Fisiopatologia da Dor

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Efectos del consumo de cigarrillo en la presentación y severidad de la dismenorrea

Introducción: La dismenorrea se presenta como una patología cada vez más frecuente en mujeres de 16-30 años. Dentro de los factores asociados a su presentación, el consumo de tabaco ha revelado resultados contradictorios. El objetivo del presente estudio es explorar la asociación entre el consumo de cigarrillo y la presentación de dismenorrea, y determinar si los trastornos del ánimo y la depresión, alteran dicha asociación. Materiales y métodos: Se realizó un estudio de prevalencia analítica en mujeres de la Universidad del Rosario matriculadas en pregrado durante el primer semestre de 2013, para determinar la asociación entre el consumo de tabaco y la presentación de dismenorrea. En el estudio se tuvieron en cuenta variables tradicionalmente relacionadas con dismenorrea, incluyendo las variables ansiedad y depresión como potenciales variables de confusión. Los registros fueron analizados en el programa Estadístico IBM SPSS Statistics Versión 20.0. Resultados: Se realizaron 538 cuestionarios en total. La edad promedio fue 19.92±2.0 años. La prevalencia de dismenorrea se estimó en 89.3%, la prevalencia de tabaquismo 11.7%. No se encontró una asociación entre dismenorrea y tabaquismo (OR 3.197; IC95% 0.694-14.724). Dentro de las variables analizadas, la depresión y la ansiedad constituyen factores de riesgo independientes para la presentación de dismenorrea con una asociación estadísticamente significativa p=0.026 y p=0.024 respectivamente. El análisis multivariado encuentra como factor determinante en la presentación de dismenorrea, la interacción de depresión y ansiedad controlando por las variables tradicionales p<0.0001. Sin embargo, esta asociación se pierde cuando se analiza en la categoría de dismenorrea severa y gana relevancia el uso de métodos de anticoncepción diferentes a los hormonales, mientras que el hecho de haber iniciado la vida sexual presenta una tendencia limítrofe de riesgo. Conclusiones: No se puede demostrar que el tabaco es un factor asociado a la presentación de dismenorrea. Los trastornos del ánimo y la ansiedad constituyen factores determinantes a la presentación de dismenorrea independientemente de la presencia de otros concomitantes. Las variables de asociación se modifican cuando la variable dependiente se categoriza en su estado más severo. Se necesitan estudios más amplios y detallados para establecer dicha asociación.

Alguns aspectos funcionais da articulação temporomandibular.

The authors emphasize the some functional characteristics of the Temporomandibular join, TMJ, and were made comparative study of the auscultatory and sphymografic techniques to TMJ examination. The findings shown that the auscultatory technique furnished important dates to preliminary diagnosis of the TMJ disfunction.

A complexa fisiopatologia dos episódios vasooclusivos na anemia falciforme

Hemolytic anemia and vasoocclusion are the cardinal clinical features of sickle cell anemia. Vasoocclusion is a complex process involving not only the polymerization of deoxygenated sickle hemoglobin tetramers, but also interactions between sickle erythrocytes, vascular endothelium, platelets, leukocytes, and plasma proteins. The increased adherence of sickle erythrocytes to endothelium has been implicated as an early step in vasoocclusion. Other researchers have focused on leukocytes and platelets which might also contribute to disturbed blood flow. Microvascular occlusion results in acute painful crises, whereas macrovascular occlusion seems to be the cause of organ failure. The anemia results from the markedly shortened circulatory survival of sickle erythrocytes, together with a limited erythropoietic response. The erythropoiesis increases intensively, but it is not enough to balance the increased rate of erythrocytes destruction to maintain normal levels of total erythrocytes and hemoglobin concentrations; mainly by the low oxygen affinity of hemoglobin S and increased 2,3-Diphosphoglycerate. It is very difficult to separate processes leading to anemia or to vasoocclusion. Understanding the involvement of multiple blood componentes in vasoocclusion may elucidate the clinical manifestations and complications of sickle cell anemia, and may give new insights into the preventive and curative therapy.

Effects of mandibular fixed implant-supported prostheses on masticatory and swallowing functions in completely edentulous elderly individuals

Purpose: To evaluate the effect of oral rehabilitation with immediately loaded fixed implant-supported mandibular prostheses on chewing and swallowing in elderly individuals. Materials and Methods: Fifteen completely edentulous patients aged more than 60 years (10 women and rive men), wearing removable dentures in both arches, had a mandibular denture replaced by an implant-supported prosthesis. All individuals were evaluated before surgery and again 3, 6, and 18 months later with regard to mastication and swallowing conditions. Examinations entailed an interview, evaluation of tactile sensitivity of the face, and observation of food intake, masticatory type, formations of bolus, and pain during mastication. The swallowing evaluation comprised observation of clinical signs related to the oral and pharyngeal stages of swallowing, as well as the presence of oral residue. The findings of different evaluations before and 3, 6, and 18 months after the surgical-prosthetic procedure were statistically compared by analysis of variance for repeated measurements at a significance level of 5%. Results: The questionnaire revealed a reduction in complaints of masticatory and swallowing disturbances, a decreased need for liquid ingestion, and reduced choking and coughing. Clinical evaluations showed improved oral function and bolus propulsion for both solid and paste-consistency foods; pain during mastication was also resolved. Conclusion: Treatment with mandibular implant-supported dentures had positive effects on the clinical aspects of mastication and swallowing in elderly individuals.

Joint sounds in complete denture wearers. Literature review.

Long-term denture wearers can present with prosthesis instability, reduced occlusal vertical dimension and incorrect positioning of the jaw. This can lead to muscular changes and joint vibration. This study presents the main considerations related to joint vibrations in partially or totally edentulous patients. Occlusal treatment improves the disc-condyle relationship in the mandibular fossa. Furthermore, a detailed clinical exam and anamnesis must be performed to identify the dysfunction and its etiology, so that appropriate treatment can be provided.

[Pathophysiology of abdominal pain]

Abdominal pain can be induced by stimulation of visceral nociceptors. Activation of nociceptors usually requires previous sensitization by pathological events, such as inflammation, ischemia or acidosis. Although abdominal pain can obviously be caused by pathology of a visceral structure, clinicians frequently observe that such a pathology explains only part of the pain complaints. Occasionally, there is lack of objective signs of visceral lesions. There is clear evidence that pain states are associated with profound changes of the central processing of the sensory input. The main consequences of such alterations for patients are twofold: 1) a central sensitization, i.e. an increased excitability of the central nervous system; 2) an alteration of the endogenous pain modulation, which under normal conditions inhibits the processing of nociceptive signals in the central nervous system. Both phenomena lead to a spread of pain to other body regions and an amplification of the pain perception. The interactions between visceral pathology and alterations of the central pain processes represent an at least partial explanation for the discrepancy between objective signs of peripheral lesions and severity of the symptoms. Today, both central hypersensitivity and alteration in endogenous pain modulation can be measured in clinical practice. This information can be used to provide the patients with an explanatory model for their pain. Furthermore, first data suggest that alterations in central pain processing may represent negative prognostic factors. A better understanding of the individual pathophysiology may allow in the future the development of individual therapeutic strategies.

Studies on the pathophysiology and genetic basis of migraine

Migraine is a neurological disorder that affects the central nervous system causing painful attacks of headache. A genetic vulnerability and exposure to environmental triggers can influence the migraine phenotype. Migraine interferes in many facets of people’s daily life including employment commitments and their ability to look after their families resulting in a reduced quality of life. Identification of the biological processes that underlie this relatively common affliction has been difficult because migraine does not have any clearly identifiable pathology or structural lesion detectable by current medical technology. Theories to explain the symptoms of migraine have focused on the physiological mechanisms involved in the various phases of headache and include the vascular and neurogenic theories. In relation to migraine pathophysiology the trigeminovascular system and cortical spreading depression have also been implicated with supporting evidence from imaging studies and animal models. The objective of current research is to better understand the pathways and mechanisms involved in causing pain and headache to be able to target interventions. The genetic component of migraine has been teased apart using linkage studies and both candidate gene and genome-wide association studies, in family and case-control cohorts. Genomic regions that increase individual risk to migraine have been identified in neurological, vascular and hormonal pathways. This review discusses knowledge of the pathophysiology and genetic basis of migraine with the latest scientific evidence from genetic studies.

Modulation of pain processing in hyperalgesia by cognitive demand.

The relationship between pain and cognitive function is of theoretical and clinical interest, exemplified by observations that attention-demanding activities reduce pain in chronically afflicted patients. Previous studies have concentrated on phasic pain, which bears little correspondence to clinical pain conditions. Indeed, phasic pain is often associated with differential or opposing effects to tonic pain in behavioral, lesion, and pharmacological studies. To address how cognitive engagement interacts with tonic pain, we assessed the influence of an attention-demanding cognitive task on pain-evoked neural responses in an experimental model of chronic pain, the capsaicin-induced heat hyperalgesia model. Using functional magnetic resonance imaging (fMRI), we show that activity in the orbitofrontal and medial prefrontal cortices, insula, and cerebellum correlates with the intensity of tonic pain. This pain-related activity in medial prefrontal cortex and cerebellum was modulated by the demand level of the cognitive task. Our findings highlight a role for these structures in the integration of motivational and cognitive functions associated with a physiological state of injury. Within the limitations of an experimental model of pain, we suggest that the findings are relevant to understanding both the neurobiology and pathophysiology of chronic pain and its amelioration by cognitive strategies.

Stress-induced visceral pain in rodents: neurochemical, hormonal, immune and epigenetic mechanisms

Visceral pain is a debilitating disorder which affects up to 25% of the population at any one time. It is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. Currently the treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The work presented in this thesis aimed to redress this issue and look in more detail at the molecular mechanisms of visceral pain in preclinical models. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here a mouse model of early-life stress-induced visceral hypersensitivity was validated. Moreover, mouse strain differences were also apparent in visceral sensitivity suggesting a possible genetic component to the underlying pathophysiology. Furthermore, gender and sex hormones were also implicated in stress sensitivity and visceral pain. Using the rat model of maternal separation, some of the epigenetic mechanisms underpinning visceral hypersensitivity, specifically the contribution of histone acetylation were unravelled. Glutamate has been well established in somatic pain processing, however, its contribution to visceral pain has not been extensively characterised. It was found that glutamate uptake is impaired in viscerally hypersensitive animals, an effect which could be reversed by treatment with riluzole, a glutamate uptake activator. Moreover, negative modulation of the metabotropic glutamate (mGlu) receptor 7 was sufficient to reverse visceral hypersensitivity in a stress sensitive rat strain, the Wistar Kyoto rat. Furthermore, toll-like receptor 4 (TLR4) was implicated in chronic stress-induced visceral hypersensitivity. Taken together, these findings have furthered our knowledge of the pathophysiology of visceral pain. In addition, we have identified glutamate transporters, mGlu7 receptor, histone acetylation and TLR4 as novel targets, amenable to pharmacological manipulation for the specific treatment of visceral pain.

The Role of ULK1 in the Pathophysiology of Osteoarthritis

L'arthrose est la maladie musculo-squelettique la plus commune dans le monde. Elle est l'une des principales causes de douleur et d’incapacité chez les adultes, et elle représente un fardeau considérable sur le système de soins de santé. L'arthrose est une maladie de l’articulation entière, impliquant non seulement le cartilage articulaire, mais aussi la synoviale, les ligaments et l’os sous-chondral. L’arthrose est caractérisée par la dégénérescence progressive du cartilage articulaire, la formation d’ostéophytes, le remodelage de l'os sous-chondral, la détérioration des tendons et des ligaments et l'inflammation de la membrane synoviale. Les traitements actuels aident seulement à soulager les symptômes précoces de la maladie, c’est pour cette raison que l'arthrose est caractérisée par une progression presque inévitable vers la phase terminale de la maladie. La pathogénie exacte de l'arthrose est encore inconnue, mais on sait que l'événement clé est la dégradation du cartilage articulaire. Le cartilage articulaire est composé uniquement des chondrocytes; les cellules responsables de la synthèse de la matrice extracellulaire et du maintien de l'homéostasie du cartilage articulaire. Les chondrocytes maintiennent la matrice du cartilage en remplaçant les macromolécules dégradées et en répondant aux lésions du cartilage et aux dégénérescences focales en augmentant l'activité de synthèse locale. Les chondrocytes ont un taux faible de renouvellement, c’est pour cette raison qu’ils utilisent des mécanismes endogènes tels que l'autophagie (un processus de survie cellulaire et d’adaptation) pour enlever les organelles et les macromolécules endommagés et pour maintenir l'homéostasie du cartilage articulaire. i L'autophagie est une voie de dégradation lysosomale qui est essentielle pour la survie, la différenciation, le développement et l’homéostasie. Elle régule la maturation et favorise la survie des chondrocytes matures sous le stress et des conditions hypoxiques. Des études effectuées par nous et d'autres ont montré qu’un dérèglement de l’autophagie est associé à une diminution de la chondroprotection, à l'augmentation de la mort cellulaire et à la dégénérescence du cartilage articulaire. Carames et al ont montré que l'autophagie est constitutivement exprimée dans le cartilage articulaire humain normal. Toutefois, l'expression des inducteurs principaux de l'autophagie est réduite dans le vieux cartilage. Nos études précédentes ont également identifié des principaux gènes de l’autophagie qui sont exprimés à des niveaux plus faibles dans le cartilage humain atteint de l'arthrose. Les mêmes résultats ont été montrés dans le cartilage articulaire provenant des modèles de l’arthrose expérimentaux chez la souris et le chien. Plus précisément, nous avons remarqué que l'expression d’Unc-51 like kinase-1 (ULK1) est faible dans cartilage humain atteint de l'arthrose et des modèles expérimentaux de l’arthrose. ULK1 est la sérine / thréonine protéine kinase et elle est l’inducteur principal de l’autophagie. La perte de l’expression de ULK1 se traduit par un niveau d’autophagie faible. Etant donné qu’une signalisation adéquate de l'autophagie est nécessaire pour maintenir la chondroprotection ainsi que l'homéostasie du cartilage articulaire, nous avons proposé l’hypothèse suivante : une expression adéquate de ULK1 est requise pour l’induction de l’autophagie dans le cartilage articulaire et une perte de cette expression se traduira par une diminution de la chondroprotection, et une augmentation de la mort des chondrocytes ce qui conduit à la dégénérescence du cartilage articulaire. Le rôle exact de ULK1 dans la pathogénie de l'arthrose est inconnue, j’ai alors créé pour la première fois, des souris KO ULK1spécifiquement dans le cartilage en utilisant la technologie Cre-Lox et j’ai ensuite soumis ces souris à la déstabilisation du ménisque médial (DMM), un modèle de l'arthrose de la souris pour élucider le rôle spécifique in vivo de ULK1 dans pathogenèse de l'arthrose. Mes résultats montrent que ULK1 est essentielle pour le maintien de l'homéostasie du cartilage articulaire. Plus précisément, je montre que la perte de ULK1 dans le cartilage articulaire a causé un phénotype de l’arthrose accéléré, associé à la dégénérescence accélérée du cartilage, l’augmentation de la mort cellulaire des chondrocytes, et l’augmentation de l'expression des facteurs cataboliques. En utilisant des chondrocytes provenant des patients atteints de l’arthrose et qui ont été transfectées avec le plasmide d'expression ULK1, je montre qu’ULK1 est capable de réduire l’expression de la protéine mTOR (principal régulateur négatif de l’autophagie) et de diminuer l’expression des facteurs cataboliques comme MMP-13 et ADAMTS-5 et COX-2. Mes résultats jusqu'à présent indiquent que ULK1 est une cible thérapeutique potentielle pour maintenir l'homéostasie du cartilage articulaire.

Myofascial Pain Syndrome as a Contributing Factor in Patients with Chronic Headaches

Objectives: The purpose of this study was to evaluate the prevalence of active and latent trigger points [TrPs], as well as analyze the prevalence of different types of headaches in chronic headache patients. The active and latent TrPs in muscles of orofacial and cervical regions were also evaluated. Methods: There were 290 subjects who participated in this study. Trigger points were identified according to Simons et al.'s diagnostic criteria. Trigger points were considered active if subjects recognized the evoked referred pain as their familiar headache. If the evoked referred pain was not recognized as the familiar headache, the TrPs were considered latent. Differential diagnosis for headache was performed on the basis of International Headache Society criteria. Results: Trigger points could be diagnosed in 77 percent of patients and, in 89 percent of these, active TrPs were found. Muscle tenderness could be observed in 22 percent of patients, and only 1 percent patients were muscle-pain-free. The headache diagnosis showed that 26 percent had tension-type headache, 13 percent had migraine, and 61 percent had combined episodes of tension-type headache and migraine. The highest number of TrPs were found in temporalis [N = 159], masseter [N = 126], and occiptofrontalis [N = 113] muscles. Active TrPs were more frequent in temporalis and occiptofrontalis muscles. Conclusions: Subjects with chronic headaches had a higher prevalence of TrPs, and headache complaints could be reproduced during stimulation of active TrPs that were localized more frequently in temporalis and occiptofrontalis muscles. The presence of TrPs may be a contributing factor in the initiation and/or perpetuation of chronic headaches.

Relationship between anxiety and chronic orofacial pain of temporomandibular disorder in a group of university students

Purpose: This study evaluated the relationship between anxiety levels and severity degrees of chronic orofacial pain of temporomandibular disorder in brazilian university students. Methods: 150 volunteers (117 men and 33 women), with age ranging from 17 to 30 years, were subjects to this study. Spielberger's trait-state anxiety inventory was used to evaluate trait and state anxiety of the students, while examination for chronic orofacial pain was performed in accordance with the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Association between anxiety levels and severity degrees of chronic orofacial pain was tested using the Chi-square test. The significance level was set at p<.05. Results: The results showed that 32.7% (n = 49) of the subjects exhibited TMD, and the intensity of chronic orofacial pain was classified as degree 1 in 85.7% (n = 42) and as degree 2 in 14.3% (n = 7) of them. Based on the results of the Spielberger's trait-state anxiety inventory, the majority of the students had moderate anxiety (48.6% and 48.1%, respectively). The correlation between trait-anxiety levels and chronic orofacial pain degrees was significant and positive (p<.05). However, no significant correlation was found to state-anxiety levels and chronic orofacial pain degrees (p>.05). Conclusion: It was concluded that chronic orofacial pain of TMD could be present in university students and anxiety may be related. © 2010 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.

Facial pain associated with fibromyalgia can be marked by abnormal neuromuscular control: A cross-sectional study

Background. Temporomandibular disorder (TMD) development in fibromyalgia syndrome (FMS) is not yet fully understood, but altered neuromuscular control in FMS may play a role in triggering TMD. Objective. The purpose of this study was to verify the association between neuromuscular control and chronic facial pain in groups of patients with FMS and TMD. Design. A cross-sectional study was conducted. Methods. This study involved an analysis of facial pain and electromyographic activity of the masticatory muscles in patients with FMS (n=27) and TMD (n=28). All participants were evaluated according to Research Diagnostic Criteria for Temporomandibular Disorders and surface electromyography (SEMG). Myoelectric signal calculations were performed using the root mean square and median frequency of signals. Results. The data revealed premature interruption of masticatory muscle contraction in both patient groups, but a significant correlation also was found between higher median frequency values and increased facial pain. This correlation probably was related to FMS because it was not found in patients with TMD only. Facial pain and increased SEMG activity during mandibular rest also were positively correlated. Limitations. Temporal conclusions cannot be drawn from the study. Also, the study lacked a comparison group of patients with FMS without TMD as well as a control group of individuals who were healthy. Conclusions. Altered neuromuscular control in masticatory muscles may be correlated with perceived facial pain in patients with FMS. © 2013 American Physical Therapy Association.

Relationship between pain and anxiety in rats

Clinically, it is well known that neuropathic pain often induces comorbid symptoms such as anxiety. In turn, also anxiety has been associated with a heightened experience of pain. Although, the link between pain and anxiety is well recognized in humans, the neurobiological basis of this relationship remains unclear. Therefore, the aim of the current study was to investigate the influence of neuropathic pain on anxiety and vice versa in rats by assessing not only pain-related behaviour but also by discovering possible key substrates which are responsible for the interrelation of pain and anxiety.rnIn rats with a chronic constriction of the sciatic nerve (CCI model) anxiety-like behaviour was observed. Since anxiety behaviour could be completely abolished after the treatment of the pure analgesic drugs gabapentin and morphine, we concluded that anxiety was caused by the strong persistent pain. Furthermore, we found that the neuropeptides oxytocin and vasopressin were upregulated in the amygdala of CCI rats, and the intra-amygdala treatment of an oxytocin antagonist but not the vasopressin antagonist could reduce anxiety-like behaviour in these animals, while no effect on mechanical hypersensitivity was observed. These data indicate that oxytocin is implicated in the underlying neuronal processes of pain-induced anxiety and helps to elucidate the pathophysiological mechanisms of neuropathic pain. rnTo assess the influence of trait anxiety on pain sensation in rats, we determined mechanical hypersensitivity after sciatic nerve lesion (CCI) in animals selectively bred for high anxiety or low anxiety behaviour. The paw withdrawal thresholds were significantly decreased in high anxiety animals in comparison to low anxiety animals 2 and 3 weeks after surgery. In a second model state anxiety was induced by the sub-chronic injection of the anxiogenic drug pentylentetrazol in naive rats. Pain response to mechanical stimuli was increased after pharmacologically-induced anxiety. These results provided evidence for the influence of both trait and state anxiety on pain sensation. rnThe studies contribute to the elucidation of the relationship between pain and anxiety. We investigated that the neuropathic pain model displays sensory as well as emotional factors of peripheral neuropathy. Changes in expression levels of neuropeptides in the central nervous system due to neuropathic pain may contribute to the pathophysiology of neuropathic pain and its related symptoms in animals which might also be relevant for human scenarios. The results of the current study also confirm that anxiety plays an important role in the perception of pain. rnA better understanding of pain behaviour in animals might improve the preclinical profiling of analgesic drugs during development. The study highlights the potential use of the rat model as a new preclinical tool to further investigate the link between pain and anxiety by determining not only the sensory reflexes after painful stimuli but also the more complex pain-related behaviour such as anxiety.rn