本研究は、先行研究で示唆されていた淡蒼球外節（GP）におけるニューロキニン１型受容体（NK-1R）の局在を、免疫染色と投射パターン、電気生理学の観点から示した。形態学的には、NK-1Rを持つ細胞がLhx6やPVを共発現し、線条体と視床下核の両方に投射するものの、FoxP2を発現する細胞とは共存しなかった。さらに、パッチクランプを用いてGP細胞の電気的性質を調べた後、NK-1Rアゴニストへの応答を観察した結果を合わせたところ、NK-1R細胞がPrototypicタイプに含まれる特定の集団であることが明らかになった。 / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

Introdução: Apesar da abordagem farmacológica multimodal profilática, as náuseas e os vômitos pós-operatórios (NVPO) correspondem a uma das principais queixas dos pacientes após procedimentos laparoscópicos. Em pacientes considerados de alto risco pelo critério de Apfel, a incidência de tais eventos pode chegar a 80%. Neste contexto, os antagonistas dos receptores de NK-1 têm sido recomendados para adultos em adição a outras estratégias antieméticas na tentativa de reduzir essa incidência. Entretanto, o efeito da associação do aprepitanto ao regime dexametasona, ondansetrona e propofol permanece indefinido. Nesta pesquisa, como desfecho principal, estudou-se o efeito da associação do aprepitanto em regime antiemético profilático multimodal para redução de risco de NVPO nas primeiras 24 horas do período pós-operatório em pacientes de alto risco pelo critério de Apfel. Como desfechos secundários, foram estudadas intensidade dos eventos de náuseas, incidência dos eventos de vômitos intensos e ocorrência de consumo de antieméticos de resgate nas primeiras 24 horas do período pós-operatório. Métodos: pacientes adultos, estratificados como alto risco pelo critério de Apfel, submetidos a procedimentos laparoscópicos oncológicos, foram alocados aleatoriamente para receber profilaticamente aprepitanto 80 mg (grupo de tratamento) ou amido (grupo controle) associados à dexametasona (4 mg ou 8 mg), ondansetrona (4 mg ou 8 mg) e anestesia venosa alvo-controlada com propofol. A análise estatística do desfecho principal foi realizada utilizando o Teste Exato de Fisher, e a hipótese nula foi descartada se p < 0,05. Resultados: Sessenta e seis pacientes concluíram o estudo. NVPO ocorreram em 13 (40,6%) pacientes nas primeiras 24 horas após emergência da anestesia no grupo controle. No grupo tratamento, ocorreram náusea em 5 pacientes (14,7%, p = 0,03) e vômito em 1 paciente (2,9%, p = 0,0002). A redução de risco relativo foi de 63,8% (IC 95% 9,9% - 86%) para náusea e de 92,7% (IC 95% 61,2% - 98,8%) para vômito. Episódios de náusea intensa ocorreram em 2 (6,3%) pacientes e de vômitos intensos, em 4 (12,5%) pacientes, no grupo controle. Um paciente apresentou vômito intenso no grupo tratamento. Em relação ao consumo de antieméticos, 9 (28,1%) pacientes solicitaram medicamentos antieméticos de resgate no grupo controle e 3 (8,8%) pacientes, no grupo tratamento, nas primeiras 24 horas pós-operatórias (p = 0,02). Conclusão: O aprepitanto (80 mg), como uma quarta estratégia antiemética profilática, pode contribuir para a redução significativa de NVPO e de consumo de antieméticos de resgate em pacientes de alto risco / Background: Despite the use of multimodal pharmacological approach, postoperative nausea and vomiting (PONV) is one of the most important causes of patients discomfort after laparoscopic surgeries. NK-1 receptor antagonists have recently being recommended for prophylaxis of PONV in adults, but the combination with serotonin (5-HT3) receptor antagonists such as ondansetron, corticosteroids such as dexamethasone and propofol, are not yet well established. The primary aim of this randomized and double-blind study was to assess whether the addition of aprepitant to a multimodal management strategy for PONV prophylaxis in a high-risk patient population would further decrease the incidence of PONV in the first 24 postoperative hours. The secondary aims were the quantification of nausea intensity, number of episodes of vomiting and rescue antiemetic consumption in the same period. Methods: patients classified as Apfel Score 3 or 4, scheduled to laparoscopic surgeries to treat cancer, were randomized to receive either oral aprepitant 80mg (treatment group) or matching placebo (control group) before induction of anesthesia. All patients received intravenous dexamethasone 4 mg or 8 mg at induction of anesthesia, ondansetron 4 mg or 8 mg at the end of the surgery and a standardized total intravenous anesthesia (TIVA) technique. Statistical analysis was performed using Fisher\'s Exact Test and the null hypothesis was ruled out if p < 0.05. Results: Sixty-six patients completed the study. Nausea and vomiting occurred in 13 (40.6%) patients during the first 24 hours in the control group (all patients who presented nausea also vomited). In the treatment group, nausea occurred in 5 patients (14.7%, P = 0.03) and vomiting occurred in 1 patient (2.9%, P = 0.0002). The reduction in the relative risk was 63.8% (95%CI 9.9% - 86%) for nausea and 92.7% (95%CI 61.2% - 98.8%) for vomiting. Severe nausea occurred in 2 (6.3%) patients, and severe vomiting occurred in 4 (12.5%) patients in the control group. One patient presented with severe vomiting in the treatment group in the first 24 postoperative hours. The administration of rescue antiemetics occurred in 9 (28.1%) patients in the control group and in 3 (8.8%) patients in the treatment group in the first 24 postoperative hours (P = 0.02). Conclusion: Eighty milligrams of aprepitant added to a three-drug multimodal prophylaxis strategy can bring benefits to a high-risk population by reducing PONV episodes and rescue antiemetic requirements

Introdução: Apesar da abordagem farmacológica multimodal profilática, as náuseas e os vômitos pós-operatórios (NVPO) correspondem a uma das principais queixas dos pacientes após procedimentos laparoscópicos. Em pacientes considerados de alto risco pelo critério de Apfel, a incidência de tais eventos pode chegar a 80%. Neste contexto, os antagonistas dos receptores de NK-1 têm sido recomendados para adultos em adição a outras estratégias antieméticas na tentativa de reduzir essa incidência. Entretanto, o efeito da associação do aprepitanto ao regime dexametasona, ondansetrona e propofol permanece indefinido. Nesta pesquisa, como desfecho principal, estudou-se o efeito da associação do aprepitanto em regime antiemético profilático multimodal para redução de risco de NVPO nas primeiras 24 horas do período pós-operatório em pacientes de alto risco pelo critério de Apfel. Como desfechos secundários, foram estudadas intensidade dos eventos de náuseas, incidência dos eventos de vômitos intensos e ocorrência de consumo de antieméticos de resgate nas primeiras 24 horas do período pós-operatório. Métodos: pacientes adultos, estratificados como alto risco pelo critério de Apfel, submetidos a procedimentos laparoscópicos oncológicos, foram alocados aleatoriamente para receber profilaticamente aprepitanto 80 mg (grupo de tratamento) ou amido (grupo controle) associados à dexametasona (4 mg ou 8 mg), ondansetrona (4 mg ou 8 mg) e anestesia venosa alvo-controlada com propofol. A análise estatística do desfecho principal foi realizada utilizando o Teste Exato de Fisher, e a hipótese nula foi descartada se p < 0,05. Resultados: Sessenta e seis pacientes concluíram o estudo. NVPO ocorreram em 13 (40,6%) pacientes nas primeiras 24 horas após emergência da anestesia no grupo controle. No grupo tratamento, ocorreram náusea em 5 pacientes (14,7%, p = 0,03) e vômito em 1 paciente (2,9%, p = 0,0002). A redução de risco relativo foi de 63,8% (IC 95% 9,9% - 86%) para náusea e de 92,7% (IC 95% 61,2% - 98,8%) para vômito. Episódios de náusea intensa ocorreram em 2 (6,3%) pacientes e de vômitos intensos, em 4 (12,5%) pacientes, no grupo controle. Um paciente apresentou vômito intenso no grupo tratamento. Em relação ao consumo de antieméticos, 9 (28,1%) pacientes solicitaram medicamentos antieméticos de resgate no grupo controle e 3 (8,8%) pacientes, no grupo tratamento, nas primeiras 24 horas pós-operatórias (p = 0,02). Conclusão: O aprepitanto (80 mg), como uma quarta estratégia antiemética profilática, pode contribuir para a redução significativa de NVPO e de consumo de antieméticos de resgate em pacientes de alto risco / Background: Despite the use of multimodal pharmacological approach, postoperative nausea and vomiting (PONV) is one of the most important causes of patients discomfort after laparoscopic surgeries. NK-1 receptor antagonists have recently being recommended for prophylaxis of PONV in adults, but the combination with serotonin (5-HT3) receptor antagonists such as ondansetron, corticosteroids such as dexamethasone and propofol, are not yet well established. The primary aim of this randomized and double-blind study was to assess whether the addition of aprepitant to a multimodal management strategy for PONV prophylaxis in a high-risk patient population would further decrease the incidence of PONV in the first 24 postoperative hours. The secondary aims were the quantification of nausea intensity, number of episodes of vomiting and rescue antiemetic consumption in the same period. Methods: patients classified as Apfel Score 3 or 4, scheduled to laparoscopic surgeries to treat cancer, were randomized to receive either oral aprepitant 80mg (treatment group) or matching placebo (control group) before induction of anesthesia. All patients received intravenous dexamethasone 4 mg or 8 mg at induction of anesthesia, ondansetron 4 mg or 8 mg at the end of the surgery and a standardized total intravenous anesthesia (TIVA) technique. Statistical analysis was performed using Fisher\'s Exact Test and the null hypothesis was ruled out if p < 0.05. Results: Sixty-six patients completed the study. Nausea and vomiting occurred in 13 (40.6%) patients during the first 24 hours in the control group (all patients who presented nausea also vomited). In the treatment group, nausea occurred in 5 patients (14.7%, P = 0.03) and vomiting occurred in 1 patient (2.9%, P = 0.0002). The reduction in the relative risk was 63.8% (95%CI 9.9% - 86%) for nausea and 92.7% (95%CI 61.2% - 98.8%) for vomiting. Severe nausea occurred in 2 (6.3%) patients, and severe vomiting occurred in 4 (12.5%) patients in the control group. One patient presented with severe vomiting in the treatment group in the first 24 postoperative hours. The administration of rescue antiemetics occurred in 9 (28.1%) patients in the control group and in 3 (8.8%) patients in the treatment group in the first 24 postoperative hours (P = 0.02). Conclusion: Eighty milligrams of aprepitant added to a three-drug multimodal prophylaxis strategy can bring benefits to a high-risk population by reducing PONV episodes and rescue antiemetic requirements

Anxiety disorders are very common and the primary feature is abnormal or inappropriate anxiety. Fear and anxiety is often mediated by the amygdala, a brain structure rich in substance P (SP) and neurokinin 1 (NK1) receptors. To learn more about how the human amygdala is modulated by fear and anxiety in event-triggered anxiety disorders and to investigate if the SP/NK1 receptor system is affected, regional cerebral blood flow (rCBF) ([15O]-water; Study I and II) and the SP/NK1 receptor system ([11C]GR205171; Study III and IV) were studied with positron emission tomography (PET). In Study I we investigated the neural correlates of affective startle modulation in persons with specific phobia by measuring rCBF during exposure to fearful and non-fearful pictures, paired and unpaired with acoustic startle stimuli. Fear-potentiated startle was associated with activation of the affective part of the anterior cingulate cortex and the left amygdaloid–hippocampal area. In Study II short-term drug treatment effects on rCBF in patients diagnosed with social phobia was evaluated, comparing the NK1 receptor antagonist GR205171 to the selective serotonin reuptake inhibitor citalopram and placebo. Social anxiety and neural activity in the medial temporal lobe including the amygdala was significantly reduced by both drugs but not placebo. In Study III we investigated if activity in the SP/NK1 receptor system in the amygdala would be affected by fear provocation in individuals with specific snake or spider phobia. Fear provocation was associated with a decreased uptake of the NK1 antagonist [11C]GR205171 in the amygdala, possibly explained by an increase in endogenous SP release occupying the NK1 receptors. Study IV was conducted to explore the resting state NK1 receptor availability in PTSD patients as compared to healthy controls. Increased resting state binding of the tracer [11C]GR205171 in the amygdala of patients with PTSD suggested an increased amount of available receptors. In summary, fear and fear-potentiated startle modulates the human amygdala, possibly through the SP/NK1 receptor system.