Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Gout, or gouty arthritis, has been associated of a range of comorbidities as hypertension and kidney diseases. Some studies have indicated that certain antihypertensive drugs, such as angiotensin I-converting enzyme inhibitors (ACEi), increase the risk of gout. Notably, ACEi block the metabolism of several peptides, in particular bradykinin hydrolysis. Bradykinin is also a substrate for kininase I, which forms des-Arg-kinin B1R agonists. Therefore, ACE inhibition can activate the B1R pathway. Moreover, ACEi are allosteric enhancers of kinin receptors and B1R are linked to inflammatory cardiovascular diseases. However, despite the body of evidence demonstrating a clear contribution of the kinin system to the pathogenesis of some arthritic conditions, the role of the kinin B1 receptor in monosodium urate (MSU) crystals crystal-induced gout is currently unknown, especially in respect to ACEi. Thus, the aim of the present study was to verify the role of the bradykinin B1 receptors and the effect of ACEi on acute gout induced by MSU crystals in rodents. Painful (overt pain and allodynia) and inflammatory parameters (joint edema, leukocyte trafficking, interleukin-1β levels) of acute gout attacks were assessed several hours after intra-articular (IA) injection of MSU (1.25 or 0.5 mg/articulation) in the ankle of rats or mice, respectively. The role of B1R was investigated by pharmacological antagonism or gene deletion. In addition, B1R immunoreactivity on ankle tissue and sensory neurons, kininase I activity and des-Arg9-bradykinin synovial levels were also measured. Similar tools were used to investigate the effects of ACEi on low dose of MSU (0.0125 mg/articulation)-induced inflammation. Bouth, bradykinin B1R antagonism or gene deletion largely reduced all painful and inflammatory signs of gout. Furthermore, MSU increased not only the B1R expression in articular tissues, but also the content of the B1 agonist des-Arg9-bradykinin and the activity of the B1 agonist-forming enzyme kininase I. Finally, low dose of MSU crystals (which did not induced inflammation in control animals) was capable of causing signs of acute gout attacks in ACEi-treated animals, which was B1R-dependent. Concluding, bradykinin B1R activation contributes to acute gouty attacks, including the ones facilitated by ACEi. Thus, B1R is a potential therapeutic target for treatment and prophylaxis of gout, especially in patients taking ACEi. / A gota, ou artrite gotosa, está associada à ocorrência de diversas comorbidades como doenças renais e cardiovasculares. Alguns dos fármacos utilizados para o tratamento destas comorbidades podem ainda precipitar ataques agudos de gota. Um exemplo são os inibidores da enzima cininase II ou enzima conversora de angiotensina (iECA). Muitos dos efeitos cardioprotetores dos iECA são mediados pelos receptores B1 para cininas. Além disso, a inibição da ECA é capaz de bloquear a hidrólise da bradicinina, que por sua vez é também um substrato para a formação do agonista do receptor B1, des-Arg9-bradicinina, pela ação da enzima cininase I. Apesar dos estudos demonstrando o envolvimento do sistema das cininas na gota e do papel do receptor B1 na iniciação e manutenção da inflamação, não se conhece a relação do receptor B1 com a gota, especialmente durante a inibição da ECA. Assim, o presente estudo tem por objetivo verificar o papel do receptor B1 para cininas durante o ataque agudo de gota induzido por cristais de urato monossódico (MSU) em roedores, incluindo aqueles tratados com iECA. Para isso, a dor (alodínia ao toque e comportamento doloroso espontâneo) e alguns parâmetros inflamatórios (edema articular, concentração de proteínas, infiltração leucocitária, avaliação da cinética de leucócitos e níveis de interleucina-1β) causados pelo ataque agudo de gota foram avaliados em diferentes tempos após a injeção intra-articular (IA) de uma alta dose de MSU no tornozelo de roedores. O papel do receptor B1 foi investigado através de seu antagonismo farmacológico, pela utilização de roedores com deleção gênica do receptor e pela inibição da enzima cininase I. Ainda, a expressão do receptor B1 no tecido do tornozelo e neurônios sensoriais, atividade da enzima cininase I e os níveis de des-Arg9-bradicinina foram analisados no fluido sinovial dos roedores submetidos ao modelo de gota. Ferramentas semelhantes foram utilizadas para a investigação do envolvimento dos receptores B1 na inflamação causadas pela inibição da ECA em animais submetidos a injeção IA de uma baixa dose de MSU, que não apresentava efeito per se. Tanto o uso de antagonistas do receptor B1, como sua deleção gênica, foram capazes de reduzir a inflamação neste modelo de gota. Além disso, o MSU causou um aumento na expressão de receptores B1 na articulação, e também um aumento dos níveis do agonista B1, des-Arg9-bradicinina e da atividade da enzima cininase I. Por último, a baixa dose de MSU foi capaz de causar um ataque agudo de gota em animais pré-tratados com iECA, por um mecanismo que envolve a ativação de receptores B1. Concluímos que a ativação do receptor B1 contribui para o desenvolvimento do ataque agudo de gota, incluindo aqueles que são precipitados pelo tratamento com iECA. Assim, o B1 apresenta um potencial terapêutico para o tratamento e profilaxia da gota, especialmente em indivíduos que fazem uso de iECA.

The first nociceptive synapse in the spinal cord dorsal horn represents an important site, where nociceptive synaptic transmission can be modulated under pathological conditions. One of the modulatory mechanism involves activation of the transient receptor potential vanilloid 1 (TRPV1) that is expressed on central terminals of primary nociceptive neurons, where it regulates release of neurotransmitters and neuromodulators. Previous studies suggested that changes in TRPV1 activity may be related to effects of chemokine CCL2 (C-C motif ligand 2) and may be also involved in synaptic transmission modulation after µ-opioid receptors (MOP-R) activation. Because CCL2 receptors CCR2 often co-localize with TRPV1 and MOP-R, the goal of this work was to studypossible interactions of these receptors on the pre-synaptic endings of primaryafferents in the spinal cord dorsal horn and their role in nociceptive signalling under pathological conditions. The presented thesis focused on the effect of CCL2 during peripheral neuropathy and its interference with µ-opioid receptor activation. To studysynaptic transmission at the spinal cord level, patch-clamp recordings of excitatory post-synaptic currents (EPSC) in superficial spinal cord dorsal horn neurons in acute lumbar spinal cord slices from rats was used....

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Parkinson´s disease (PD) is a common neurodegenerative disorder of movement, which affects 1% of the population over 65 years and 4% to 5% of the population over 75 years. Currently, it is known that the disease is not only characterized by motor abnormalities, but also by a set of non-motor abnormalities that precede perhaps over several years, in preclinical phase of the disease. Studies in the premotor phase of PD are important for the understanding of when and where the disease begins to develop and how it evolves in the early stages. Although still incipient, some studies have pointed to the presence of sensory nociceptive and auditory disorders in PD. Using an animal model of PD that takes into account the progressive nature, allows a better understanding of the relationship between the pathophysiological aspects and non-motor abnormalities of the disease and enables the exploration of temporal manifestation of these changes. The aim of this study was to evaluate the nociceptive, motor and hearing functions of Wistar rats submitted to progressive model of parkinsonism induced by low and repeated doses of reserpine (RES). In the first stage, 19 Wistar rats were used, divided into two groups (n = 9/10 per group): G1: RES (0.1 mg / kg sc) and G2: CTR (RES vehicle). The animals were subjected daily to catalepsy test and the nociceptive von Frey electronic test and received injections every 48 hours for 20 days. The grip strength test was performed on days 9, 12, 14 and 17. In the second stage, the animals were divided into two groups (n = 10/11 per group) G1: RES (0, 1 mg / kg sc) and G2: CTR (RES vehicle). The catalepsy test was performed daily and the injections were made every 48 hours. On day 8, the animals were sedated to perform the hearing test of otoacoustic emissions by distortion product (DPOAE). On day 10, the nociceptive formalin test was performed, and 60 minutes later, each animal was anesthetized, perfused and their brains removed for subsequent immunohistochemical analysis for tyrosine hydroxylase (TH) and c-FOS. Repeated treatment with RES induced progressive motor abnormalities evidenced by catalepsy test from the 16th day. Likewise, induced changes in the nociceptive response of rats evidenced in electronic von Frey test and the formalin test, which occurred on the 10th day, i.e, before the motor changes. Muscle strength as measured by grip strength test, did not change with treatment. Changes in the auditory function were observed on the 8th day of treatment. Neurochemically on the 10th day, repeated treatment with the RES induced a decrease in the number of TH+ cells in the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA) and not changed TH levels in the striatum. Regarding the immunostaining for c-FOS, noxious stimulation caused an increase in the number of cells c- FOS+ in the dorsal raphe nucleus (NDR), periaqueductal gray (PAG) and rostral ventromedial medulla (SVR) after repeated treatment with the RES, on the 10th day. We conclude that nociceptive changes precede motor changes, while the strength remains unchanged in the progressive model of parkinsonism induced by low and repeated doses of RES, reinforcing the idea that pain is one of the early signs of PD. In addition, animals with parkinsonism were more susceptible to hearing loss due to exposure to environmental noise, suggesting a possible link between the DP and the predisposition to hearing loss, including the premotor phase of the disease. / A doença de Parkinson (DP) é uma desordem neurodegenerativa comum do movimento, que afeta 1% da população acima de 65 anos e 4% a 5% da população acima de 75 anos. Atualmente, sabe-se que a doença não é caracterizada somente pelas alterações motoras, mas também por um conjunto de alterações não motoras, que talvez as precedam por vários anos, em fase pré-clínica da doença. Estudos na fase pré-motora da DP são importantes para o entendimento sobre quando e onde a doença começa a se desenvolver e como ela evolui nos estágios iniciais. Apesar de ainda incipientes, alguns estudos têm apontado para a presença de alterações sensoriais, nociceptivas e auditivas, na DP. O uso de um modelo animal da DP, que leve em conta a sua natureza progressiva, possibilita uma melhor compreensão das relações entre os aspectos fisiopatológicos e as alterações não motoras da doença e viabiliza a exploração temporal da manifestação dessas alterações. O objetivo desse estudo foi avaliar as funções nociceptiva, motora e auditiva de ratos Wistar submetidos ao modelo progressivo de parkinsonismo, induzido por doses baixas e repetidas de reserpina (RES). Na primeira etapa, foram utilizados 19 ratos Wistar, divididos em dois grupos (n=9/10 por grupo): G1: RES (0,1 mg/kg s.c.) e G2: CTR (veículo da RES). Os animais foram submetidos diariamente ao teste motor de catalepsia e ao teste nociceptivo do von Frey eletrônico, e receberam as injeções a cada 48h, durante 20 dias. O teste de força de preensão (grip strenght test) foi realizado nos dias 9, 12, 14 e 17. Na segunda etapa, os animais foram divididos em dois grupos (n=10/11 por grupo): G1: RES (0,1 mg/kg s.c.) e G2: CTR (veículo da RES). O teste de catalepsia foi realizado diariamente e as injeções foram feitas a cada 48h. No dia 8, os animais foram sedados para realização do teste auditivo de otoemissões acústicas por produto de distorção (OEAPD). No dia 10, foi realizado o teste nociceptivo da formalina e, 60 minutos depois, cada animal foi anestesiado, perfundido e seus cérebros extraídos para posterior análise imunohistoquímica para tirosina hidroxilase (TH) e c-FOS. O tratamento repetido com a RES induziu alterações motoras progressivas evidenciadas através do teste de catalepsia a partir do 16º dia. Da mesma forma, ocasionou alterações na resposta nociceptiva dos ratos evidenciadas no teste do von Frey eletrônico e no teste da formalina, as quais ocorreram a partir do 10º dia, ou seja, antes das alterações motoras. A força muscular, avaliada através do teste de força de preensão, não se alterou com o tratamento. Alterações na função auditiva foram observadas no 8º dia de tratamento. Neuroquimicamente, no 10º dia, o tratamento repetido com a RES induziu diminuição na quantidade de células TH+ na substância negra parte compacta (SNpc) e na área tegmental ventral (do inglês ventral tegmental área VTA) e não alterou os níveis de TH no estriado. Quanto à imunomarcação para c-FOS, o estímulo nocivo provocou aumento na quantidade de células c-FOS+ nas regiões do núcleo dorsal da rafe (NDR), substância cinzenta periaquedutal (do inglês, periaqueductal gray PAG) e no bulbo rostro ventromedial (do inglês, rostral ventromedial medulla RVM), após o tratamento repetido com a RES, no 10º dia. Concluímos que alterações nociceptivas precedem as alterações motoras, enquanto a força permanece inalterada no modelo progressivo de parkinsonismo induzido por repetidas e baixas doses de RES, reforçando a ideia de que a dor seja um dos sinais precoces da DP. Além disso, animais com parkinsonismo se mostraram mais suscetíveis às alterações auditivas por exposição aos ruídos ambientais, sugerindo uma possível relação entre a DP e a predisposição à perda de audição, inclusive em fase pré-motora da doença.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The affective-motivational component of pain refers to the effects of experiencing pain on emotions and behavior. Studies suggest that social contact induces changes in nociceptive and affective responses in individuals with pain. Motor activity as a parameter for pain assessment in both animals and humans has already been used in some studies, but the association of these variables with social components has not yet been tested. In addition, most of the studies related to nociception are directed to the subject who is in an allergic condition, and his or her contacts end up becoming coadjuvant. Our objective was to evaluate how social contact interferes in the motor activity of rats submitted to a model of inflammatory pain and the pro-social behavior of their contacts. We used 42 Wistar rats, 2 to 3 months old. For this, two experiments were performed, in all of them the n = 6 animals per group. In the experiment I was evaluated the behavior of resident mouse during contact with control animals (CTRL), saline (SAL) and with inflammatory pain (FORM). For this, the latency time for the first contact and the duration of the contact were measured over 20 min. The inflammatory pain did not alter the latency time of the first contact of the residents with the control animals. However, the duration of contact was higher with animals of the FORM group when compared to the CTRL group and the SAL group. In experiment II the effect of social contact in the motor response of the animals with inflammatory pain was evaluated. The animals were divided into four groups: Formalin Isolate (FI) that received formalin and then was isolated, Formalin Contact (FC) that received formalin and had contact with the animal from the box where it resided, Control Contact (CC) that was only Manipulated and put in contact with the resident and the Isolated Control (CI) that has been manipulated and placed in isolation. After 20 min of contact or isolation, the video of the animals was analyzed in the ANY-maze to verify the motor activity. The behaviors analyzed were: total distance traveled, rearing time, number of outflows of quadrants and immobility time, during the total time of the test and divided in intervals of 5 minutes making 4 blocks. The animals of the FC group presented less rearing time and number of exits of the quadrants in relation to the CI. On the other hand, the FI animals had less time rearing and exit of the quadrants in relation to the CI, and a longer time of immobility in relation to all the other groups. When analyzed by time block there was a difference in the interval of 0 to 5 minutes for the distance traveled between CC and FC, and CC and FI, in which the CC animals moved more during the test. The rearing time was higher for the CC and CI animals compared to the FC and FI in the range of 0 to 5, in the second interval the CI group had a longer rearing time than the FC and in the third interval there was a longer time of the CI rats in Relation to CF and FI. There was longer immobility time of the FI animals in relation to all the other groups in the range of 0 to 5 min. It was observed that the social interaction preserved the motor activity of the FC rats, but not the FI compared to their controls. In addition, the resident animal could differentiate the nociceptive conditions of the cohabitant, and this resulted in a longer time of interaction between these animals and the adopted social behavior. / O componente afetivo-motivacional da dor refere-se aos efeitos da vivência da dor sobre emoções e comportamento. Estudos sugerem que o contato social induz alterações nas respostas nociceptivas e afetivas em indivíduos com dor. A atividade motora como um parâmetro para avaliação da dor tanto em animais como em humanos já foi utilizada em alguns trabalhos, porém a associação dessas variáveis aos componentes sociais, ainda não foram testados. Além disso, a maioria dos estudos relacionados a nocicepção são direcionados ao sujeito que está em condição álgica, sendo que seus contactantes acabam se tornando coadjuvantes. O nosso objetivo foi avaliar como o contato social interfere na atividade motora de ratos submetidos a um modelo de dor inflamatória e o comportamento pró-social dos seus contactantes. Foram utilizados 42 ratos Wistar, com 2 a 3 meses de idade. Para isso foram realizados dois experimentos, em todos eles o n = 6 animais por grupo. No experimento I foi avaliado o comportamento do rato residente durante o contato com animais controle (CTRL), salina (SAL) e com dor inflamatória (FORM). Para tanto, foram medidos o tempo de latência para o primeiro contato e a duração do contato ao longo de 20 min. A dor inflamatória não alterou o tempo de latência do primeiro contato dos residentes com os animais controle. Contudo a duração do contato foi maior com animais do grupo FORM quando comparado com o grupo CTRL e ao grupo SAL. No experimento II foi avaliado o efeito do contato social na resposta motora dos animais com dor inflamatória. Os animais foram divididos em quatro grupos: Formalina Isolado (FI) que recebeu formalina e em seguida foi isolado, Formalina Contato (FC) que recebeu formalina e teve contato com o animal da caixa onde residia, o Controle Contato (CC) que apenas foi manipulado e colocado em contato com o residente e o Controle Isolado (CI) que foi manipulado e colocado em isolamento. Após 20 min de contato ou isolamento, o vídeo dos animais foi analisado no ANY-maze para verificar a atividade motora. Os comportamentos analisados foram: distância total percorrida, tempo de rearing, número de saídas dos quadrantes e tempo de imobilidade, durante o tempo total do teste e dividido em intervalos de 5 minutos perfazendo 4 blocos. Os animais do grupo FC apresentaram menor tempo de rearing e número de saídas dos quadrantes em relação ao CI. Já os animais FI apresentaram menor tempo rearing e de saída dos quadrantes em relação aos CI, e maior tempo de imobilidade em relação a todos os outros grupos. Quando analisados por bloco de tempo houve diferença no intervalo de 0 a 5 minutos para a distância percorrida entre CC e FC, e CC e FI, no qual os animais CC se deslocaram mais durante o teste. O tempo de rearing foi maior para os animais CC e CI em relação aos FC e FI no intervalo de 0 a 5, no segundo intervalo o grupo CI teve maior tempo de rearing que o FC e no terceiro intervalo houve maior tempo dos ratos CI em relação aos FC e FI. Houve maior tempo de imobilidade dos animais FI em relação a todos os outros grupos no intervalo de 0 a 5 min. Percebe-se que a interação social preservou a atividade motora dos ratos FC, não ocorrendo o mesmo com os FI em relação a seus controles. Somado a isso o animal residente conseguiu diferenciar as condições nociceptivas do seu companheiro de caixa, e isso acarretou num maior tempo de interação entre esses animais e no comportamento pró-social adotado. / São Cristóvão, SE

Modulation of a synaptic transmission in the spinal cord dorsal horn plays a key role in nociceptive signalling, especially in states of pathological pain. The goal of this study was to develop a method for calcium imaging in spinal cord slices in vitro. This method allowed us to record changes of intracellular free calcium ions concentration (iCa2+ ), that are a major mediator of neuronal plasticity. In this work, we have focused on application of this method in a conventional fluorescence microscope and on the role of different neuromodulators of synaptic activity. Changes of iCa2+ induced by dorsal root electrical stimulation were recorded altogether in 744 dorsal horn (lamina I and II) neurons. In the first series of experiments, stimulation protocols activating preferentially A and A + C dorsal root fibers were used and long-term stability of the calcium responses was verified. The dorsal root stimulation induced in the neurons fast and delayed type of calcium response. Application of AMPA and NMDA receptors antagonists, CNQX (50μM) and MK801 (45μM), reduced the calcium response amplitude and confirmed the importance of glutamate receptors in synaptic activation. In several experiments the effect of capsaicin a TRPV1 receptors agonist, application was tested. Application of even low...

Dorsoradial and anterior oblique ligaments were harvested during surgery in 13 patients with symptomatic trapeziometacarpal osteoarthritis, which had been graded preoperatively by a modified Eaton-Littler radiographic grading. Ligaments, including the periligamentous synovium, were stained with S100 protein, neurotrophic receptor p75, protein gene product 9.5, calcitonin gene related peptide, acetylcholine, substance P, neuropeptide Y, noradrenaline, N-methyl-D-aspartate-receptor and Met/Leu-enkephalin. The synovium was classified as showing no, low-grade or high-grade synovitis. Free nerve endings had higher immunoreactivity for substance P than for N-methyl-D-aspartate-receptor, enkephalin and noradrenaline. The synovial stroma had less immunoreactivity for N-methyl-D-aspartate-receptor than for noradrenaline, substance P and calcitonin gene related peptide. There was no relation between the grade of osteoarthritis and the visual pain analogue scale, synovitis score, immunoreactivity of all antibodies and quantity of free nerve endings or blood vessels. Synovium in trapeziometacarpal joint osteoarthritis produces several neuromediators causing a polymodal neurogenic inflammation and which may serve as biomarkers for osteoarthritis or therapeutic targets.

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第24943号 / 生博第505号 / 新制||生||67(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 上村 匡, 教授 今吉 格, 教授 鈴木 淳 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

Hintergrund Die Gabe von Opioiden zur Schmerzunterdrückung spielt eine zentrale Rolle in der modernen Anästhesiologie. Messungen von Hypnosetiefe und Muskelrelaxierung sind im Gegensatz zur Schmerzmessung seit Jahren etabliert. Seit Kurzem ist das PMD200 („Pain Monitoring System“; Fa. Medasense Biometrics™ Ltd., Ramat-Gan, Israel) verfügbar. Dieser Schmerzmonitor misst nichtinvasiv und errechnet einen dimensionslosen Schmerzindex („nociceptor level“, NoL). Die Validität und Zuverlässigkeit des Verfahrens sind Gegenstand von klinischen Studien. Fragestellung Reduziert die Verwendung des PMD200 die Gabe von Analgetika während einer Da-Vinci-Prostatektomie? Material und Methoden In die Studie wurden 50 Patienten aufgenommen. Nach gewichtsadaptierter Sufentanilgabe zur Narkoseinduktion und einem 10 µg Bolus vor Hautschnitt erfolgte die intraoperative Analgesie durch subjektive Entscheidung (CONT) oder aufgrund eines erhöhten NoL-Index (INT). Die statistische Auswertung erfolgte durch Mann-Whitney-U-, Kolmogorow-Smirnow-Test und Levene-Statistik. Ergebnisse In der INT-Gruppe war die Anzahl der Sufentanilboli/h nicht signifikant geringer als in der CONT-Gruppe (p = 0,065). Die Varianz der Sufentanilgaben unterschied sich signifikant (p = 0,033). In der CONT-Gruppe war die Applikation normal verteilt (p = 0,2), in der INT-Gruppe hingegen nicht (p = 0,003). Diskussion Eine mögliche Interpretation der Daten ist, dass die Schmerzmittelgabe in der INT-Gruppe individualisierter erfolgte, d. h., es wurden nichterforderliche Schmerzmittelgaben vermieden, und gleichzeitig detektierte das NoL-Monitoring einzelne Patienten mit deutlich erhöhtem Schmerzmittelbedarf. Diese Schlussfolgerung ist nur unter der Voraussetzung zulässig, dass das PMD200 auch tatsächlich die Entität Schmerz misst. / Background Administration of opioids to suppress pain plays a major role in modern anesthesia. Measuring depth of hypnosis and neuromuscular recovery are already well established, and devices for pain monitoring are available. Nonetheless pain monitoring is rare in clinical practice. Recently, the pain monitoring device PMD200 (Medasense Biometrics™ , Israel) was introduced. It non-invasively measures heart rate, heart rate variability, skin resistance, resistance variability, temperature and movement to calculate a nociception level (NoL) index. The NoL index range starts at zero, which is equivalent to being painless, and goes up to a value of 100. The validity and reliability of NoL monitoring is the content of current studies. Objective We tested the hypothesis if the use of the PMD200 significantly reduces opioid consumption during da Vinci prostatectomy. Material and methods A total of 50 male patients were included in this randomized, single blinded study. Exclusion criteria were arrhythmia because the pain monitoring device requires a sinus rhythm for reliable results. Patients received a weight-adjusted sufentanil bolus (0.3 µg/kg ideal body weight) during induction of anesthesia. Additionally, they received 10 µg of sufentanil before skin incision. Both groups received total intravenous anesthesia with propofol and continuous muscle relaxation through cis-atracurium. In the control group (CONT; n = 26), a standardized sufentanil bolus of 10 µg were administered by common criteria (heart rate/blood pressure increase, lacrimation, gut feeling) at the anesthesiologistʼs discretion. In the intervention group (INT; n = 24), patients received the standardized sufentanil bolus when the NoL index was above 25 for 2 min, which corresponds to the manufacturerʼs recommendation. The NoL index and bolus administrations were recorded for every patient. In the control group, the display of the pain monitor showing the NoL index was not visible for the anesthesiologist. Postoperatively, pain/nausea scores and piritramide consumption were taken every 10 min for 1h in the recovery room. None of the patients had prior chronic pain with long-term use of painkillers. Statistics were done using Mann-Whitney U‑test, Kolmogorov-Smirnov test and Levene test. Results Sufentanil bolus administrations, normalized for duration of surgery, were not significantly lower in the intervention group (p = 0.065). We noticed a significant difference in variation of opioid administrations (p = 0.033). Sufentanil boluses per hour in the INT were normally distributed (p = 0.2), whereas in CONT they were not (p = 0.003). Postoperative data like nausea, opioid consumption and pain scale showed no differences between groups. Conclusion The use of PMD200 did not significantly reduce cumulative opioid consumption. Following on we must reject the initial hypothesis. The difference in sufentanil bolus variances may point to an individualized antinociceptive therapy when NoL monitoring is used. We suppose patients with high opioid demands are detected and patients with low opioid demands did not receive unnecessary opioids. This assumption is only true if the PMD200 measures the entity pain. Further studies with more participants during surgery with higher tissue damage could lead to more convincing data and conclusions.

Hintergrund: Die Gabe von Opioiden zur Schmerzunterdrückung spielt eine zentrale Rolle in der modernen Anästhesiologie. Messungen von Hypnosetiefe und Muskelrelaxierung sind im Gegensatz zur Schmerzmessung seit Jahren etabliert. Seit wenigen Jahren ist das pain monitoring device 200 (PMD-200TM; Medasense BiometricsTM Ltd., Israel) verfügbar. Dieser Schmerzmonitor misst nicht-invasiv und errechnet den dimensionslosen Schmerzindex Nozizeptor-Level (NoL). Die Validität und Zuverlässigkeit des Verfahrens ist Gegenstand klinischer Studien. Fragestellung: Reduziert die Verwendung des PMD-200TM die Gabe von Analgetika während einer Da- Vinci-Prostatektomie? Material und Methoden: In die Studie wurden 50 Patienten aufgenommen. Die Studie wurde einfach verblindet, prospektiv und randomisiert durchgeführt. 26 Patienten wurden der Interventionsgruppe (INT) und 24 Patienten der Kontrollgruppe (CONT) zugeordnet. Nach gewichtsadaptierter Sufentanil-Gabe zur Narkoseinduktion und einem 10 μg Bolus vor Hautschnitt, erfolgte die intraoperative Analgesie durch subjektive Entscheidung (CONT) oder aufgrund eines erhöhten NoL-Index (INT). Die statistische Auswertung erfolgte durch Chi-Quadrat-Homogenitätstest, Mann-Whitney-U-Test, Kolmogorov-Smirnov- Test und Levene-Statistik. Ergebnisse: In der Interventionsgruppe war die Anzahl der Sufentanil-Boli je OP-Stunde nicht signifikant geringer als in der Kontrollgruppe (p=0,065). Die Varianz der Sufentanil- Gaben unterschied sich signifikant (p=0,033). In der Kontrollgruppe war die Applikation normalverteilt (p=0,2), in der Interventionsgruppe hingegen nicht (p=0,003). Schlussfolgerungen: Eine mögliche Interpretation der Daten ist, dass die Schmerzmittelgabe in der Interventionsgruppe individualisierter erfolgte, d.h. es wurden nicht-erforderliche Schmerzmittelgaben vermieden und gleichzeitig detektierte das NoL-Monitoring einzelne Patienten mit deutlich erhöhtem Schmerzmittelbedarf. Diese Schlussfolgerung ist nur unter der Voraussetzung zulässig, dass der PMD-200TM auch tatsächlich die Entität Schmerz misst.:1 Einleitung 5 1.1 Schmerz 5 1.1.1 Definition 5 1.1.2 Physiologische Klassifikation von Schmerz 5 1.1.3 Physiologie des nozizeptiven Schmerzes 6 1.1.4 Beeinflussung der Nozizeption durch Opioide 10 1.1.5 Analgesie in der Anästhesiologie 11 1.1.6 Bedeutung für die Patient*Innen 12 1.2 Nozizeptions-Monitoring 12 1.2.1 ANI – Analgesia Nociception Index 12 1.2.2 NFTS – Nociceptive Flexion Reflex threshold (Pain-tracker) 13 1.2.3 PPI – Pupillary Pain Index 13 1.2.4 Skin conductance Algesimeter Index (PainMonitor) 13 1.2.5 SPI – Surgical Pleth Index 14 1.2.6 CARDEAN – Cardiovascular Depth of Analgesia 14 1.2.7 NoL-Index – Nozizeptor Level Index (PMD-200TM) 14 1.2.8 Zukunft des Nozizeptions-/Analgesie-Monitorings 16 2 Fragestellung 17 3 Material und Methoden 18 3.1 Ethik und Patienten 18 3.2 Randomisierung und Zuordnung 18 3.3 Ablauf 19 3.3.1 Präoperative Phase 19 3.3.2 Intraoperative Phase 22 3.3.3 Postoperative Phase 26 3.4 Statistische Auswertung 27 4 Ergebnisse 28 4.1 Patientenkollektiv 28 4.2 Intraoperative Daten 30 4.2.1 Co-Analgesie 30 4.2.2 Anästhesie- und OP-Zeiten 30 4.2.3 Indikationsstellung Sufentanil-Boli in Gruppe CONT 32 4.2.4 Propofol-Dosierung und BIS-Wert 33 4.2.5 NoL-Index Aufzeichnung 34 4.2.6 Vergleich der Sufentanil-Boli 35 4.3 Postoperative Daten 38 5 Diskussion 39 5.1 Interpretation der Ergebnisse 39 5.2 Limitationen 44 5.3 Schlussfolgerungen 46 6 Zusammenfassung 47 7 Summary 48 8 Literatur- und Quellenverzeichnis 50 9 Abkürzungsverzeichnis 58 10 Abbildungsverzeichnis 59 11 Tabellenverzeichnis 61 12 Danksagung 62 13 Anlagen 63 13.1 Erklärung zur Eröffnung des Promotionsverfahrens 63 13.2 Erklärung zur Einhaltung aktueller gesetzlicher Vorgaben 65

Les facteurs psychologiques tels que l'hypnose, l'émotion, le stress et l’attention exercent un effet modulant puissant sur la nociception et la douleur. Toutefois, l’influence de l'attention sur la nociception et la douleur, ainsi que les mécanismes neuronaux sous-jacents, ne sont pas clairs. La littérature actuelle sur la modulation attentionnelle des réponses spinales nociceptives, telles que mesurées par le réflexe RIII, et de la perception de l’intensité de la douleur est discordante et souvent contradictoire. Ce mémoire fournit un nouveau cadre pour examiner la modulation du réflexe RIII et de la douleur par l’attention. Une tâche de discrimination sensorielle a été décomposée en trois composantes attentionnelles : la vigilance, l’orientation, et le contrôle exécutif. Auparavant, la nature multidimensionnelle de l’attention fut largement ignorée dans la littérature. Nous démontrons que les composantes attentionnelles ont des effets modulatoires distincts sur la nociception et la douleur et suggérons que ceci représente une partie de la confusion présente dans la littérature. En prenant compte du stress indépendamment, nous démontrons, pour la première fois, que le stress inhibe la modulation attentionnelle du réflexe RIII ce qui indique une interaction et dissociation de la modulation des réponses nociceptives par l’attention et le stress. Ces résultats importants clarifient, en grande partie, les contradictions dans la littérature, puisque les tâches cognitives produisent souvent des augmentations du stress ce qui confond l’interprétation des résultats. De plus, la tâche de discrimination inclut des stimuli visuels et somatosensoriels et révèle que l’influence de l'attention sur la douleur est spatialement spécifique tandis que la modulation attentionnelle de la nociception est spécifique à la modalité des stimuli, au moins en ce qui concerne les modalités examinées. A partir de ces résultats, un nouveau modèle de la modulation attentionnelle des processus de la douleur, basée sur les composantes attentionnelles, a été proposé. Celui-ci est appuyé par la littérature et fournit une explication systématique et intégratrice des résultats antérieurement contradictoires. De plus, à partir de ce modèle, plusieurs mécanismes neuronaux ont été proposés pour sous-tendre la modulation attentionnelle de la nociception et de la douleur. / Psychological factors such as hypnosis, emotion, stress, and attention produce powerful modulatory effects on nociception and pain. However, the influence of attention on nociception and pain and the underlying neural mechanism responsible are unclear. The current literature on attentional modulation of spinal nociceptive responses, as measured by the RIII reflex, and pain perception (pain intensity) is inconsistent and often contradictory. The present thesis provides a new component-based framework for the examination of attentional modulation of the RIII reflex and pain. A delayed-discrimination task was decomposed into the three components of attention – namely alerting, orienting, and executive control (sensory working memory). Previously, the multidimensional nature of attention was largely ignored in the pain literature. We show that each component of attention exerts a distinct modulatory effect on nociception and pain and suggest that this accounts for some of the confusion in the literature. By considering stress separately, we demonstrate for the first time that stress blocks attentional modulation of the RIII reflex, indicating an interaction and dissociation of attention- and stress-mediated modulation of spinal nociceptive responses. This important finding clarifies much of the disagreement in the literature, since cognitive tasks often induce increases in stress that consequently confound interpretation. Additionally, both visual and somatosensory stimuli were included in the discrimination task, revealing that the influence of attention on pain intensity is spatially-specific whereas attentional modulation of nociception is modality-specific, at least for the modalities investigated. From these findings a component-based model for the attentional modulation of pain processes is proposed. This model is substantially supported by the literature and provides a meaningful and cohesive explanation of the seemingly contradictory results across studies. Moreover, this model suggests potential neural mechanisms underlying the attentional modulation of pain.