Striatal dopamine D-2 receptors attenuate neuropathic hypersensitivity in the rat

Earlier studies indicate that striatal dopamine D-2 receptors are involved in pain regulation in non-neuropathic conditions. We assessed whether striatal dopamine D-2 receptors contribute to pain regulation also in neuropathic conditions. The spared nerve injury model of neuropathy was induced by unilateral ligation of the tibial and common peroneal nerves in the rat. In awake nerve-injured animals, pain-related withdrawal responses to calibrated monofilaments or noxious heating were attenuated following striatal administration of a dopamine D-2 receptor agonist quinpirole. Pain-related responses were attenuated only in the nerve-injured limb ipsilateral to the injection and in the midline (tail). In unoperated controls, striatal administration of quinpirole at an antihypersensitive dose did not influence withdrawal responses to mechanical stimulation. Attenuation of pain-related responses induced by striatal administration of quinpirole was reversed by intrathecal administration of a dopamine D-2 receptor antagonist (eticlopride) or a non-selective 5-HT receptor antagonist (methysergide), but not by an alpha(2)-adrenoceptor antagonist (atipamezole). In the rostroventromedial medulla of lightly anesthetized neuropathic animals, striatal administration of quinpirole significantly decreased the activity of presumably pronociceptive cells that are activated by noxious stimulation. The innocuous H-reflex in lightly anesthetized control animals was not suppressed by striatal administration of quinpirole at an antihypersensitive dose. The results indicate that striatal dopamine D-2 receptors attenuate neuropathic hypersensitivity. The antihypersensitive effect induced by striatal dopamine D-2 receptors in peripheral neuropathy involves suppression of impulse discharge of presumably pronociceptive neurons in the rostroventromedial medulla, and a descending influence acting on spinal 5-HT and dopamine D-2 receptors.This study was supported by the Academy of Finland and the Sigrid Jusélius Foundation, Helsinki, Finlandinfo:eu-repo/semantics/publishedVersio

Impact of chronic pain in emotional and cognitive behaviour in the rat : the effects of age and lateralization

Tese de doutoramento em Ciências da Saúde - Especialidade de Ciências Biológicas e BiomédicasMultiple areas along the neuroaxis mediate pain modulation and perception. Dysfunction at any of these stations can have devastating consequences that result in pain chronification and in the surfacing of emotional and cognitive disturbances. In the past decade, it was demonstrated that these comorbidities frequently associated with chronic pain also manifest in the animal model, paving the way for further research on the underling pathophysiology. However, conflicting observations have been published probably as a result of experimental heterogeneity. This prompted us to further characterize emotional and cognitive behaviour alterations in a rodent model of chronic neuropathic pain – the spared nerve injury (SNI). In the first set of experiments, the effect of chronic neuropathic pain was studied in the context of ageing. We observed an age-related increase of anxiety-like behaviour in the elevated-plus maze (EPM), which was further augmented in young and old males, but not mid-aged SNI animals. On the contrary, only SNI mid-aged animals had a depressive-like phenotype in the forced-swimming test (FST) when compared to age-matched controls. SNI mid-aged animals had also an impaired ability to perform a reversal learning task when compared with the respective age-matched controls. In this task, the SNI lesion affected neither young nor old groups, although in the last, controls themselves had a poorer performance. In fact, in this cognitive domain ageing was a major determinant of incapacity. Ageing was also demonstrated to have a mild negative influence in the performance of a spatial working memory (WM) but not in a long-term spatial memory – Morris water maze (MWM). The SNI lesion had no observable effect in both WM and MWM. In the second set of experiments, the effect of pain lateralization was accessed in young rats. Left-sided (but not right-sided) SNI was shown to be anxiogenic in the EPM. On the contrary, right-sided (but not left-sided) SNI was detrimental in all prefrontal cortex (PFC)-dependent cognitive paradigms, namely WM, reversal learning (in the attentional-set shifting task; ASST) and response inhibition (impulsivity). Neither right- nor left-side SNI affected the performance in the MWM.These observations indicate that both the age of the animal at the pain onset as well as the location of pain are determinant in the behavioural outcome on emotional and cognitive paradigms. Additionally, our behavioural observations suggest that the PFC has a major role in the observed emotional and cognitive shifts occurring after SNI installation.A modulação e percepção da dor dependem da contribuição de várias áreas ao longo do neuro-eixo. A disfunção deste eixo pode resultar em consequências devastadoras que incluem a cronificação da dor e a manifestação de perturbações emocionais e cognitivas. Na última década, demonstrou-se que estas comorbilidades associadas a estados de dor crónica também se manifestavam no modelo animal, o que abriu novas perspectivas de investigação sobre os mecanismos subjacentes. No entanto, dados contraditórios têm vindo a ser publicados quanto à natureza destas manifestações. Este cenário esteve na base dos estudos desta tese, que pretenderam aprofundar a caracterização das alterações do comportamento emocional e cognitivo num modelo de dor crónica neuropática – o modelo SNI (spared nerve injury). No primeiro conjunto de experiências, o efeito da dor crónica foi estudado no contexto do envelhecimento. Com o envelhecimento observamos um aumento do comportamento do tipo ansioso no paradigma elevated-plus maze (EPM) e que este efeito era potenciado nos animais novos e velhos submetidos à lesão neuropática SNI. Pelo contrário, apenas o grupo de meiaidade submetido ao SNI apresentava um comportamento do tipo depressivo no teste do forced-swimming (FST) quando comparado com o respectivo controlo da mesma idade. O mesmo grupo SNI de meia-idade mostrou também uma capacidade reduzida de aprendizagem reversa, o que não se verificava nos grupos de animais mais novos ou mais velhos embora, nestes últimos, os próprios controlos tenham tido um mau desempenho. De facto, neste paradigma o aumento da idade revelou-se um factor determinante de insucesso. O envelhecimento estava também associado a uma deterioração do desempenho numa tarefa de memória de trabalho (WM; working memory) não havendo no entanto qualquer influência na tarefa de memória de longo prazo (MWM; Morris water maze). A lesão SNI não teve qualquer influência no desempenho destes paradigmas pelos animais dos diferentes grupos etários. No segundo conjunto de estudos, avaliou-se o efeito da lateralidade da dor em animais jovens. A lesão SNI esquerda, (mas não a direita), resultou no aumento do comportamento do tipoansioso no EPM. Pelo contrário, a lesão SNI direita, (mas não a esquerda), induziu um pior desempenho nos paradigmas de comportamento cognitivo, nomeadamente em todos aqueles com um componente prefrontal (prefrontal cortex; PFC): WM, aprendizagem reversa (no contexto de um paradigma de attentional-set shifting task; ASST) e controlo da resposta impulsiva. A lesão SNI, independentemente do lado onde era instalada, não teve qualquer efeito na execução do MWM. Os nossos dados indicam que, quer a idade do individuo aquando da instalação da neuropatia, quer o lado do corpo onde esta se localiza, influenciam o desempenho em paradigmas de comportamento emocional e cognitivo. Resulta também das nossas observações que o PFC tem um papel determinante nas alterações comportamentais observadas após a instalação da neuropati

Differential effects of left/right neuropathy on rats’ anxiety and cognitive behavior

Chronic pain is frequently accompanied by a deterioration of emotional behavior and cognitive function. A small number of studies in humans concluded that pain-associated negative affect is more pronounced when pain is localized in the left side of the body. It has been suggested that such side bias results from cortical function lateralization. It is not known, however, if other pain-associated behavioral changes are differentially affected by left- and right-sided pain. To test this hypothesis, the performance of rats with a unilateral spared nerve injury neuropathy installed in the left (SNI-L) or in the right (SNI-R) side was compared in anxiety (elevated-plus maze) and cognitive (spatial working and reference memory, attentional set-shifting task, and delay-to-signal impulsivity task) behavioral paradigms. Results show that SNI-L animals presented an increased anxiety-like profile while maintaining preserved cognitive function. On the contrary, SNI-R animals presented cognitive deficits in all tasks except in the reference memory, but displayed a normal anxiety-like profile. Our results show that left- and right-sided neuropathic pain differentially affects emotional behavior, which is in accordance with previous observations in human subjects, both in experimentally induced pain and in chronic pain conditions. Additionally, our results demonstrate that the cognitive function deteriorationThis work was funded by the Portuguese Science Foundation Project PTDC/SAU-NEU/108557/2008, COMPETE and FEDER, and Grant SFRH/BD/29166/200

Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy

BACKGROUND: Recently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat's emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task. RESULTS: SNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area. CONCLUSIONS: Our results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning.This work was granted by the Portuguese Science Foundation (FCT) project PTDC/SAU-NEU/108557/2008 and grant SFRH/BPD/80118/2011

Structural laterality is associated with cognitive and mood outcomes: An assessment of 105 healthy aged volunteers

The human brain presents multiple asymmetries that dynamically change throughout life. These phenomena have been associated with cognitive impairments and psychiatric disorders although possible associations with specific patterns of cognitive aging are yet to be determined. We have therefore mapped and quantified morphological asymmetries in a heterogeneous and aged population (65.2 +/- 8.0 years old, 52 male and 53 female) to explore potential associations between the asymmetries in specific brain regions and cognitive performance. The sample was characterized in a battery of neuropsychological tests and in terms of brain structural asymmetries using a ROI-based approach. A substantial number of brain areas presented some degree of asymmetry. Such biases survived a stringent statistical correction and were largely confirmed in a voxel-based analysis. In specific brain areas, like the thalamus and insula, asymmetry was correlated with cognition and mood descriptors as the Stroop words/colors test or depressive mood scale, respectively. Curiously in the latter, the association was independent of its left/right direction. Altogether, results reveal that asymmetry is widespread in the aged brain and that area-specific biases (degree and direction) associate with the functional profile of the individual.European Commission (FP7): “SwitchBox” [contract HEALTH-F2-2010-259772] and Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) – PM and NCS; Fundação para a Ciência e a Tecnologia (FCT) [grant numbers SFRH/BD/52291/2013 to ME via Inter-University Doctoral Programme in Ageing and Chronic Disease (PhDOC), SFRH/BPD/80118/2011 to HA and SFRH/BD/90078/2012 to TCC]; and FCT/MEC and ON.2 – ONOVONORTE – North Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/2013, through FEDER [project FCTANR/NEU-OSD/0258/2012 to RM]info:eu-repo/semantics/publishedVersio

Medullary control of nociceptive transmission: reciprocal dual communication with the spinal cord

Control of pain perception, essential for organism surviving and recovery from disease, is exerted by higher brain centers integrating nociception with emotional and cognitive information and modulating the brainstem-spinal feedback loops that regulate spinal nociceptive transmission. Development of chronic pain deregulates the forebrain-brainstem-spinal pain control system, which leads to neuroplasticity and disruption of a balanced brain-spinal communication. Targets for impeding pain chronification are being developed using the manipulation of the cross talk between brain and dorsal horn, at both sites of the loop.FCT -Fuel Cell Technologies Program(POCTI/NSE/46399/2002

Benefits of spine stabilization with biodegradable scaffolds in spinal cord injured rats

Spine stabilization upon spinal cord injury (SCI) is a standard procedure in clinical practice, but rarely employed in experimental models. Moreover, the application of biodegradable biomaterials for this would come as an advantage as it would eliminate the presence of a nondegradable prosthesis within the vertebral bone. Therefore, in the present work, we propose the use of a new biodegradable device specifically developed for spine stabilization in a rat model of SCI. A 3D scaffold based on a blend of starch with polycaprolactone was implanted, replacing delaminated vertebra, in male Wistar rats with a T8-T9 spinal hemisection. The impact of spinal stabilization on the locomotor behavior was then evaluated for a period of 12 weeks. Locomotor evaluation—assessed by Basso, Beatie, and Bresnahan test; rotarod; and open field analysis—revealed that injured rats subjected to spine stabilization significantly improved their motor performance, including higher coordination and rearing activity when compared with SCI rats without stabilization. Histological analysis further revealed that the presence of the scaffolds not only stabilized the area, but also simultaneously prevented the infiltration of the injury site by connective tissue. Overall, these results reveal that SCI stabilization using a biodegradable scaffold at the vertebral bone level leads to an improvement of the motor deficits and is a relevant element for the successful treatment of SCI.The authors would like to acknowledge the Portuguese Foundation for Science and Technology (Doctoral fellowship to Nuno Silva, SFRH/BD/40684/2007; Ciência 2007 Program to António Salgado; Grant N PTDC/SAU-BMA/114059/2009) and the Foundation Calouste de Gulbenkian to funds attributed to A.J. Salgado under the scope of the The Gulbenkian Programme to Support Cutting Edge Research in the Life Sciences

Stress induced risk-aversion is reverted by D2/D3 agonist in the rat

Stress exposure triggers cognitive and behavioral impairments that influence decision-making processes. Decisions under a context of uncertainty require complex reward-prediction processes that are known to be mediated by the mesocorticolimbic dopamine (DA) system in brain areas sensitive to the deleterious effects of chronic stress, in particular the orbitofrontal cortex (OFC). Using a decision-making task, we show that chronic stress biases risk-based decision-making to safer behaviors. This decision-making pattern is associated with an increased activation of the lateral part of the OFC and with morphological changes in pyramidal neurons specifically recruited by this task. Additionally, stress exposure induces a hypodopaminergic status accompanied by increased mRNA levels of the dopamine receptor type 2 (Drd2) in the OFC; importantly, treatment with a D2/D3 agonist quinpirole reverts the shift to safer behaviors induced by stress on risky decision-making. These results suggest that the brain mechanisms related to risk-based decision-making are altered after chronic stress, but can be modulated by manipulation of dopaminergic transmission.Pedro Morgado was supported by a fellowship SFRH/SINTD/60129/ 2009 funded by FCT—Foundation for Science and Technology. Supported by FEDER funds through Operational program for competitive factors - COMPETE and by national funds through FCT - Foundation for Science and Technology to project PTDC/SAU-NSC/111814/2009

PREVALÊNCIA DE CÂNCER DE MAMA E ASSOCIAÇÃO COM SEUS FATORES PROGNÓSTICOS E PREDITIVOS DIAGNOSTICADOS NUM HOSPITAL UNIVERSITÁRIO

O câncer de mama é o tipo de câncer mais freqüente em mulheres no Brasil. Apesar de ser considerado um câncer de relativamente bom prognóstico, se diagnosticado e tratado oportunamente, as taxas de mortalidade por câncer de mama continuam elevadas no Brasil, muito provavelmente porque a doença ainda é diagnosticada em estádios avançados. O objetivo do presente estudo foi avaliar a prevalência de câncer de mama num hospital universitário através do exame anátomo-patológico e os fatores prognósticos e preditivos associados a cada caso, para observar o estágio de diagnóstico das pacientes. Foi realizado um estudo retrospectivo com seleção dos laudos anatomo-patológicos de exérese de tumor mamário com diagnóstico de câncer de mama, provenientes do Hospital Universitário de Presidente Prudente - SP, realizados no período de 1998 a 2009. Dos laudos de exame foram retirados os dados relacionados à idade da paciente, os fatores prognósticos e os fatores preditivos. Foram encontrados 183 casos de câncer de mama. A maior incidência ocorreu na faixa etária entre 40 a 49 anos (29,5%) e o tipo histológico mais frequente foi o Carcinoma ductal invasivo (61,2%). Em 45% dos casos, os tumores mediram até 2cm. A maioria (71%) não apresentava metástases para os linfonodos axilares. Em 27 casos houve expressão de receptores hormonais e em 26 hiperexpressão de Her2/neu. Conclui-se que as pacientes estudadas foram diagnosticadas na fase inicial do câncer de mama

Development and characterization of PHB-HV based 3D scaffolds for a tissue engineering and cell-therapy combinatorial approach for spinal cord Injury regeneration

Spinal cord injury (SCI) leads to devastating neurological deficits. Several tissue engineering (TE)- based approaches have been investigated for repairing this condition. Poly (3-hydroxybutyrateco- 3-hydroxyvalerate) (PHB-HV) is found to be particularly attractive for TE applications due to its properties, such as biodegradability, biocompatibility, thermoplasticity and piezoelectricity. Hence, this report addresses the development and characterization of PHB-HV-based 3D scaffolds, produced by freeze-drying, aimed to SCI treatment. The obtained scaffolds reveal an anisotropic morphology with a fully interconnected network of pores. In vitro studies demonstrate a lack of cytotoxic effect of PHB-HV scaffolds. Direct contact assays also reveal their ability to support the culture of CNS-derived cells and mesenchymal-like stem cells from different sources. Finally, histocompatibility studies show that PHB-HV scaffolds are well tolerated by the host tissue, and do not negatively impact the left hindlimb locomotor function recovery. Therefore results herein presented suggest that PHB-HV scaffolds may be suitable for SCI treatment.This study was supported by the Portuguese Foundation for Science and Technology (FCT; Grant no PTDC/SAU-BMA/114059/2009; PEst-C/SAU/LA0001/2013-2014 and RNEM-REDE/1506/REM/2005) and Foundation Calouste Gulbenkian, under the scope of the Gulbenkian Program to Support Cutting Edge Research in Life Sciences (A.J.S.). This work was also partially supported by the European FP7 Project Find and Bind (NMP4-SL-2009-229292). The authors would like to thank Miguel Carvalho, Fabio Teixeira, and Filipa Campos for their collaboration in in vivo experiments