Animal Intervention Studies” (SYRCLE). Os dados dos estudos elegíveis foram extraídos e sintetizados qualitativamente. Trinta foram selecionados, analisados e a partir dos mesmos, foi possível concluir que o tratamento com PM pode ser efetivo na PA experimental. Para o estudo experimental, foi realizada a avaliação da capacidade antioxidante do EpVm por redução do radical DPPH, do NO e pela inibição da lipoperoxidação. A PA foi induzida em camundongos Swiss machos (30-35 g, n = 6 por grupo) por duas injeções sucessivas de L-arginina (4 g/kg, i.p.) e eutanasiados 72 h após a indução. Os animais foram tratados com EpVm (50, 100 e 200 mg/kg, v.o.), ou dexametasona (5 mg/kg, s.c.) ou morfina (5 mg/kg, i.p.) ou veículo (NaCl, 0,9%) a cada 24 h, iniciando-se 1 h após indução da PA. Após a eutanásia, foram avaliados parâmetros inflamatórios (atividade de mieloperoxidase e concentração de fator de necrose tumoral [TNF]-α, interleucina [IL]-1β e IL-6 nos tecidos pancreático e pulmonar, contagem de leucócitos no sangue e índice de edema no pâncreas), marcadores de estresse oxidativo (formação de substâncias reativas ao ácido tiobarbitúrico [TBARS], conteúdo de grupos sulfidrila não proteicos [NP-SH], conteúdo de radicais carbonil e capacidade total de redução do ferro [FRAP] em pâncreas e pulmão), atividade das enzimas antioxidantes (atividade de catalase [CAT], superóxido dismutase [SOD] e glutationa peroxidase [GSH-Px] no pâncreas e pulmão), parâmetros bioquímicos (amilase, lipase, alanina aminotransferase, aspartato aminotransferase, ureia e creatinina no soro) e a hiperalgesia abdominal. A indução da PA pela L-arginina alterou significativamente os parâmetros de inflamação e estresse oxidativo, bem como a hiperalgesia, em relação ao grupo veículo. O tratamento com EpVm inibiu a hiperalgesia abdominal causada pela PA. Todos os parâmetros inflamatórios foram reduzidos quando os animais foram tratados com EpVm. O tratamento com EpVm diminuiu parcialmente as alterações nos parâmetros bioquímicos no soro. A atividade de SOD e CAT no pâncreas e pulmão, que se encontravam reduzidas pela PA, foram restauradas após tratamento com EpVm, mas a atividade de GSH-Px não foi alterada. A formação de TBARS e radical carbonil foi reduzida após tratamento com EpVm e o NP-SH foi aumentado após este tratamento, assim como o FRAP no pâncreas e no pulmão. Em suma, estes resultados indicam que as PM possuem potencial para o tratamento da PA experimental e que o EpVm diminui a inflamação, o estresse oxidativo e a hiperalgesia na PA em camundongos, tornandoo de interesse em abordagens futuras para tratar esta condição.

A técnica de laserterapia é um método não-invasivo que demonstra clinicamente ser eficaz na redução da sensibilidade à dor. O presente estudo visou examinar os efeitos da aplicação do LASER sobre a sensibilidade dolorosa induzida pela constrição crônica do nervo isquiático (CCI) de ratos. Os animais foram submetidos a ensaios comportamentais e a dez sessões de laserterapia. Observamos melhora para os testes comportamentais o que corrobora com os ensaios de imunoblotting no gânglio da raiz dorsal, onde observamos uma diminuição de Substância P no grupo de animais tratados com LASER. Com relação aos ensaios imunoenzimático de ELISA, observamos diminuição de citocinas pró-inflamatória e uma tendência ao aumento de citocina anti-inflamatória. Não observamos diferença estatística na análise dos receptores opióides MOR , DOR e KOR . Podemos concluir que o LASER é eficaz e age na modulação da dor neuropática. / The technique of laser therapy is a not invasive method that demonstrates clinically to be effective in reducing sensitivity to pain. This study aimed to examine the effects of application of LASER on pain sensitivity induced by chronic constriction of the sciatic nerve (CCI) in rats. The animals were subjected to behavioral tests and the ten sessions of laser therapy. We observed and improvement for behavioral tests which corroborates with immunoblotting assays in the dorsal root ganglion, where we observes a decrease of substance P in the group of animals treated with LASER. Regarding immunoenzymatic ELISA assay, we observed a decrease of pro-inflammatory cytokines and a possible increase in anti-inflammatory cytokine. No statistical difference in the analysis of opioid receptor MOR, DOR and KOR.

No description available.

La chiropratique est une profession de la santé qui s’intéresse au diagnostic, au traitement, et à la prévention des troubles musculosquelettiques. L’intervention la plus communément utilisée en chiropratique est la manipulation vertébrale (dite « ajustement chiropratique »). D’ailleurs, les consultations en chiropratique sont principalement pour des douleurs vertébrales, particulièrement dans la région lombaire. La lombalgie est la principale cause d'incapacité à travers le monde. Elle engendre des coûts considérables pour la société et les individus atteints. Chez environ un tiers des individus, la lombalgie persiste et devient chronique, entraînant une incapacité et une diminution de la qualité de vie. Chez ces individus, aucun processus pathologique affectant les tissus vertébraux ne peut être mis en évidence. En effet, cette douleur, dite nociplastique, serait plutôt causée par des mécanismes pathologiques du système nociceptif. La lombalgie chronique, dite primaire chez ces individus, est ainsi considérée comme le diagnostic en soi, et non un symptôme secondaire à une pathologie sous-jacente. Chez certains individus, les manipulations vertébrales peuvent soulager la lombalgie chronique primaire. Cependant, leur efficacité comme intervention de première ligne et leurs mécanismes hypoalgésiques restent à démontrer. L'objectif général de cette thèse est d’examiner les mécanismes hypoalgésiques des manipulations vertébrales. Le premier objectif spécifique est d’examiner les mécanismes hypoalgésiques d’une manipulation vertébrale à l’aide d’un modèle expérimental de douleur persistante chez des individus en santé. Le deuxième objectif spécifique est d’examiner les mécanismes du soulagement de la douleur lombaire chronique primaire par une intervention chiropratique de quatre semaines, qui comprend douze séances de manipulations vertébrales. La thèse comprend deux études empiriques, soit une étude expérimentale et une étude clinique, qui sont précédées d’une revue de littérature ciblée. Le premier article est une revue narrative explorant les mécanismes neurophysiologiques de la manipulation vertébrale pour soulager la douleur vertébrale. Le deuxième article décrit les résultats d’une étude expérimentale chez des individus en santé. Dans cette étude, nous avons examiné les mécanismes d'inhibition de la douleur en réponse à une manipulation vertébrale ciblant un segment vertébral dont la peau a été sensibilisée par une application topique de capsaïcine. Le troisième article est une revue narrative examinant l'efficacité des manipulations vertébrales pour le traitement des douleurs vertébrales. Le quatrième article décrit les résultats d’un essai contrôlé randomisé avec groupe placebo chez des individus atteints de lombalgie chronique primaire. Dans cette étude, nous avons examiné si le soulagement de la lombalgie chronique primaire par une intervention chiropratique s’accompagne d’une atténuation de processus pathologiques contribuant à la douleur nociplastique. Les résultats indiquent qu’une manipulation vertébrale peut atténuer l’hyperalgésie mécanique secondaire observée avec le modèle expérimental de douleur persistante. Ceci suggère qu’une manipulation vertébrale pourrait agir sur des processus pathologiques qui mènent à la douleur chronique. Ces résultats sont cohérents avec la réduction de la douleur observée chez les patients atteints de lombalgie chronique primaire recevant des manipulations vertébrales. De plus, la réduction de la lombalgie chronique était accompagnée d’une réduction de l’hyperalgésie mécanique lombaire et de la dramatisation de la douleur. Dans l’ensemble, ces résultats suggèrent qu’une intervention chiropratique comprenant des manipulations vertébrales est efficace pour réduire la lombalgie chronique primaire, et que cet effet pourrait découler en partie d’une réduction de processus contribuant à la douleur nociplastique. Ceci renforce les recommandations cliniques sur l’utilisation de la chiropratique pour le soulagement de la lombalgie chronique primaire. D’autres études seront nécessaires pour clarifier les mécanismes neurophysiologiques et anti-inflammatoires des manipulations vertébrales. / Chiropractic is a health profession focused on the diagnosis, treatment, and prevention of musculoskeletal disorders, mainly through spinal manipulation (also known as "chiropractic adjustment"). The majority of patients consult a chiropractor seeking spine pain relief, primarily in the lower back. Low back pain is the leading cause of global disability, generating considerable costs for society and affected individuals. At least one third of people with low back pain experience persistent pain, leading to chronic disability and a decrease in quality of life. In affected individuals, no pathological process affecting the spinal tissues can be identified. Instead, this pain, called nociplastic, is presumed to be caused by pathological mechanisms within the nociceptive system. Thus, in these individuals, low back pain is considered as chronic primary pain, and not the symptom of an underlying disease. In some individuals, spinal manipulations can relieve chronic primary low back pain. However, their effectiveness as a first-line intervention and their hypoalgesic mechanisms remain to be demonstrated. The overarching aim of this thesis is to examine the hypoalgesic mechanisms of chiropractic spinal manipulations. The first specific objective is to investigate the hypoalgesic mechanisms of a spinal manipulation using an experimental model of persistent back pain in healthy individuals. The second specific objective is to investigate the mechanisms of relief of chronic primary low back pain by a four-week chiropractic intervention, including twelve sessions of spinal manipulations. The thesis includes two empirical studies: an experimental study and a clinical study, both preceded by a targeted literature review. The first study is a narrative review exploring the neurophysiological mechanisms of spinal manipulation to relieve spine pain. The second article describes the results of an experimental trial on healthy individuals, where we examined the mechanisms of pain inhibition following a spinal manipulation targeting a spinal segment sensitized by the topical application of capsaicin The third article is a narrative review examining the effectiveness of spinal manipulation for the treatment of spine pain. The fourth article describes the results of a randomized placebo-controlled trial with individuals suffering from chronic primary low back pain. In this study, we examined whether the relief of chronic primary low back pain by a chiropractic intervention is accompanied by an attenuation of pathological processes contributing to nociplastic pain. The results indicate that a single spinal manipulation can mitigate segmental mechanical hyperalgesia observed with the experimental model of persistent pain. This suggests that spinal manipulations could act on pathological processes that lead to chronic pain. These results are consistent with the pain reduction observed in patients with chronic primary low back pain receiving spinal manipulations. Furthermore, low back pain relief was accompanied by a reduction in mechanical hyperalgesia and in pain catastrophizing. Overall, these results indicate that a chiropractic intervention including spinal manipulations is efficacious in reducing chronic primary low back pain, and that this effect could in part stem from a reduction in processes contributing to nociplastic pain. This reinforces clinical recommendations on the use of chiropractic for the relief of chronic primary low back pain. Further studies will be needed to clarify the neurophysiological and anti-inflammatory mechanisms of spinal manipulations.

The trigeminal ganglion (TG) is a complex sensory structure and multiple lines of evidence suggest that significant differences exist in anatomical, neurochemical and physiological properties between it and its equivalent structure in the somatosensory system, the dorsal root ganglion (DRG). This is likely to be a reflection, first on the unique areas of tissue innervation of the TG and second, on the unusual responses to injury which give rise to distinct pain symptoms such as toothache, migraine and temporomandibular joint disorders. In an attempt to address this disparity in knowledge, we have carried out an in-depth in vivo study investigating neurochemical populations and cell size distributions of sensory neurons within the rat TG. We have performed a detailed analysis of expression patterns for receptor components of important inflammatory mediators, NGF (TrkA), TNFα (p55) and IL-6 (gp130), along with the thermo-transducers TRPV1 and TRPM8. For each analysis we have compared our findings with those of the rat DRG. We have shown a significantly larger population of NF200+ neurons within the TG (51%) compared to the DRG (40%), and most interestingly, the majority of NF200+ neurons in the TG were within the small to medium cell size range, conferring a nociceptive phenotype. We have for the first time, determined expression of p55 and gp130 protein levels within neurochemically defined subpopulations of the TG. We show that a large proportion (33%) of TG neurons, in particular 27% of NF200+ neurons co-express p55, and thereby have the potential to respond directly to TNFα. Furthermore, we have observed gp130 protein expression to be ubiquitous within the TG, suggesting all neurons, including non-nociceptors, could respond to IL-6. In addition, we have utilised biochemical and electrophysiological techniques in vitro to measure the functional outcome of exposure of TG neurons to IL-6. We have demonstrated that IL-6 activates the JAK/STAT signalling pathway, preferentially within NF200+ neurons. Furthermore, we have shown that IL-6 sensitises the response of TG neurons to the TRPV1 agonist capsaicin, altering the gating properties and prolonging the opening time of the channel. Taken together, our findings support the emerging picture of a complex combinatorial pattern of co-expression of sensory neurochemicals, transducers and receptor components that help to define TG neuronal modality and function. We would advocate caution in making generalisations across sensory ganglia in particular in extrapolating data from the DRG to the trigeminal ganglion.

Made available in DSpace on 2016-06-02T19:22:05Z (GMT). No. of bitstreams: 1 3116.pdf: 11974848 bytes, checksum: d69698c04f669985473e9e441c532444 (MD5) Previous issue date: 2009-12-11 / Universidade Federal de Sao Carlos / In innate or learned threatening situations, animals display a set of defensive behaviors specie-specific such as autonomic alterations, flight, fight and antinociception. Exposure of mice to open elevated plus-maze (oEPM: four open arms), an aversive situation, elicits antinociception of high magnitude. However, mechanisms involved in this kind of antinociception are not clear yet. This study investigated whether antinociception induced by exposure to an oEPM shows cross-tolerance with morphine (Exp. I and II); is attenuated by repetead exposure to the oEPM (Exp. III); is blocked by systemic treatment with naltrexone (Exp. IV); is prevented by adrenalectomy (Exp. V); persists after animal removal from the oEPM and if there are sex-related differences in this factor (Exp. VI); is mediated by CB1 cannabinoid receptor (Exp. VII). Rats were daily treated with morphine (M, 5 mg/kg, i.p.) or distilled water (DW) for 5 consecutive days (antinociceptive tolerance assessed by the tailflick test). Next day, rats received formalin 2.5% injection (50 μL) into the right hind paw and, after first phase of formalin test, they were treated with M or DW. 25 minutes after formalin injection into the paw, time spent licking the injected paw was recorded for 10 minutes (Exp. 1). Similar procedure was followed in the Experiment II, except that time spent licking the paw was recorded during exposure to the oEPM or enclosed EPM (eEPM: four arms enclosed) in undrugged rats. In Experiment III, nociception was evaluated in rats submitted to 1, 2, 3, 4 or 6 exposures to either eEPM or oEPM (formalin was injected only during the last exposure). Experiment IV investigated the effects of naltrexone (0 and 2.5 mg/kg; s.c.) on nociception during eEPM or oEPM exposure. Nociception was also assessed during the eEPM or oEPM exposure in sham and adrenalectomized rats (exp. V). In experiment VII, rats were treated with vehicle (DMSO 60%) or AM251 (1 mg/kg, i.p., CB1 receptor antagonist). Fifteen minutes later, animals received formalin injection into the paw and, 25 minutes after, they were exposed to the eEPM or oEPM. In experiment VI, male and female rats were exposed to eEPM or oEPM (with no noxious stimulus during exposure) and imediately after they were tested on the hot plate test (52.4 °C). Results showed that antinociception induced by oEPM does not display cross-tolerance to morphine; was not altered for at least 6 exposures to the maze; failed to be reversed by naltrexone; was not prevented by adrenalectomy and was not blocked by AM251. In addition, this antinociception does not persist after animal removal of the apparatus, by contrast, it occurs a hyperalgesia (as assessed by hot plate test), a response that does not depend on sex-related differences. Results suggest that antinociception induced by oEPM: is not mediated by opioid system or CB1 cannabinoid receptors and it is not sensitive to corticosterone. Furthermore, animal removal of aversive environment alters nociceptive response from antinociception to hyperalgesia, a phenomenon that is independent of the gender. / Em situações ameaçadoras de natureza inata ou aprendida, animais exibem um conjunto de comportamentos defensivos espécie-específicos, tais como alterações autonômicas, fuga, luta e antinocicepção. A exposição de camundongos ao labirinto em cruz elevado aberto (LCEa: quatro braços abertos), uma situação aversiva, induz antinocicepção de alta magnitude. Todavia, os mecansimos envolvidos em tal antinocicepção ainda não estão elucidados. O presente estudo investigou se a antinocicepção induzida por exposição ao LCEa: mostra tolerância cruzada a morfina (experimentos I e II); é atenuada por exposição repetida ao LCEa (experimento III); é revertida por tratamento sistêmico com naltrexona (experimento IV); é impedida por adrenalectomia (experimento V); persiste após remoção do animal do LCEa e se há diferenças relacionadas ao sexo neste fator (experimento VI); é mediada pelo receptor canabinóide, CB1 (experimento VII). Ratos foram diariamente tratados com morfina (M, 5 mg/Kg, i.p.) ou água destilada (AD) por 5 dias consecutivos (tolerância antinociceptiva avaliada pelo teste de retirada da cauda). No dia seguinte, os ratos receberam injeção de formalina 2,5% (50L) na pata traseira direita e, após a primeira fase do teste de formalina, foram tratados com M ou AD. Vinte e cinco minutos após injeção de formalina na pata, o tempo de lambidas na pata foi registrado por 10 minutos (experimento I). Procedimento semelhante foi utilizado no experimento II, exceto que o tempo de lambidas na pata foi registrado durante exposição ao LCEa ou LCE fechado (LCEf: quatro braços fechados). No experimento III, nocicepção foi avaliada em ratos submetidos a 1, 2, 3, 4 ou 6 exposições ao LCEf ou LCEa (formalina injetada somente durante a última exposição). O experimento IV investigou os efeitos de naltrexona (2,5 mg/kg; s.c.) sobre a nocicepção durante exposição ao LCEf ou LCEa. A nocicepção também foi avaliada durante exposição ao LCEf ou LCEa em ratos sham operados e adrenalectomizados (experimento V). No experimento VII, os ratos foram tratados com veículo (DMSO 60%) ou AM251 (1 mg/kg, i.p., antagonista CB1). Quinze minutos após, os animais receberam formalina na pata e, após 25 minutos, foram expostos ao LCEf ou LCEa. Já no experimento VI, ratos machos e fêmeas foram expostos ao LCEf ou LCEa, sem nenhum estímulo nociceptivo aplicado durante exposição e, imediatamente após, foram testados no teste da placa quente (52,4 °C). Os resultados mostraram que a antinocicepção induzida pelo LCEa não exibe tolerância cruzada a morfina; não foi alterada por ao menos 6 exposições ao labirinto; mostrou-se insensível à naltrexona; não foi impedida por adrenalectomia e não foi bloqueada por AM251. Ainda, tal antinocicepção não perdura após remoção dos animais do aparelho, pelo contrário, ocorre uma hiperalgesia (conforme avaliado pelo teste de placa quente), uma resposta que independe de diferenças relacionadas ao sexo. Os resultados sugerem que a antinocicepção induzida pelo LCEa: não é mediada por sistema opióide ou receptores canabinóides CB1 e não é sensível a corticosterona. Além disso, a retirada dos animais do ambiente aversivo altera a resposta nociceptiva de antinocicepção para hiperalgesia, um fenômeno que independe do gênero.