Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This goal of this dissertation was to conduct preclinical research experiments designed to address a set of three inter-related aims that examine the expression, mechanisms and treatment of pain-related depression of Intracranial Self-Stimulation (ICSS) in rats. First, studies evaluated the hypothesis that acute acid-induced depression of ICSS was mediated by a kappa opioid receptor mediated decrease in mesolimbic dopamine release in the nucleus accumbens. Results support a role for depressed mesolimbic dopamine release in pain-related depression of ICSS; however, a role for kappa opioid receptors is not supported. Second, studies evaluated the effectiveness of a more sustained inflammatory noxious stimulus (intraplantar CFA) and a sustained neuropathic stimulus (intraplantar formalin) to produce a long-term pain-related depression of ICSS, and the role of kappa opioid receptors in mediating this sustained pain-related depression of ICSS. Results indicated that only the neuropathic stimulus (formalin) was sufficient to produce sustained depression of ICSS, and as in the initial studies, our data did not support a role for kappa receptors in mediating this effect. Given the poor effectiveness of a kappa receptor antagonist to block acute or chronic pain-related depression of ICSS, the final set of studies evaluated the pharmacology of representative drugs from five different classes of established or candidate analgesics (mu opioid agonists, non-steroidal anti-inflammatory drugs, monoamine uptake inhibitors, anticonvulsants, and cannabinoid agonists) to reverse the sustained depression of ICSS produced by formalin as a neuropathic stimulus. Results demonstrate the mu agonist morphine, the monoamine uptake inhibitor bupropion, the anticonvulsant gabapentin, and the cannabinoid agonist THC were able to reverse formalin-induced mechanical allodynia as a pain-stimulated behavior, but only the mu agonist morphine and the monoamine uptake inhibitor bupropion were effective to reverse formalin-induced depression of ICSS. These results provided additional evidence for dissociable drug effects in preclinical assays of pain-stimulated and pain-depressed behavior and also support further studies with monoamine uptake inhibitors with a dopaminergic component (like bupropion) for treatment of neuropathic pain.

"Diabetic cardiovascular autonomic neuropathy (DCAN) is common in patients with diabetes mellitus, and causes abnormalities in heart rate control as well as central and peripheral nervous system dynamics. A good understanding of DCAN is not established yet. An effective way to detect diabetes mellitus at an early stage is still undiscovered, which method is highly desired by researchers and patients. One reason why the pathogenesis of DCAN is unclear is that non- invasive assessment of DCAN in humans and animals has been problematic. The non-stationary and non- linear natures of the interested physiological signals have placed great limitation on traditionally algorithms. To overcome this limitation, this work proposes a series of time- varying, nonlinear and non-invasive methods to assess cardiac autonomic dysregulation from ECG and PPG records. Including a non-stationary method called PDM, which is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV), nonstationary power spectral density called TVOPS-VFCDM and also standard spectrum analysis method of HRV. We are also able to study and analyze a series of long term and short term ECG and PPG data. In a pilot study, ECG was measured via telemetry in conscious 4 month old C57/Bl6 controls and in Akita mice, a model of insulin- dependent type I diabetes, while PPG was measured via tail pulse oximetry system from 2 month old to 4 month old. The results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls at 4 month old and such impairment start to present at 3 month old. Further, both immunohistochemistry and Western blot analyses show a reduction in nerve density in Akita mice as compared to the control mice, thus, corroborating our data analysis records."

The research in this thesis has examined the use of texture and shape analysis to characterise Magnetic Resonance (MR) images of peripheral nerves in order to provide a potential quantitative tool for better diagnosis and treatments. Texture and shape can be considered as inherent properties of all surfaces and have the potential to provide sensitive information which cannot be quantitatively perceived by human vision. Texture analysis has been successfully used in image classification of aerial and satellite imagery and the diagnosis and prognosis of several types of cancer. However, to date, it has never been used in investigating peripheral nerve damage. In this thesis, we study the application of texture and shape analysis to the peripheral nerves in the upper extremities of patients suffering from Whiplash Associated Disorders (WAD). Specifically, quantitative texture analysis was performed on MR images of the carpal tunnel which contains the median nerve. The median nerve was studied to identify differences in textural patterns. Texture methods such as: first order features; co-occurrence matrices; run-length matrices and autocorrelation function were applied and their performance was assessed. Texture analysis was also performed to investigate nerve damage in the MR images of the brachial plexus, both in controls and patients. Further, spatial domain shape metrics were used to quantify and study the morphological differences of the median nerve in controls and patients. This highlighted that some significant differences exist between groups and thus could potentially be reliably used in combination with clinical scale metrics to identify possible nerve damage. As MR images contain noise, locating the median nerve accurately to perform image analysis is very important. Therefore, we further investigated the application of an enhanced correlation filtering method that could be trained on images of the median nerve and then applied to detect the median nerve in test images. The Optimal Trade-off Maximum Average Correlation Height (OT-MACH) filter includes the expected distortions in the target in the construction of the filter reference function. The OT-MACH filter was tuned in a bandpass to maximize the correlation peak and thereby successfully locate the position of the median nerve in the carpal tunnel. This study has successfully demonstrated that texture and shape analysis can be used to investigate possible peripheral nerve damage. Further research is required using larger datasets to establish a quantitative image analysis tool to support clinical decision making and thereby improve patient care and treatment outcome.

HSCR has been felt to be a polygeneic disease on the basis of an incompletely penetrant sex modified transmission, which may be either autosomal dominant or recessive in different kindred. During the 1990's several of the genes involved in this transmission have come to light. Other genes remain to be discovered.

D-lactic acidosis (DLA) is a disease associated with D-lactatemia, acidosis and neurological signs. However, these associations are ill-defined. Bacterial fermentation in the intestine causes increasing D-lactic acid concentrations in the body. Therefore, DLA is reported secondary to gastrointestinal diseases, such as short bowel syndrome, gastroenteritis or diarrhea. Despite intestinal origin, sudden D-lactatemia is often a result of impaired D-lactate metabolism in the body.<p> Aims of this work were to determine: 1) Influence of the presence of D-lactate or acidity on neurological disturbances; 2) Effectiveness of parenteral NaHCO3 therapy in correcting cerebrospinal acidity and DLA; 3) Prevalence of DLA in diarrheic lambs and fecal D-lactate thresholds; 4) Effectiveness of malate in preventing DLA.<p> The methodological tools consisted of animal models (calves and lambs): 1) Advanced surgical procedure in calves for long-lasting atlanto-occipital catheterizations; 2) Intravenous infusions of acids to experimentally induce acidosis; 3) Intravenous NaHCO3 therapies; 4) Sampling of cerebrospinal fluid (CSF), blood, urine and feces from experimental / treated calves or diarrheic lambs for blood gas analysis, and D-lactate separation by chromatography.<p> D-lactate entered the central nervous system (> 2 mmol/L) from the circulation following experimentally induced D-lactatemia (> 5 mmol/L) and was responsible for neurological disturbances which correlated (r = 0.9, P < 0.05) with both CSF and serum D-lactate concentrations. A zenith of neurological disturbances, ataxia was evident when D-lactate concentration exceeded 12 mmol/L (CSF) and 26 mmol/L (serum), however, a nadir of acidosis (pH 6.9) caused by HCl infusions produced only mild neurological disturbances (P < 0.05). Therapeutic NaHCO3 infusions did not result paradoxical CSF acidosis, but supportive in correcting (P < 0.05) acidosis (ÄpH + 0.11) and D-lactatemia in calves.<p> In lambs, metabolic acidosis following a range of mild to severe diarrhea was observed with a corresponding range of D-lactate concentrations in both serum (< 0.05−24.0 mmol/L) and feces (< 0.05−31.0 mmol/L). D-lactate was absorbed into the circulation when the fecal D-lactate concentration exceeded 10.2 mmol/L (threshold). In calves, moderate oral use of malate produced a > 50% (P < 0.05) decrease in fecal and serum D-lactate concentrations suggesting prebiotic properties to prevent DLA. <p> This dissertation answers the critical questions about the onset of neurological signs in D-lactic acidosis, and advances the current knowledge on the metabolism of D-lactate, the prevention and treatment of acidosis.

Damage to peripheral nerves following trauma or disease has a number of consequences including burning pain, muscle wasting, paralysis, or organ dysfunction. The most common form of neuropathy is that associated with metabolic abnormality, notably diabetes. Many diabetics, especially those with poor blood sugar control, ultimately develop a distal symmetrical and painful neuropathy that initially affects the longest peripheral axons, but with time spreads proximally. Deficiency in neurotrophic support has been proposed to contribute to the development of diabetic neuropathy. Recently, peripheral gene delivery of vascular endothelial growth factor (VEGF), neurotrophin-3 (NT-3), NGF, BDNF or hepatocyte growth factor (HGF) has been shown to facilitate the continuous production of neurotrophic factors and alleviate the diabetic neuropathy. The role of glial cell-derived neurotrophic factor (GDNF) in the pathogenesis and therapeutics of diabetic neuropathy is not well defined. The main objectives of this research sought to inspect the protective effect of GDNF peripheral gene delivery during hyperglycemia- or constriction- induced sciatic nerve injury in rats. In present proposal, we propose to investigate the change in organization and expressions of GDNF signaling complex in the sciatic nerve following injury in the initial stage. Subsequently, the recombinant adenovirus was used gene delivery system for GDNF to evaluate the potential of intramuscular administration of gene delivery for prevent nerve degeneration, and the molecular mechanism of GDNF to ameliorate neuropathy will be clarified. The above study would enable us to test the hypothesis that the topical gene delivery might be a suitable strategy for the treatment of diabetic neuropathy and other disorders in peripheral nerve. Furthermore, the results of animal studies might be extrapolated for future clinical application.

The goal of this thesis was to examine the processing of clinical pain in two patient groups with well defined primary pathologies, i.e. neuropathic pain patients and patients with rheumatoid arthritis (RA). It was hypothesized that chronic pain is associated with plastic changes in pain processing brain structures that can be detected using functional magnetic resonance imaging (FMRI). The first study, presented in Chapter 3, demonstrates that the neural representation of experimental heat pain is different in neuropathic pain patients than in age- and gender-matched healthy control subjects, although the pain stimulus was applied outside clinically affected areas. Increased activation was found in amygdala and anterior insula in the patient group and was accompanied by increased state anxiety and depression scores. Anterior insula is the focus of Chapter 4 in which it is demonstrated that clinical pain processing is located significantly more anteriorly in the insula than experimental pain processing, in close proximity to neural correlates of highly negative emotions and the conscious perception of bodily sensations. This offers a potential explanation for the shift of clinical pain processing. In Chapter 5, clinical pain is contrasted with experimental pain in the same patient population, i.e. patients with RA. In addition to comparing clinical and experimental pain processing, it was investigated if emotional and cognitive determinates of the pain experience, specifically depression and catastrophizing, exert different influences on the two types of pain. It is shown that clinical pain, but not experimental pain, is likely to be driven partially by depressive symptoms whereas catastrophizing is associated with the same neural activation pattern in both conditions. The cerebral representation of allodynic pain in neuropathic pain patients is presented Chapter 6. Chapters 6 and 7 demonstrate that the FMRI signal encodes the perceived intensity of clinical allodynic pain across subjects and that it reflects longitudinal variations of the perceived intensity within subjects. This thesis illustrates that FMRI can reveal subtle differences in the processing of clinical and experimental pain, despite brain activation patterns being similar on the whole. It also indicates that FMRI can be used to elucidate the origin of these differences, for instance by studying the influence of emotional and cognitive variables. This suggests that neuroimaging methods, in particular FMRI, have the potential to dissect clinical pain into its constituent parts, including central sensitization, brainstem facilitation and amplification by psychological factors. Such knowledge could potentially be exploited to target treatment selectively at different components of clinical pain and to monitor longitudinal changes of these components separately.

HSCR has been felt to be a polygeneic disease on the basis of an incompletely penetrant sex modified transmission, which may be either autosomal dominant or recessive in different kindred. During the 1990's several of the genes involved in this transmission have come to light. Other genes remain to be discovered.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / HansenÃase ainda à um problema de saÃde em alguns paÃses no mundo. A neuropatia à a principal complicaÃÃo da hansenÃase, e leva à incapacidade e deformidades. A meta da OrganizaÃÃo Mundial de SaÃde à reduzir em 35% o nÃmero de casos novos com classificaÃÃo de incapacidade grau 2 atà o ano de 2015. Para atingir esse objetivo, à fundamental realizar o diagnÃstico precoce da doenÃa e da lesÃo neural, para que se possa intervir com o tratamento de corticosteroide e conseguir a prevenÃÃo da deformidade. Testes clÃnicos (monofilamentos e teste muscular) apresentam um atraso de 12 semanas em relaÃÃo à eletroneuromiografia (ENMG) para detectar a neuropatia hansÃnica. O objetivo desse estudo foi identificar os fatores clÃnicos associados com a eletroneuromiografia positiva para neuropatia hansÃnica, alÃm disso, avaliar a concordÃncia entre os testes clÃnicos e a ENMG. Foi conduzido um estudo com delineamento caso-controle aninhado a um estudo de teste diagnÃstico no Centro de ReferÃncia em Dermatologia Dona LibÃnia no perÃodo de 2007 a 2013. A amostra foi composta por 166 (77,1%) casos e 38 controles (22,9%). Os fatores significativamente associados com a ENMG positiva para neuropatia hansÃnica foram: idade entre 41-60 anos, presenÃa de formigamento e espessamento neural. Nenhum fator dermatolÃgico ou de classificaÃÃo foi associado com a neuropatia hansÃnica. A concordÃncia entre os testes clÃnicos e a eletroneuromiografia variou de baixa a moderada (monofilamentos k=0,02 e teste muscular k=0,16), o nervo mais acometido foi o ulnar com 67 (40,3%) casos e o padrÃo eletrofisiolÃgico mais prevalente foi a mononeuropatia mÃltipla sensitiva motora com 62 (37,3%) casos. Conclui-se que a neuropatia hansÃnica à muito prevalente, e que os fatores clÃnicos associados podem ser utilizados para identificar precocemente pacientes em alto risco de desenvolver a lesÃo do nervo. Sugere-se um aumento dos esforÃos e investimentos na qualificaÃÃo e treinamento dos profissionais de saÃde para o diagnÃstico precoce. / Leprosy is still a health problem in some countries in the world. Neuropathy is the main complication of leprosy, and leads to disability and deformity. The goal of the World Health Organization is to reduce by 35% the number of new cases with grade-2 disability rating until the year 2015. In order to achieve this target, it is fundamental that the early diagnosis of disease and nerve damage, to allow an intervention with corticosteroid treatment and achieve the prevention of deformity. Clinical tests (monofilaments and muscle strength) have a delay of 12 weeks compared to electroneuromyography (ENMG) to detect leprosy neuropathy. The aim of this study was to identify the clinical factors associated with positive electroneuromyography to leprosy neuropathy, in addition, to evaluate the correlation between clinical tests and ENMG. We conducted a case-control study nested to a diagnostic test design at the Dona Libania Dermatology Center in the period 2007-2013. Sample was composed of 166 (77.1%) cases and 38 (22.9%) controls. Factors significantly associated with positive ENMG for leprosy neuropathy were: age between 41-60 years, the presence of tingling and nerve enlargement. No dermatological or classification factors were associated with leprosy neuropathy. Concordance between the clinical tests and electroneuromyography ranged from low to moderate (k = 0.02 for monofilaments and k = 0.16 for muscle strength), the most affected nerve was the ulnar with 67 (40.3%) cases and the most prevalent electrophysiological pattern was the multiple sensorimotor mononeuropathy with 62 (37.3%) cases. We conclude that the leprosy neuropathy is very prevalent, and that the associated clinical factors can be used to identify patients at high risk of developing nerve damage. It is suggested that increased efforts and investments in skills and training of health professionals for the early diagnosis.

nÃo hà / Oxaliplatina (OXL) à a 3 geraÃÃo de agentes platinos com amplo espectro de atividade antitumoral. Exibe potente atividade citotÃxica, incluindo cÃncer colorretal, ovariano e pulmonar. Dentre os efeitos tÃxicos estÃo: laringoespasmo, nÃuseas, vÃmitos, fadiga e neuropatia perifÃrica, foco desse trabalho. Essa pesquisa objetivou desenvolver um modelo experimental para estudo da neuropatia sensitiva perifÃrica induzida por OXL em camundongos que sÃo animais geneticamente mais semelhantes ao ser humano, econÃmicos e dado a existÃncia de espÃcies diferentes para vÃrios fatores. O estudo foi aprovado pelo Comità de Ãtica em Pesquisa Animal da UFC (protocolo n 70/07). Camundongos Swiss machos (20-40g) foram tratados com OXL (1-4 mg/kg, EV) por 4 semanas paralelamente aos testes neuropÃticos utilizados para avaliar o desenvolvimento da neuropatia sensitiva e Rota Rod para verificar comprometimento motor. A hiperalgesia e alodÃnia tÃrmica foram avaliadas pelo teste de imersÃo da cauda (TIC) em Ãgua fria (4 ou 10ÂC) e em Ãgua aquecida (46 ou 42ÂC). O teste de hiperalgesia e alodÃnia mecÃnico (HPM; Von Frey) consistiu na estimulaÃÃo das patas traseiras com um sensor de forÃa (g) atà a sua retirada por um movimento de âflinchâ. Foi ainda verificado a aÃÃo analgÃsica da carbamezepina (CZP), oxcarbazepina (OZP), gabapentina (GABAP) e indometacina (INDO) no TIC Ãgua fria. Foi realizado a imunohistoquÃmica das patas traseiras dos animais em 24h e de 7 a 28 dias. Como resultados observou-se que no HPM houve uma diminuiÃÃo significativa (p<0,001) no limiar nociceptivo a partir do 14 dia atingindo o mÃximo na dose de 2mg/kg comparado ao grupo controle. No TIC 4ÂC houve uma diminuiÃÃo significativa (p<0,05) no limiar nociceptivo no 56 dia, no TIC alodÃnia pelo frio (10ÂC) foi observado uma diminuiÃÃo significativa (p<0,01) no limiar nociceptivo tambÃm no 56 dia, no TIC alodÃnia pelo quente (42ÂC) foi observado uma diminuiÃÃo significativa (p<0,05) no limiar nociceptivo a partir do 35 dia. Esses testes atingiram o mÃximo na dose de 1mg/kg comparados com o grupo controle e no TIC 46ÂC foi observado uma diminuiÃÃo significativa (p<0,01) no limiar nociceptivo a partir do 49 dia atingindo o mÃximo na dose de 1 e de 4mg/kg comparado ao grupo controle. No teste Rota Rod nenhuma variaÃÃo significativa foi observada em nenhum dos grupos, indicando a ausÃncia de comprometimento motor. O tratamento com CZP (0,3-30mg/kg), OZP (0,3-100mg/kg) e GABAP (6-54mg/kg) aumentou o limiar nociceptivo, indicando efeito analgÃsico e INDO (1-4mg/kg) nÃo demonstrou atividade analgÃsica nesse modelo. Na anÃlise da imunohistoquÃmica ficou comprovado que existe a participaÃÃo provÃvel de SP, CGRP e NMDA perifÃricos e nitrotirosina. Portanto, o uso de camundongos e do diferente mÃtodo de administraÃÃo da OXL (EV) pode ser utilizado em modelos futuros viabilizando o uso do fÃrmaco para tratamento do cÃncer, principalmente o colorretal, com todo o esquema terapÃutico, sem que a NSP interfira nas atividades de vida do paciente tratado. / Oxaliplatin (OXL) is a third-generation platinum-based chemotherapy with broad spectrum of anti-tumoral activity. Exhibt potent cytotoxic activity including against cancer colorectal, ovarian and lung cancer. Among the toxic effects are: laryngospasm, nauseas, vomiting, fatigue and peripheral neuropathy, focus of that work. That research planned to develop an experimental model for study of the peripheral neuropathy induced by OXL in mice that are animal genetically more similar to the human, economic and given the knockout species existence for several factors. The study was approved by the Committee of Ethics in Animal Research of the UFC (protocol n 70/07). Mice Swiss male (20-40g) were treated with OXL (1-4 mg/kg, EV) for 4 weeks in parallel to the neurophatic tests utilized for evaluate the development of the peripheral neuropathy and Route Rod for verify some motor compromise. To mechanical hyperalgesia and allodynia thermal were evaluated by the test of immersion of the tail (TIC) in cold water (4 or 10ÂC) and in water heated (46 or 42ÂC). The test of hyperalgesia and allodynia (HPM; Von Frey) consisted of the stimulation of the rear paws with a sensor of force (g) up to his retreat by a movement of "flinch". It was still verified the analgesic action of the carbamezepine (CZP), oxcarbazepine (OZP), gabapentin (GABAP) and indomethacin (INDO) in the TIC cold water. It was carried out to immunohistochemical of the hands paws of the animals in 24h and of 7 to 28 days. The results shows that in the HPM had a significant reduction (p<0,001) in the nociceptive threshold from the 14 day reaching the maximum one in the dose of 2mg/kg compared to the control group. In the TIC 4ÂC had a significant reduction (p<0,05) in the nociceptive threshold in the 56 day, in the TIC allodynia by the cold one (10ÂC) was observed a significant reduction (p<0,01) in the nociceptive threshold also in the 56 day, in the TIC allodynia by the hot one (42ÂC) was observed a significant reduction (p<0,05) in the nociceptive threshold from the 35 day. Those tests reached the maximum one in the dose of 1mg/kg compared with the control group and in the TIC 46ÂC was observed a significant reduction (p<0,01) in the nociceptive threshold from the 49 day reaching the maximum one in the doses of 1 and 4mg/kg compared to the control group. In the test Route Rod no significant variation was observed in no of the groups, indicating the absence of motor compromise. The handling with CZP (0,3-30mg/kg), OZP (0,3-100mg/kg) and GABAP (6-54mg/kg) increased the nociceptive threshold, indicating analgesic effect and INDO (1-4mg/kg) did not show analgesic activity in that model. In the analysis of the immunohistochemical was verified that exists the probable participation of SP, CGRP and NMDA peripheral and nitrotyrosine. Therefore, the use of mice and of the different approach of administration of the OXL (EV) can be utilized in future models making feasible the use of the drug for handling of the cancer, mainly the colorectal, with all the therapeutic plan without that to NSP interfere in the activities of the treated patient.