Obesity constitutes a problem whose manifestations have consequences in almost every field of the medicine and nowadays there is a lack of pharmacological therapy alternatives for its long term treatment. Lipidic compounds as endocannabinoids and PPAR-α ligands are known to play an important role in the modulation of appetite and metabolism. Three series of fatty acid derivatives of catechol compounds were synthesized and their biological activity evaluated. Some of the synthesized compounds presented LDL antioxidant activity and/or food intake modulation in an animal model and their mechanism of action was also evaluated. The pharmacodynamics of the synthesized compounds could be explained by CB1 and PPAR-α interactions nevertheless it does not explain the activity of all compounds. / La obesidad es un problema cuyas manifestaciones tienen consecuencias en casi todos los campos de la medicina y actualmente existe una escasez de terapias farmacológicas para su tratamiento de uso continuo. Se sabe que algunos compuestos lipídicos como los endocanabinoides y ligandos del PPAR-α participan de manera importante en la modulación del apetito y en el metabolismo. Tres series de compuestos derivados de ácidos grasos con compuestos catecólicos fueron sintetizadas y sus actividades biológicas fueron evaluadas. Algunos de los compuestos presentó inhibición de la oxidación de la LDL y/o modulación de la ingesta en modelo animal y sus mecanismos de acción fueron también evaluados. La actividad de los compuestos pasa por interacciones con el receptor CB1 y el PPAR-α pero estas interacciones no explican la actividad de todos los compuestos

Dissertation (Ph.D.)--University of South Florida, 2009. / Includes vita. Includes bibliographical references. Also available online.

INTRODUCTION: It is estimated that 100 million individuals suffer from chronic pain in the United States. Many of the options involved in chronic pain management have limited effectiveness come with risks of addiction, and/or have numerous side effects. The toll of chronic pain is even more substantial when complications with addiction arise. With an estimated 13.7% of adults having admitted to using pain relief medication for nonmedical purposes in the United States totaling a cost of approximately 55 billion dollars annually, the combined burden of chronic pain and addiction is considerable. To curb the sufferings created by chronic pain, it is essential to investigate its sources, the risks involved with current treatments, and alternative methods to alleviate chronic pain. PURPOSE: The objective of this study is to review the current literature on the topic of nonopioid therapies in the treatment of chronic pain, their ability to reduce opioid prescriptions, and assess their pros and cons. Three different forms of alternative treatments were chosen: 1) psychotherapeutic treatment Cognitive Behavioral Therapy, 2) Eastern Medicine Acupuncture, and 3) pharmacological class cannabinoids. RESULTS AND CONCLUSION: The current literature on alterative therapies show that cannabinoids had the most potential to decrease pain, followed by CBT, and acupuncture showing the least consistent efficacy. The literature on CBT elucidate a great potential to decrease the use of prescribed opioids without increasing pain while cannabinoids showed a synergistic effect with opioids. The combined results for acupuncture were not consistent, with only one of the studies showing potential to reduce the use of opioids, while the others showed no difference between real and sham acupuncture.

The thesis research the frequency of illegal drugs use by student sof Univerzity of South Bohemia in the Czech Budějovice. In the theoretical part are characterized by drugs, illegal drugs and the effects of drug use on health, describes the emergence of drug addiction and its types and developmental stages of drug use. Furthermore, illegal drugs are divided into categories according to their effects and further described. The main aim of the practical part is the analysis of illegal drug use by students of the University of South Bohemia. On the basis of a questionnaire compiled data was found and it was statistically analyzed by the method, compares and conclusions were drawn. Over the past year have used an illegal drug 37.83% of respondents, that 2.91% of the respondents use illegal drugs daily. Earlier experience with illegal drugs has 18.78% of students of the University of South Bohemia. Past experience with drugs is more common in women, while use in the last year is much more common in men. The most commonly used substances are cannabinoids, as well as hallucinogens, opiates and finally stimulanci.

A Cannabis sativa L. (canábis) contém centenas de substâncias químicas em diferentes classes, contudo, a classe dos canabinoides é encontrada unicamente nesta espécie. Popularmente conhecida como maconha, a canábis é a droga ilícita mais consumida no mundo, sendo o Δ9-tetrahidrocanabinol (Δ9-THC), o principal canabinoide de interesse toxicológico, por ser o responsável pela maioria dos efeitos psicotomiméticos ocasionados e estar associado ao uso abusivo da planta. De outro modo, há alguns anos, vem crescendo significativamente o interesse em pesquisas científicas com a canábis, devido aos importantes efeitos terapêuticos que alguns canabinoides têm apresentado. O canabidiol (CBD), por exemplo, é um canabinoide que além de modular os efeitos eufóricos do Δ9-THC, tem apresentado importantes atividades farmacológicas. Embora haja um crescente aumento nas toneladas de apreensões de canábis realizadas no Brasil, não existem dados que caracterizem o perfil químico e a potência da droga que é utilizada ilegalmente no país. Outro aspecto singular com relação às apreensões de canábis refere-se à nova forma de tráfico internacional de drogas, que vem crescendo significativamente no país. Trata-se da remessa de sementes de canábis em pequenas quantidades através de empresas de transporte. Desta forma, este estudo foi realizado a partir de sementes de canábis apreendidas pela Superintendência de Polícia Federal no Rio Grande do Sul. As sementes foram germinadas e as plântulas foram cultivadas, secas e analizadas, sendo todos os passos em condições controladas. As metodologias analíticas utilizadas foram: espectroscopia no infravermelho próximo (NIRS), espectrometria de massas por ressonância ciclotrônica de íons com transformada de Fourier (FT-ICR MS) e cromatografia à gás com detector de massas (CG/EM). O elevado número de compostos presente nas plantas torna os dados obtidos muito complexos, onde pequenas diferenças entre amostras podem ser negligenciadas. Por isso, foram utilizadas as seguintes ferramentas quimiométricas: HCA, PCA, PLS-DA e SVM-DA. As diferentes metodologias de análise utilizadas neste trabalho, permitiram a análise de um total de 73 amostras de canábis que forneceram dados sob químicos, bem como aspectos distintos e relevantes em toxicologia. As informações obtidas por NIRS associadas às ferramentas quimiométricas HCA e PCA possibilitaram agrupar 29 amostras de canábis em diferentes períodos de crescimento; e as ferramentas quimiométricas PLS-DA e SVM-DA permitiram classificar 29 amostras de canábis em diferentes períodos de crescimento com 100% de acerto. O altíssimo poder de resolução da FT-ICR MS possibilitou a identificação 123 compostos canabinoides e metabólitos a partir das análises realizadas em 73 amostras de canábis, o que resultou na compilação de um abrangente perfil químico de canabinoides, até então não obtido. A eficiência de separação da CG acoplada à identificação dos compostos utilizando EM tornou possível a diferenciação de 73 amostras de canábis em tipo fibra ou tipo droga, além da caracterização do perfil químico de canabinoides e terpenoides presentes nas amostras, obtido pela análise em CG/EM. Desta forma, os dados gerados com o desenvolvimento desta tese possibilitaram a identificação e o conhecimento do perfil químico de amostras de canábis apreendidas no Brasil, apresentando informações até então desconhecidas pela polícia brasileira, bem como pelos profissionais da saúde, comunidade científica, órgãos governamentais e políticos do país e também para a população em geral. / Cannabis sativa L. (cannabis) contains hundreds of different classes of chemicals, however, the class of cannabinoids is found only in this plant. Popularly known marijuana, cannabis is the most used illicit drug worldwide, and the Δ9-tetrahydrocannabinol (Δ9-THC), the main cannabinoid regarding toxicological interest, being responsible by the majority of psychotomimetic effects and it is associated with the abuse of the plant. Otherwise, for a few years has grown significantly the interest and scientific research with cannabis due to significant therapeutic effects that certain cannabinoids have shown. The cannabidiol (CBD), for example, is a cannabinoid which in addition to modulate the euphoric effects of Δ9-THC, it has shown significant pharmacological activity. Although there is a growing increase in tons of cannabis seizures conducted in Brazil, there are no data which characterize the chemical profile and potency of the drug that is illegally used in the country. Another unique aspect regarding cannabis seizures refers to the new form of international drug trafficking that has grown significantly in the country. This is the shipment of cannabis seeds in small quantities by transportation companies. Thus, this study was based on samples from cannabis seeds seized by the Superintendence of the Federal Police in Rio Grande do Sul. The seeds were germinated and the seedlings were grown, dried and analyzed, all of the steps under controlled conditions. The analytical methods used were: near infrared spectroscopy (NIRS), Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and gas chromatography coupled with mass spectrometry (GC/MS). The high number of compounds presente in plants renders them very complex data set, where small differences between samples may be wasted. Therefore, the following chemometric tools were used: HCA, PCA, PLS-DA and DA-SVM. The different methods of analysis used in this study allowed the analysis of a total of 73 samples of cannabis that provided data on chemical and distinct and relevant aspects in toxicology. Information obtained by NIRS chemometric tools associated with HCA and PCA group allowed 29 samples of cannabis in different periods of growth; and chemometric tools PLS-DA and SVM-DA can be classified 29 samples of cannabis in different periods of growth with 100% accuracy. The very high resolution power of FT-ICR MS possible to identify 123 compounds cannabinoids and metabolites from the analyzes carried out on 73 samples of cannabis, which resulted in the compilation of a comprehensive chemical profile of cannabinoids, has not been surpassed. The GC separation efficiency coupled with the identification of compounds using MS made it possible to differentiate 73 cannabis samples in type or fiber type drug, besides the characterization of the chemical profile of cannabinoids and terpenoids present in the samples obtained through the analysis on GC/MS. Thus, the data generated with the development of this thesis allowed the identification and knowledge of the chemical profile of cannabis samples seized in Brazil, presenting information previously unknown to Brazilian police as well as by health professionals, the scientific community, government agencies and politicians of the country and also to the general population.

A Cannabis sativa L. (canábis) contém centenas de substâncias químicas em diferentes classes, contudo, a classe dos canabinoides é encontrada unicamente nesta espécie. Popularmente conhecida como maconha, a canábis é a droga ilícita mais consumida no mundo, sendo o Δ9-tetrahidrocanabinol (Δ9-THC), o principal canabinoide de interesse toxicológico, por ser o responsável pela maioria dos efeitos psicotomiméticos ocasionados e estar associado ao uso abusivo da planta. De outro modo, há alguns anos, vem crescendo significativamente o interesse em pesquisas científicas com a canábis, devido aos importantes efeitos terapêuticos que alguns canabinoides têm apresentado. O canabidiol (CBD), por exemplo, é um canabinoide que além de modular os efeitos eufóricos do Δ9-THC, tem apresentado importantes atividades farmacológicas. Embora haja um crescente aumento nas toneladas de apreensões de canábis realizadas no Brasil, não existem dados que caracterizem o perfil químico e a potência da droga que é utilizada ilegalmente no país. Outro aspecto singular com relação às apreensões de canábis refere-se à nova forma de tráfico internacional de drogas, que vem crescendo significativamente no país. Trata-se da remessa de sementes de canábis em pequenas quantidades através de empresas de transporte. Desta forma, este estudo foi realizado a partir de sementes de canábis apreendidas pela Superintendência de Polícia Federal no Rio Grande do Sul. As sementes foram germinadas e as plântulas foram cultivadas, secas e analizadas, sendo todos os passos em condições controladas. As metodologias analíticas utilizadas foram: espectroscopia no infravermelho próximo (NIRS), espectrometria de massas por ressonância ciclotrônica de íons com transformada de Fourier (FT-ICR MS) e cromatografia à gás com detector de massas (CG/EM). O elevado número de compostos presente nas plantas torna os dados obtidos muito complexos, onde pequenas diferenças entre amostras podem ser negligenciadas. Por isso, foram utilizadas as seguintes ferramentas quimiométricas: HCA, PCA, PLS-DA e SVM-DA. As diferentes metodologias de análise utilizadas neste trabalho, permitiram a análise de um total de 73 amostras de canábis que forneceram dados sob químicos, bem como aspectos distintos e relevantes em toxicologia. As informações obtidas por NIRS associadas às ferramentas quimiométricas HCA e PCA possibilitaram agrupar 29 amostras de canábis em diferentes períodos de crescimento; e as ferramentas quimiométricas PLS-DA e SVM-DA permitiram classificar 29 amostras de canábis em diferentes períodos de crescimento com 100% de acerto. O altíssimo poder de resolução da FT-ICR MS possibilitou a identificação 123 compostos canabinoides e metabólitos a partir das análises realizadas em 73 amostras de canábis, o que resultou na compilação de um abrangente perfil químico de canabinoides, até então não obtido. A eficiência de separação da CG acoplada à identificação dos compostos utilizando EM tornou possível a diferenciação de 73 amostras de canábis em tipo fibra ou tipo droga, além da caracterização do perfil químico de canabinoides e terpenoides presentes nas amostras, obtido pela análise em CG/EM. Desta forma, os dados gerados com o desenvolvimento desta tese possibilitaram a identificação e o conhecimento do perfil químico de amostras de canábis apreendidas no Brasil, apresentando informações até então desconhecidas pela polícia brasileira, bem como pelos profissionais da saúde, comunidade científica, órgãos governamentais e políticos do país e também para a população em geral. / Cannabis sativa L. (cannabis) contains hundreds of different classes of chemicals, however, the class of cannabinoids is found only in this plant. Popularly known marijuana, cannabis is the most used illicit drug worldwide, and the Δ9-tetrahydrocannabinol (Δ9-THC), the main cannabinoid regarding toxicological interest, being responsible by the majority of psychotomimetic effects and it is associated with the abuse of the plant. Otherwise, for a few years has grown significantly the interest and scientific research with cannabis due to significant therapeutic effects that certain cannabinoids have shown. The cannabidiol (CBD), for example, is a cannabinoid which in addition to modulate the euphoric effects of Δ9-THC, it has shown significant pharmacological activity. Although there is a growing increase in tons of cannabis seizures conducted in Brazil, there are no data which characterize the chemical profile and potency of the drug that is illegally used in the country. Another unique aspect regarding cannabis seizures refers to the new form of international drug trafficking that has grown significantly in the country. This is the shipment of cannabis seeds in small quantities by transportation companies. Thus, this study was based on samples from cannabis seeds seized by the Superintendence of the Federal Police in Rio Grande do Sul. The seeds were germinated and the seedlings were grown, dried and analyzed, all of the steps under controlled conditions. The analytical methods used were: near infrared spectroscopy (NIRS), Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and gas chromatography coupled with mass spectrometry (GC/MS). The high number of compounds presente in plants renders them very complex data set, where small differences between samples may be wasted. Therefore, the following chemometric tools were used: HCA, PCA, PLS-DA and DA-SVM. The different methods of analysis used in this study allowed the analysis of a total of 73 samples of cannabis that provided data on chemical and distinct and relevant aspects in toxicology. Information obtained by NIRS chemometric tools associated with HCA and PCA group allowed 29 samples of cannabis in different periods of growth; and chemometric tools PLS-DA and SVM-DA can be classified 29 samples of cannabis in different periods of growth with 100% accuracy. The very high resolution power of FT-ICR MS possible to identify 123 compounds cannabinoids and metabolites from the analyzes carried out on 73 samples of cannabis, which resulted in the compilation of a comprehensive chemical profile of cannabinoids, has not been surpassed. The GC separation efficiency coupled with the identification of compounds using MS made it possible to differentiate 73 cannabis samples in type or fiber type drug, besides the characterization of the chemical profile of cannabinoids and terpenoids present in the samples obtained through the analysis on GC/MS. Thus, the data generated with the development of this thesis allowed the identification and knowledge of the chemical profile of cannabis samples seized in Brazil, presenting information previously unknown to Brazilian police as well as by health professionals, the scientific community, government agencies and politicians of the country and also to the general population.

La persistance et la récurrence de la réponse inflammatoire dans le foie est la principale cause de développement des lésions hépatiques et de ses complications. Cette réponse immune est caractérisée par le recrutement de cellules inflammatoires, notamment de monocytes/macrophages et de lymphocytes. Elle est aussi impliquée d'une part dans le développement de la fibrose en activant les cellules fibrogéniques du foie, et d'autre part dans les mécanismes de régénération. Récemment, la présence d'une sous-population de lymphocytes T appelés Th17 a été identifiée dans de nombreuses pathologies hépatiques incluant la fibrose. Leur présence a également été observée lors de la régénération hépatique à partir de cellules progénitrices. Ces lymphocytes Th17 sont caractérisés principalement par la production de deux cytokines l'IL-17 et l'IL-22. Alors que le rôle de l'IL-22 a été récemment caractérisé dans la fibrose et la régénération hépatique, le rôle de l'IL-17 nécessitait d'être défini.Les objectifs de ma thèse ont donc été d'étudier le rôle et la régulation de l'IL-17 dans 1) les mécanismes de développement de la fibrose, et 2) son impact sur la régénération hépatique à partir de cellules progénitrices.1) L'équipe a démontré l'implication du système endocannabinoïde dans les maladies chroniques du foie. Ce système est composé de deux types de récepteurs, CB1 et CB2, couplés aux protéines G, et de ligands lipidiques endogènes. Alors que CB1 est majoritairement exprimé dans le cerveau et faiblement dans les tissus périphériques, CB2 est très fortement exprimé par les cellules immunitaires et présente en général des propriétés anti-inflammatoires. Notre hypothèse a donc été que l'activation du récepteur CB2, exprimé par les lymphocytes T régulerait négativement la réponse de type Th17 et le développement de la fibrose hépatique. Dans un modèle murin de fibrose induite par la ligature de la voie biliaire principale, nous avons montré que des souris CB2-/- développent une fibrose plus importante associée à une réponse inflammatoire de type Th17 augmentée par rapport à des souris sauvages. De plus, l'inhibition de la production de l'IL-17 chez ces souris CB2-/- à l'aide d'un inhibiteur de la différenciation Th17 (la digoxine), permet de réduire le développement de la fibrose. In vitro, l'activation du récepteur CB2 sur les lymphocytes Th17 par un agoniste sélectif, le JWH-133, diminue leur capacité à produire l'IL-17. Par ailleurs, nous avons montré par immunocyto-fluorescence, que l'activation de CB2 inhibe la production de l'IL-17 par une voie STAT5-dépendante. Ainsi, l'immuno-modulation de la réponse inflammatoire associée à la fibrose représente une stratégie anti-fibrosante prometteuse.2) L'infiltration de ces cellules Th17 a également été observée dans de nombreuses hépatopathies associées à une accumulation de cellules progénitrices intra-hépatiques (CPIH), appelées cellules ovales chez les rongeurs. La deuxième partie de ma thèse a donc consisté en l'étude du rôle de l'IL-17 dans la régénération du foie à partir de CPIH. Dans un modèle murin de régénération hépatique à partir de CPIH induit par un régime déficient en choline, et supplémenté en éthionine (CDE), nous avons montré que des souris invalidées pour l'IL-17 (IL-17-/-) présentent une diminution du nombre de CPIH CK19+, par rapport aux souris sauvages. L'invalidation de l'IL-17-/- a également été associée à une réduction du recrutement macrophagique et de la réponse pro-inflammatoire incluant l'IL-6, l'IL-1b et l'IL-27. Parmi ces cytokines, nous avons identifié l'IL-27 comme étant un facteur clé dans la différenciation des CPIH. In vitro, nous avons également montré que la production de l'IL-27 est induite par la stimulation des macrophages par l'IL-17. Ainsi, nos résultats révèlent que l'action combinée de l'IL-17 et de l'IL-27 orchestre la régénération du foie à partir de CPIH en favorisant leur prolifération et leur différenciation en hépatocytes, respectivement. / Persistence and recurrence of inflammatory response in the liver is the major cause of liver damage and its complications. This immune response is characterized by inflammatory cell recruitment, in particular monocytes / macrophages and lymphocytes. It has also been implicated in fibrosis development by activating liver fibrogenic cells, and also in regeneration mechanisms. Recently, a sub population of T lymphocytes called Th17 has been identified in numerous liver pathologies including fibrosis. These cells have also been observed in regenerating livers from progenitor cells. Th17 lymphocytes are mainly characterized by the production of two cytokines, namely IL-17 and IL-22. While the role of IL-22 has been recently described in liver fibrosis and regeneration, the role of IL-17 remained to be studied.The aims of my thesis were to study the role and the regulation of IL-17 in 1) fibrosis development, and 2) its impact on liver regeneration from progenitor cells.1) Our team has demonstrated the implication of the endocannabinoid system in chronic liver disease. This system is composed of two G-protein coupled receptors, CB1 and CB2, and their endogenous lipidic ligands. While CB1 is mainly expressed in the brain and slightly in peripheral tissues, CB2 is strongly expressed by immune cells and generally displays anti-inflammatory properties. Our hypothesis was that CB2 receptor activation, expressed by T lymphocytes, would negatively regulate Th17 response and liver fibrosis development. In a murine fibrosis model induced by bile duct ligation and section, we have showed that CB2-/- mice have an enhanced fibrosis associated with an increased Th17 inflammatory response as compared to wild-type animals. Additionally, IL-17 production inhibition in these CB2-/- mice with an inhibitor of Th17 differentiation (digoxin), reduced fibrosis development. In vitro, CB2 receptor activation on Th17 lymphocytes by a selective agonist, JWH-133, diminished their ability to produce IL-17. Moreover, we demonstrated by immunocyto-fluorescence, that CB2 activation inhibits IL-17 production in a STAT5-dependent manner. Thus, the modulation of the inflammatory response associated with fibrosis is a promising strategy against fibrosis.2) Th17 cell infiltration has also been observed in liver disease associated with liver progenitor cell (LPC) accumulation, called oval cells in rodents. The second part of my thesis was aimed to study IL-17 role in liver regeneration from LPC. In a murine model of liver regeneration from LPC induced by a choline deficient and éthionine supplemented diet (CDE), we have demonstrated that IL-17 deficient mice (IL-17-/-) have a reduced number of CK19+ LPC as compared to wild-type animals. IL-17 deficiency was also associated with a decrease in macrophage recruitment and reduced pro-inflammatory response including IL-6, IL-1b and IL-27. Among these cytokines, we identified IL-27 as a key factor in LPC differentiation. In vitro, we also showed that IL-27 production is induced after IL-17-induced macrophage activation. Thereby our results revealed that the combined action of IL-17 and IL-27 leads to LPC driven liver regeneration by enhancing their proliferation and their differentiation towards hepatocytes, respectively.

The obesity epidemic is a major health threat affecting one in four people in the affluent western world, where high-energy foods are easily available and there is little need for exercise. To identify novel therapeutic targets for the treatment of obesity, one important step is to further define the complex circuitry in the brainwhich is ultimately responsible for our appetite and body weight regulation. Although complex, appetite can be thought of as having two distinct, though none mutually exclusive, aspects: the need to eat (homeostatic) and the desire to eat(hedonistic).The need to eat, a product of energy homeostasis, is what drives the consumption offood for basic survival. In an attempt to further define the mainly “homeostatic” neuronal circuitry, we combined blood-oxygen-level-dependent (BOLD)pharmacological-challenge magnetic resonance imaging (phMRI) with c-Fosfunctional activity mapping to characterise “whole brain” responsiveness to anorexigenic dose of the glucose anti metabolite 2-deoxy-D-glucose (2-DG). Using thesecomplementary methods, we demonstrated functional brain activity in a number ofknown glucose-sensing brain regions, including parts of the hypothalamus andbrainstem, following administration of 2-DG when compared with vehicle treatment.The desire to eat is a result of a complex interplay between the reward andmotivational circuits implicated in addictive behaviours, and those which controlenergy homeostasis. Recent research has pointed to the endocannabinoid system,and specifically the central cannabinoid 1 (CB1) receptor, as a key target mediatingthe functional cross talk between the two appetitive systems. To define the sites ofaction of cannabinoids, we used an orexigenic dose of the full CB1 agonist, CP55940,to map responsive brain regions again using BOLD phMRI and whole-brain c-Fosfunctional activity mapping. Areas of interest demonstrated a drug interaction whenthe CB1 receptor inverse agonist, Rimonabant was co-administered. These complementary methods demonstrated functional activity in the cortico-striatalhypothalamicpathway, a key system in the motivational drive to eat.The appetitive actions of synthetic CB1 inverse agonists such as Rimonabant are welldocumented. We, however, described a putative novel endogenous CB1 inverseagonist, hemopressin, which is the first identified peptide ligand of CB1 receptors.We showed that hemopressin inhibits agonist-induced receptor internalisation in aheterologous cell model in vitro. When administered centrally or systemically in vivo,we found that hemopressin decreases nocturnal food intake in out-bred rats andmice, as well as in obese, leptin-deficient ob/obmice. Importantly, hemopressininduces hypophagia without causing any apparent adverse side effects. We have also shown that the anorectic effect is absent in CB1-/- mice, and that hemopressin canblock CB1 agonist-induced hyperphagia in male rats, providing strong evidence forantagonism of the CB1 receptor in vivo. We speculate that hemopressin may be one of a family of endogenous functional CB1 receptor ligands that modulate the activity of appetite pathways in the brain.

Tricomas secretores são apêndices epidérmicos presentes nas maiorias das plantas desempenhando funções diversas, dentre elas a defesa contra herbivoria. Dentre as famílias que apresentam tricomas secretores destaca-se Cannabaceae, que é amplamente estudada por produzir compostos psicoativos e outros utilizados como aromatizantes de cerveja. Recentemente alguns gêneros pertencentes à Ulmaceae foram inseridos em Cannabaceae, como Celtis e Trema. Tais gêneros são os mais numerosos em espécies da família. Considerando que tricomas secretores são os principais sítios de produção de substâncias de interesse econômico, e que são amplamente utilizados como caráter de valor taxonômico, o presente trabalho comparou a distribuição e morfologia de tricomas secretores de duas espécies de Cannabaceae (Celtis pubescens e Trema micrantha) e três espécies afins de Ulmaceae (Ampelocera glabra, Phyllostylon rhamnoides e Ulmus parvifolia). Os dados foram comparados aos existentes na literatura e discutidos em um contexto sistemático. Os tricomas secretores de Trema micranta foram, ainda, analisados em detalhe quanto à ontogenia, análise química do exsudato (in situ e direto) e ultraestrutura. Para tal, amostras de folhas e flores (pistiladas e estaminadas) foram coletadas, fixadas e processadas para análise de microscopia de luz, eletrônica de varredura e de transmissão. Foram encontrados cinco morfotipos diferentes nas espécies estudadas. C. pubescens e T. micrantha apresentaram tricomas secretores capitados e filiformes, que diferiram quanto ao pedúnculo, unisseriado em C. pubescens e bisseriado em T. micrantha. As três espécies de Ulmaceae apresentaram um único morfotipo (capitado com pedúnculo unicelular). Os tricomas de T. micranta iniciam o desenvolvimento com uma divisão anticlinal, semelhante ao que ocorre em Cannabis sativa. Seus tricomas secretam terpenos, alcaloides e compostos fenólicos. Testes químicos comprovaram a presença de alcaloides e os indicadores de canabinoides sugerem que T. micrantha apresenta potencial para produção desses compostos. A morfologia dos tricomas encontrados nas espécies de Cannabaceae é diferente da observada nas espécies de Ulmaceae, o que apoia a atual circunscrição destas famílias. A diversidade morfológica e de termos utilizados torna difíceis a classificação e comparação entre os tipos de tricomas secretores, sendo necessários esforços no sentido de padronizar a caracterização destas estruturas secretoras, em especial nas famílias que compõem o clado urticoide. / Secretory trichomes are epidermal appendages that are present in most plants performing various functions, among them the defense against herbivory. Cannabaceae comprises plants covered with secretory trichomes, and is a well-known family for producing psychoactive compounds and others used as beer flavorings. Recently some genera belonging to Ulmaceae were inserted into Cannabaceae, such as Celtis and Trema, the species-richest genera of the family. As the secretory trichomes are the main plant source of economically important substances and are widely used as taxonomic markers, the present study compared the distribution and morphology of secretory trichomes of two species of Cannabaceae (Celtis pubescens and Trema micrantha) and three related species of Ulmaceae (Ampelocera glabra, Phyllostylon rhamnoides and Ulmus parvifolia). The data were compared to those in the literature and discussed in a systematic context. The secretory trichomes of Trema micranta were also analyzed in detail regarding ontogeny, histolocalization of substances and ultrastructure. For this, samples of leaf and flower (pistillate and staminate) were collected, fixed and processed for analyses of light microscopy, scanning electron microscopy and transmission electron microscopy. For T. micranta chemical tests in situ and direct were carried out; in addition, samples were prepared for ultrastructural study in transmission electron microscopy. Five different morphotypes of secretory trichomes were found in the species studied. C. pubescens and T. micrantha exhibited capitate and filiform secretory trichomes that differed in the stalk, uniseriate in C. pubescens and biseriate in T. micrantha. The three species of Ulmaceae had a single morphotype (capitate with a unicellular stalk). The trichomes of T. micranta originate of a first anticlinal cell division, similar to what occurs in Cannabis sativa. They secrete terpenes, alkaloids and phenolic compounds. Chemical tests have confirmed the presence of alkaloids and cannabinoid indicators suggest that T. micrantha is a putative species for the production of these compounds. The morphology of the trichomes found in the species of Cannabaceae is different from that observed in the species of Ulmaceae, which supports the current circumscription of these families. The diversity of morphology and terms employed makes it difficult to classify and compare the types of secretory trichomes. In this sense, efforts are needed to standardize the characterization of these secretory structures, especially in the families that comprise the urticalean rosids.

Appartenant à la sous-famille des récepteurs couplés aux protéines G (RCPGs) apparentés àla rhodopsine et identifiés comme des cibles à fort potentiel thérapeutique, les récepteurs MT, et MT2à la mélatonine, 5-HT2C à la sérotonine et CB2 aux cannabinoïdes ont été étudiés par des approches insilico afin de mettre en évidence les déterminants structuraux critiques pour l'affinité, la sélectivité etl'activité pharmacologique de leurs ligands. Bénéficiant de données cristallographiques récentes,plusieurs états conformationnels de ces quatre récepteurs ont été modélisés en fonction du profilpharmacologique recherché. L'étude comparative de ces différents états conformationnels par dessimulations de dynamique moléculaire a permis de caractériser le rôle prépondérant joué par la boucleextracellulaire E2 et l'hélice 6 dans les mécanismes d'activation de ces RCPGs. Sur la base deméthodes chémoinformatiques, le criblage virtuel de ligands ciblant ces modèles tridimensionnels apermis de caractériser un modèle du récepteur 5-HT2C très spécifique de ligands agonistes inverses etd'identifier des touches pharmacologiques sur les récepteurs MTi et CB2. / Identified as highly relevant therapeutical targets, the MT, and MT2 melatonin receptors, the5-HT2C serotonin and the CB2 cannabinoid receptors, which belong to the rhodopsin-like G proteincoupledreceptors (GPCRs) subfamily, have been studied by in silico approaches in order to identifycritical structural features for the binding, the selectivity and the pharmacological activity of theirligands. Gaining by sottie recent crystallographic data, various conformational states of these fourreceptors have been modeled according to the expected pharmacological profile. The comparativestudy of these various conformational states by molecular dynamics simulations has led to emphasizethe crucial rôle of the E2 extracellular loop and hélix 6 in the activation mechanisms of these GPCRs.On the basis of chemoinformatic methods, the virtual ligand screening targeting these threedimensionalmodels has promoted the characterization of a 5-HT2C receptor model able to bindspecifically inverse agonist ligands and the identification of pharmacological hits targeting the MTiand CB2 receptors.