2,649 research outputs found

    Astroglial changes in the zona incerta in response to motor cortex stimulation in a rat model of chronic neuropathy

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    Although astrocytes are known to regulate synaptic transmission and affect new memory formation by influencing long-term potentiation and functional synaptic plasticity, their role in pain modulation is poorly understood. Motor cortex stimulation (MCS) has been used to reduce neuropathic pain through the incertothalamic pathway, including the primary motor cortex (M1) and the zona incerta (ZI). However, there has been no in-depth study of these modulatory effects and region-specific changes in neural plasticity. In this study, we investigated the effects of MCS-induced pain modulation as well as the relationship between the ZI neuroplasticity and MCS-induced pain alleviation in neuropathic pain (NP). MCS-induced threshold changes were evaluated after daily MCS. Then, the morphological changes of glial cells were compared by tissue staining. In order to quantify the neuroplasticity, MAP2, PSD95, and synapsin in the ZI and M1 were measured and analyzed with western blot. In behavioral test, repetitive MCS reduced NP in nerve-injured rats. We also observed recovered GFAP expression in the NP with MCS rats. In the NP with sham MCS rats, increased CD68 level was observed. In the NP with MCS group, increased mGluR1 expression was observed. Analysis of synaptogenesis-related molecules in the M1 and ZI revealed that synaptic changes occured in the M1, and increased astrocytes in the ZI were more closely associated with pain alleviation after MCS. Our findings suggest that MCS may modulate the astrocyte activities in the ZI and synaptic changes in the M1. Our results may provide new insight into the important and numerous roles of astrocytes in the formation and function.ope

    Environmental enrichment promotes resilience to neuropathic pain-induced depression and correlates with decreased excitability of the anterior cingulate cortex.

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    Depression is a common comorbidity of chronic pain with many patients being affected. However, efficient pharmacological treatment strategies are still lacking. Therefore, it is desirable to find additional alternative approaches. Environmental enrichment has been suggested as a method to alleviate pain-induced depression. However, the neuronal mechanisms of its beneficial effects are still elusive. The anterior cingulate cortex (ACC) plays a central role in processing pain-related negative affect and chronic pain-induced plasticity in this region correlates with depressive symptoms. We studied the consequences of different durations of environmental enrichment on pain sensitivity and chronic pain-induced depression-like behaviors in a mouse model of neuropathic pain. Furthermore, we correlated the behavioral outcomes to the activity levels of pyramidal neurons in the ACC by analyzing their electrophysiological properties ex vivo. We found that early exposure to an enriched environment alone was not sufficient to cause resilience against pain-induced depression-like symptoms. However, extending the enrichment after the injury prevented the development of depression and reduced mechanical hypersensitivity. On the cellular level, increased neuronal excitability was associated with the depressive phenotype that was reversed by the enrichment. Therefore, neuronal excitability in the ACC was inversely correlated to the extended enrichment-induced resilience to depression. These results suggest that the improvement of environmental factors enhanced the resilience to developing chronic pain-related depression. Additionally, we confirmed the association between increased neuronal excitability in the ACC and depression-like states. Therefore, this non-pharmacological intervention could serve as a potential treatment strategy for comorbid symptoms of chronic pain

    Complex interaction of sensory and motor signs and symptoms in chronic CRPS.

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    Spontaneous pain, hyperalgesia as well as sensory abnormalities, autonomic, trophic, and motor disturbances are key features of Complex Regional Pain Syndrome (CRPS). This study was conceived to comprehensively characterize the interaction of these symptoms in 118 patients with chronic upper limb CRPS (duration of disease: 43±23 months). Disease-related stress, depression, and the degree of accompanying motor disability were likewise assessed. Stress and depression were measured by Posttraumatic Stress Symptoms Score and Center for Epidemiological Studies Depression Test. Motor disability of the affected hand was determined by Sequential Occupational Dexterity Assessment and Michigan Hand Questionnaire. Sensory changes were assessed by Quantitative Sensory Testing according to the standards of the German Research Network on Neuropathic Pain. Almost two-thirds of all patients exhibited spontaneous pain at rest. Hand force as well as hand motor function were found to be substantially impaired. Results of Quantitative Sensory Testing revealed a distinct pattern of generalized bilateral sensory loss and hyperalgesia, most prominently to blunt pressure. Patients reported substantial motor complaints confirmed by the objective motor disability testings. Interestingly, patients displayed clinically relevant levels of stress and depression. We conclude that chronic CRPS is characterized by a combination of ongoing pain, pain-related disability, stress and depression, potentially triggered by peripheral nerve/tissue damage and ensuing sensory loss. In order to consolidate the different dimensions of disturbances in chronic CRPS, we developed a model based on interaction analysis suggesting a complex hierarchical interaction of peripheral (injury/sensory loss) and central factors (pain/disability/stress/depression) predicting motor dysfunction and hyperalgesia

    Encoding strategies of primary somatosensory cortex for touch and pain in physiological and pathological conditions

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    학위논문(박사)--서울대학교 대학원 :의과대학 의과학과,2019. 8. 김상정.일차 체성감각 피질은 촉각과 통증을 지각하고 구별하는 데에 있어서 매우 중요한 역할을 한다. 전통적으로, 일차 체성감각피질을 포함한 체성감각계의 신경세포는 브러쉬, 핀치와 같은 무해한 자극과 유해한 자극에 대한 그 세포의 전기생리학적 반응에 따라 저역치, 고역치 또는 광동적범위 신경세포로 분류되어 왔다. 브러쉬와 포셉을 이용한 이 자극은 유해성뿐만 아니라 브러쉬와 포셉의 촉감, 동적/정적인 역동성과 같은 다른 특성들도 포함하고 있다. 하지만 감각 자극의 이렇게 다양한 특성들을 일차 체성감각피질의 개별세포와 집단 수준에서 종합적으로 어떻게 부호화하고 있는 지에 대한 연구는 부족하다. 조직 및 신경 손상은 이질통, 통각 과민과 같은 과민증을 동반하는 염증성 또는 신경병성 통증을 초래한다. 하지만 통증 과민성일 때 무해하고 유해한 기계적 자극에 대한 일차 체성감각 피질 신경 세포의 반응 속성이 어떻게 달라지며, 이 변화가 통각 과민증과 어떻게 연관되어 있는 지에 대한 연구는 부족하다. 나는 일차 체성감각 피질 세포가 촉각과 통증에 대한 다양한 자극 특성을 동시다발적으로 어떻게 암호화 하고 있는 지 조사했다. 또한 촉각 및 통증 자극에 대한 그 세포들의 반응 속성이 통증 과민증 일 때 어떻게 달라지는 지 조사했다. 이 조사를 위해, 나는 이광자 칼슘 이미징을 통해 무해하고, 유해한 촉각 및 통증 자극을 생쥐의 발바닥에 가하면서 생쥐의 일차 체성감각 피질 신경세포의 칼슘 반응을 기록했다. 이 논문은 촉각 및 통증 자극에 대한 일차 체성감각 피질 세포의 반응 속성을 설명하는 두 가지 부분으로 구성되어 있다. 제 1장에서는, 일차 체성감각 피질 신경세포가 촉감이 다른 자극에 대해서 높은 선택적 반응을 보인 것을 확인했다. 하지만 역동성 또는 유해성 특성에 대해서는 낮은 선택성을 보였으며, 그 중 역동성에 약간 더 높은 선택성을 보인 것을 확인했다. 제 2장에서는, 통증 과민증 일 때, 유해-선호 신경세포가 무해한 촉각 자극에도 반응하는 것을 확인했다. 하지만, 촉각 및 통증 자극 모두에 반응한 세포 (광범위하게 조정된 세포)는 자극에 대한 튜닝 속성이 과민증일 때 유지됐고, 그 세포의 일부는 촉각 및 통증 자극에 대한 반응성이 증가했다. 이 논문은 일차 체성감각 피질 신경세포가 자극 특성-의존적 방식으로 특이성 부호화와 패턴 부호화의 혼합 된 전략을 사용하는 걸 제시했다. 또한, 통증 과민증 일 때, 일체 체성감각 피질은 자극에 대한 반응 속성이 바뀌고, 광범위하게 조정된 세포의 반응성이 전반적으로 증가하는 방식으로 과민증에 기여하고 있다는 것을 보여줬다. 본 논문은 생리 및 병리적 조건에서 촉각 및 통증 자극에 대한 일차 체성감각 피질의 암호화 전략과 반응 속성에 대해 이해하기 위한 중요한 정보를 제공한다.Primary somatosensory cortex (S1) plays an important role in the perception and discrimination of touch and pain. Conventionally, neurons in the somatosensory system including S1 cortex have been classified by noxiousness feature with innocuous brush and noxious pinch stimuli. Besides this noxiousness feature, each stimulus also includes other stimulus features, such as different textures or dynamics. However, it remains unexplored how S1 neurons comprehensively encode such diverse features of cutaneous stimuli at single-cell and population levels. Tissue or nerve injury can lead to an inflammatory or neuropathic pain, in which hypersensitivity is accompanied. However, it is unclear how the response properties of S1 neurons towards mechanical stimuli are altered. It is also unknown how these S1 response changes are involved in pain hypersensitivity. I investigated how S1 neurons comprehensively encode multiple stimulus features for touch and pain in physiological conditions and how the response properties of S1 neurons are changed in pain hypersensitivity. To explore this, using in vivo two-photon Ca2+ imaging, I recorded neural activities of S1 neurons in mice while applying innocuous and noxious mechanical stimuli into hind paw. This thesis is composed of two research parts on response properties of S1 neurons to touch and pain. In chapter 1, it is shown that S1 neurons exhibited highly selective response to the difference in texture (specificity coding), but low selectivity to the difference in dynamics or noxiousness with slightly more specificity to dynamics (pattern coding). In chapter 2, I found some of the noxious-preferred neurons, which responded to noxious pinch stimuli at normal states, responded to innocuous touch stimuli in CFA-induced hypersensitivity. The majority of broadly tuned neurons, however, maintained their normal tuning properties during hypersensitivity, but some of those showed increased responses to both innocuous and noxious mechanical stimuli in CFA-induced hypersensitivity. This thesis demonstrates that S1 neurons use a mixed strategy of specificity coding and pattern coding for multiple stimulus features in a feature-dependent manner. In addition, it is also revealed how S1 cortex contributes to CFA-induced hypersensitivity in a way that tuning properties are changed and activities of broadly tuned neurons are generally increased in CFA-induced hypersensitivity. These findings would be important to understand the encoding rules and response properties of S1 to touch and pain in physiological and pathological conditions.Abstract 1 Chapter 1. Differential selectivity of S1 neurons to multiple stimulus features of touch and pain Introduction 5 Results 9 Discussion 29 Chapter 2. Alterations in response properties of S1 neurons to innocuous and noxious stimuli in CFA-induced hypersensitivity Introduction 41 Results 43 Discussion 51 Materials and Methods 58 References 66 Abstract in Korean 71Docto

    Neural mechanisms of orofacial pain - effects of transcranial magnetic stimulation

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    Neuropathic orofacial pain is challenging to treat. Limited knowledge of the underlying pain-syndrome-specific pathophysiology is one of the reasons for poor response to current pharmacotherapy. Patients with treatment-resistant neuropathic pain are susceptible to concomitant psychiatric and sleep disorders. Psychiatric disorders, sleep problems, and certain personality traits may, in turn, predispose to chronic pain. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been shown to alleviate neuropathic pain, but the mechanisms of its action and optimal treatment parameters are still unclear. We investigated rTMS effects in healthy subjects and chronic neuropathic orofacial pain patients, and compared the analgesic efficacy of stimulation given to different cortical targets. We also evaluated the brain mechanisms involved in rTMS-induced analgesia, especially the dopamine-opioid system. The genetically determined function of the endogenous dopamine system was also investigated regarding thermal and pain perception. We discovered that rTMS targeted to the right secondary somatosensory cortex (S2) alleviated neuropathic orofacial pain (Cohen’s d = 0.60). Pain intensity assessed in numerical rating scale was significantly lower after the S2 stimulation than after the stimulation of the primary somatosensory and motor cortex (S1/M1) (p = 0.007) or placebo (p = 0.019). The analgesic effect of stimulation of the S2 region was not mediated or predicted by comorbid psychiatric or sleep disorders. Orofacial pain patients had more psychiatric and sleep disorders than the general population and there were several associations between these comorbid disorders. The variation caused by single nucleotide polymorphism 957C>T in dopamine receptor D2 (DRD2) gene had an effect on thermal perception and rTMS effects in healthy subjects. rTMS to S1 cortex increased heat pain detection thresholds only in subjects homozygous for the 957T allele (F = 3.78, p = 0.009), whose mean heat pain detection thresholds 6,24 were initially lower than those of 957C allele carriers (p < 0.05). The “pain sensitive” 957TT genotype was overrepresented (50% vs. 27% in general population, p = 0.019) in our unselected group of neuropathic pain patients. In the positron emission tomography (PET) study on healthy subjects, lower μ-opioid receptor availability indicting activation of the endogenous opioid system, was seen in a brain network associated with pain processing after active S1/M1 rTMS compared to sham (p ≤ 0.0001). Our results suggest that the brain dopamine-opioid system is important in the perception and modulation of pain, and in rTMS-induced analgesia. Genetic regulation of striatal DRD2 function may explain some of the individual differences in pain sensitivity and in risk for neuropathic pain.Kasvokivun neuraaliset mekanismit - transkraniaalisen magneettistimulaation vaikutukset Kroonisen neuropaattisen kasvokivun hoito on haasteellista. Neuropaattisen kasvokivun syitä ja sille altistavia tekijöitä ei vielä täysin tunneta, mikä vaikeuttaa tehokkaan hoidon löytämistä. Krooninen hoitoresistentti kipu voi altistaa mielialaongelmille ja univaikeuksille, jotka yhdessä tiettyjen persoonallisuuden piirteiden kanssa taas altistavat kivun pitkittymiselle. Repetitiivinen transkraniaalinen magneettistimulaatio (rTMS) on kajoamaton neuromodulaatiomenetelmä, jonka on osoitettu lievittävän neuropaattista kipua. Magneettistimulaation tarkat vaikutusmekanismit ja parhaat hoitoprotokollat ovat kuitenkin vielä epäselviä. Tässä tutkimuksessa selvitimme rTMS:n vaikutusmekanismeja terveillä vapaaehtoisilla ja kroonisesta neuropaattisesta kasvokivusta kärsivillä potilailla, sekä vertasimme eri aivoalueiden stimulaation vaikutuksia kipupotilaiden kipuun, mielialaan, uneen ja elämänlaatuun. Lisäksi selvitimme rTMS:n aivotason vaikutusmekanismeja, erityisesti aivojen dopamiini-opiodi järjestelmän osalta. Tutkimme myös aivojen sisäsyntyisen dopamiinijärjestelmän geneettisen säätelyn merkitystä kivun kokemisessa ja käsittelyssä sekä sen vaikutusta neuropaattisen kivun riskiin. Totesimme, että oikealle sekundaariselle tuntoaivokuorelle (S2) suunnattu rTMS lievitti neuropaattista kasvokipua. Kivun voimakkuus mitattuna numeerisella arviointiasteikolla oli S2-seudun stimulaation jälkeen merkittävästi matalampi kuin primaarisen tuntoaivokuoren ja liikeaivokuoren (S1/M1) stimulaation (p = 0,007) tai lumestimulaation (p = 0,019) jälkeen. S2-seudun stimulaation hoitovaste oli riippumaton potilaiden mieliala- tai unihäiriöistä. Kasvokipupotilailla oli selvästi enemmän psykiatrisia sairauksia ja uniongelmia kuin väestössä yleensä, ja näiden rinnakkaissairauksien välillä oli riippuvaisuutta. Dopamiini D2-reseptorin (DRD2) perinnöllisellä vaihtelulla oli vaikutusta terveiden koehenkilöiden kylmä-, lämpö- ja kiputuntokynnyksiin. S1-aivokuorelle annettu rTMS nosti kuumakipukynnyksiä vain 957T-genotyypin kantajilla (F = 3,78, p = 0,009), joiden 6,24 kuumakipukynnykset olivat lähtökohtaisesti matalammat kuin 957C-genotyypin kantajien (p < 0,05). Kivulle herkimmän TT-genotyypin kantajia oli enemmän kasvokipupotilaiden ryhmässä kuin väestössä yleensä (50% vs. 27%, p = 0,019). Aivojen positroni-emissiotomografiatutkimuksessa (PET) todettiin, että lumehoitoon verrattuna S1/M1 rTMS laski μ-opioidireseptorien saatavuutta aivoalueilla jotka osallistuvat kiputuntemuksen käsittelyyn (p ≤ 0,000). Löydös viittaa rTMS:n aktivoivan aivojen sisäsyntyistä opioidijärjestelmää. Tulostemme perusteella aivojen dopamiini-opioidisysteemi vaikuttaa kivun kokemiseen ja säätelyyn, sekä rTMS-hoidon tehoon. Tyvitumakkeiden DRD2-tiheyttä säätelevä geneettinen muuntelu saattaa osaltaan selittää yksilöiden välisiä eroja kipuherkkyydessä ja alttiudessa saada neuropaattinen kipu hermovaurion jälkeen.Siirretty Doriast

    Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization.

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    Physical exercise promotes neural plasticity in the brain of healthy subjects and modulates pathophysiological neural plasticity after sensorimotor loss, but the mechanisms of this action are not fully understood. After spinal cord injury, cortical reorganization can be maximized by exercising the non-affected body or the residual functions of the affected body. However, exercise per se also produces systemic changes - such as increased cardiovascular fitness, improved circulation and neuroendocrine changes - that have a great impact on brain function and plasticity. It is therefore possible that passive exercise therapies typically applied below the level of the lesion in patients with spinal cord injury could put the brain in a more plastic state and promote cortical reorganization. To directly test this hypothesis, we applied passive hindlimb bike exercise after complete thoracic transection of the spinal cord in adult rats. Using western blot analysis, we found that the level of proteins associated with plasticity - specifically ADCY1 and BDNF - increased in the somatosensory cortex of transected animals that received passive bike exercise compared to transected animals that received sham exercise. Using electrophysiological techniques, we then verified that neurons in the deafferented hindlimb cortex increased their responsiveness to tactile stimuli delivered to the forelimb in transected animals that received passive bike exercise compared to transected animals that received sham exercise. Passive exercise below the level of the lesion, therefore, promotes cortical reorganization after spinal cord injury, uncovering a brain-body interaction that does not rely on intact sensorimotor pathways connecting the exercised body parts and the brain

    Neurophatic Pain

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    To date, both basic and human data suggest that a lesion of afferent pathways is required for development of NP. In addition, numerous studies demonstrate that not one but various mechanisms can induce to NP. This not only evidence the complexity of NP, but also underline the clinical significance of identifying underlying pain mechanisms in every single patient. Because different management plans are required for different pain mechanisms, a mechanism-based treatment approach can guide clinicians to better outcomes. With these concepts in mind the second chapter of this study aim to clarify some links between one of the most novel techniques used in the diagnosis of NP, the Quantitative Sensory Testing (QST), which has been used to determine the pathological mechanisms functioning and the phenotype expressed. With the painDETECT Questionnaire as screening tool for NP, we analyse whether the overall PDQ score or its items reflect phenotypes of sensory loss in NP as determined by QST. The results of our study conclude that patients with loss of thermal sensation significantly more often reported pain evoked by light touch, and patients with loss of mechanical sensation significantly more often reported numbness and significantly less often burning sensations and pain evoked by light touch. Although the PDQ was not designed to assess sensory loss, single items reflect thermal and/or mechanical sensory loss at group level, but because of substantial variability, the PDQ does not allow for individual allocation of patients into sensory profiles. Finally, the last part of this thesis focuses its attention in the management of NP, more precisely in Complex Regional Pain Syndrome (CRPS) in children. This chapter review the evidence for invasive pain procedures along with presenting a management algorithm for paediatric CRPS, including invasive procedures for patients who do not respond to the conventional first-line treatment. We also report on the course and management of a series of children diagnosed with CRPS, applying the multidisciplinary management approach described above. We conclude that because of the severity and rapid progression of the symptoms in CRPS an early diagnosis of the condition together with comprehensive, and individualized multidisciplinary treatment offers children with CRPS the best opportunity for a complete recovery. Within this approach we encourage clinicians to consider invasive procedures as a reliable option of treatment.   RESUMEN El Dolor Neuropático (DN) abarca, o acompaña, a una amplia variedad de patologías ligadas con enfermedad o lesión del sistema somatosensorial a nivel central o periférico, oscilando su prevalecía en la población general en torno al 7-10%. En la actualidad la mayor parte del conocimiento que tenemos de los mecanismos subyacentes al origen y desarrollo del DN han sido obtenidos de estudios en ciencias básicas. Los obvios problemas que surgen de la traslación en investigación médica revelan las importantes limitaciones de ciertos modelos experimentales, y desde esa línea se originan esenciales limitaciones para la investigación clínica. A pesar de estas dificultades, la comunidad científica escruta sin cesar nuevas y mejores ideas que nos ayuden a entender mejor la patofisiología del dolor basándose fundamentalmente en nuevos descubrimientos en el campo de las ciencias básicas. Por esta razón, la primera de las tres partes de las que se compone este trabajo tiene como objetivo el reconocimiento de cambios o hallazgos no descritos en el sistema somatosensorial en un modelo experimental de DN. El DN tras un daño nervioso periférico esta asociado con la hiperexcitabilidad de los axones sensoriales mielinizados afectos, la cual comienza a normalizarse con el tiempo. Este trabajo investiga la composición y distribución de los canales de potasio voltaje dependientes de la familia Shaker (Kv1) en el complejo nodal de los axones mielinizados tras la lesión nerviosa. En el neuroma que se forma tras el daño, la expresión de Kv1.1 y Kv1.2 estaba considerablemente reducida. Por el contrario Kv1.4 y Kv1.6, que eran casi imperceptibles en el estado naive, mostraron un importante aumento en su expresión tras el daño. En la raíz dorsal se pudo demostrar una redistribución de los canales Kv1 hacia el paranodo. El bloqueo de los canales Kv1 con a-DTX tras la inducción de la lesión reinstauró la hipersensibilidad de las fibras A y aumentó la sensibilidad mecánica. Los cambios observados en la composición molecular y distribución axonal de los canales Kv1, representan por tanto un mecanismo protector que disminuye la hiperexcitabilidad de los axones sensoriales mielinizados tras un daño nervioso. Actualmente, tanto la evidencia animal como la humana coinciden en que para el desarrollo del DN una lesión de las vías aferentes somatosensoriales es necesaria. Además, numerosos estudios demuestran que son varios los mecanismos que pueden inducir el desarrollo del DN. Esto no solo pone de manifiesto la complejidad del DN, sino que también destaca la importancia clínica de identificación de los mecanismos subyacentes del dolor en cada uno los individuos que lo sufren. Ya que diferentes planes de tratamiento son necesarios para el manejo de los diferentes mecanismos, un abordaje terapéutico basado mecanismos podrá guiar a los profesionales de la salud hacia mejores resultados. Con estos conceptos en mente el segundo apartado de esta tesis tiene como objetivo descubrir posibles asociaciones entre una de las mas novedosas técnicas utilizadas para el diagnostico del DN, el Test de Cuantificación Sensorial (QST), el cual se puede aplicar para determinar los posibles mecanismos subyacentes activos, y el fenotipo sensorial expresado. Con el cuestionario painDETECT (PDQ) como herramienta de screening para DN, nosotros analizamos si el resultado obtenido para el PDQ o sus ítems reflejan fenotipos de perdida sensorial en DN demostrados con QST. Los resultados de nuestro estudio concluyen que los pacientes con perdida significativa de sensación térmica reportaban mas frecuentemente dolor evocado por tacto fino, y los pacientes con perdida significativa de sensibilidad mecánica reportaban mas frecuentemente adormecimiento, así como una menos frecuente sensación de quemazón y dolor evocado por tacto fino. A pesar de que el PDQ no fue diseñado para evaluar la perdida de sensibilidad, sus ítems individuales pueden reflejar la perdida de sensibilidad térmica y/o mecánica, pero debido a la importante variabilidad existente, el PDQ no nos permite la asignación de pacientes en perfiles sensoriales. Finalmente, la ultima parte de este trabajo enfoca su atención en el tratamiento del DN, mas específicamente en el tratamiento del Síndrome de Dolor Regional Complejo (CRPS) en niños. Este capitulo revisa la evidencia científica actual para el tratamiento de este síndrome con procedimientos invasivos, además de presentar un algoritmo terapéutico para el manejo del CRPS pediátrico. Destacar que en este algoritmo se incluyen los procedimiento invasivos para aquellos sujetos no respondedores a los tratamientos convencionales de primera línea. Conjuntamente, este capitulo detalla el curso y manejo de una serie de casos de pacientes pediátricos con CRPS refractarios al tratamiento convencional y a los que se les aplicó de manera satisfactoria el algoritmo terapéutico descrito en este trabajo. La conclusión de este capitulo nos hace ver que debido a la rápida progresión y severidad de los síntomas en el CRPS solo con un diagnostico precoz acompañado de un manejo metódico, multidisciplinar e individualizado pueden ofrecer a estos pacientes la mejor oportunidad para una recuperación satisfactoria. Cabe destacar la inclusión de los procedimientos invasivos en el momento adecuado como una opción eficaz de tratamiento.Neuropathic pain (NP) embraces a broad range of conditions linked with a disease or lesion of the peripheral or central somatosensory system and its prevalence in the general population may be as high as 7-10%. Up to the present, the larger part of our understanding of pain mechanisms come from basic sciences studies which has resulted in a vast increase in our knowledge. The obvious issues in translational pain research reveal the limitations of certain experimental models, and on that account result of limitations in clinical research. In spite of such difficulties, the scientific community wish for a better understanding of pain mechanisms helped by the new insights of basic research. For that reason, the first of the three parts of this work aim to recognise additional changes in the somatosensory system through a series of experiments done in an experimental model of NP. NP following peripheral nerve injury is associated with hyperexcitability in damaged myelinated sensory axons, which begins to normalise over time. We investigated the composition and distribution of shaker-type-potassium channels (Kv1 channels) within the nodal complex of myelinated axons following injury. At the neuroma that forms after damage, expression of Kv1.1 and 1.2 was markedly decreased. In contrast Kv1.4 and 1.6, which were hardly detectable in the naıve state, showed increased expression following injury. Within the dorsal root we noted a redistribution of Kv1-channels towards the paranode. Blockade of Kv1 channels with a-DTX after injury reinstated hyperexcitability of A-fibre axons and enhanced mechanosensitivity. Changes in the molecular composition and distribution of axonal Kv1 channels, therefore represents a protective mechanism to suppress the hyperexcitability of myelinated sensory axons that follows nerve injury

    Principles of nociceptive coding in the anterior cingulate cortex.

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    The perception of pain is a multidimensional sensory and emotional/affective experience arising from distributed brain activity. However, the involved brain regions are not specific for pain. Thus, how the cortex distinguishes nociception from other aversive and salient sensory stimuli remains elusive. Additionally, the resulting consequences of chronic neuropathic pain on sensory processing have not been characterized. Using in vivo miniscope calcium imaging with cellular resolution in freely moving mice, we elucidated the principles of nociceptive and sensory coding in the anterior cingulate cortex, a region essential for pain processing. We found that population activity, not single-cell responses, allowed discriminating noxious from other sensory stimuli, ruling out the existence of nociception-specific neurons. Additionally, single-cell stimulus selectivity was highly dynamic over time, but stimulus representation at the population level remained stable. Peripheral nerve injury-induced chronic neuropathic pain led to dysfunctional encoding of sensory events by exacerbation of responses to innocuous stimuli and impairment of pattern separation and stimulus classification, which were restored by analgesic treatment. These findings provide a novel interpretation for altered cortical sensory processing in chronic neuropathic pain and give insights into the effects of systemic analgesic treatment in the cortex

    Functional Cortical Changes in an Animal Model of Neuropathic Pain

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