Liu Na, Sonawane Mitali, Sommerfeld Oliver, Svensson Carl-Magnus, Figge Marc Thilo, Bauer Reinhard, Bischoff Sabine Juliane, Bauer Michael, Osuchowski Marcin Filip, Press Adrian Tibor
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.
Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany.
Front Immunol. 2024 Aug 30;15:1432307. doi: 10.3389/fimmu.2024.1432307. eCollection 2024.
Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and anti-inflammatory properties of two non-opioid analgesics.
Adult C57BL/6J mice were intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry.
Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1β compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups.
Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model.
阿片类药物的可用性有限且存在副作用，这导致在动物疾病模型中使用非阿片类镇痛药的情况增多。然而，镇痛可能会通过影响免疫炎症反应，干扰宿主炎症的消退，并调节脓毒症动物的存活率。本研究使用了一种临床相关的腹膜污染和感染（PCI）脓毒症小鼠模型，以研究两种非阿片类镇痛药的镇痛和抗炎特性。
成年C57BL/6J小鼠腹腔注射人粪便悬液，并口服给予无镇痛药（非A组）、美洛昔康或安乃近。监测小鼠的疼痛和疾病情况。在PCI后7天评估死亡率。另一组小鼠在感染后24小时处死。采集血液、腹腔灌洗液（PLF）、肝脏和脾脏，通过qPCR进行病原体载量定量，通过流式细胞术进行巨噬细胞表型分析、中性粒细胞浸润/活化以及全身/组织细胞因子释放分析。
与非A组相比，美洛昔康而非安乃近在第7天将脓毒症小鼠的死亡率降低了31%。两种镇痛药均有效减轻疼痛，但不影响疾病严重程度、体重和体温。美洛昔康使血液和PLF中的细菌负荷增加了四倍。在高白细胞介素-6反应者中，与非A脓毒症组相比，美洛昔康治疗使循环中的白细胞介素-10和白细胞介素-1β水平降低。在低白细胞介素-6反应者中，与非A脓毒症小鼠相比，美洛昔康使循环中的单核细胞趋化蛋白-1水平升高，前列腺素E2水平降低。值得注意的是，与其他两个脓毒症组相比，美洛昔康使脾脏中性粒细胞浸润减少了20%。
在PCI脓毒症模型中，安乃近和美洛昔康有效缓解疼痛并增加动物的基础活动。美洛昔康延长了生存期，但由于其免疫抑制特性在脓毒症期间降低了组织细菌清除率，从而引发了适应不良反应。相比之下，在非手术PCI脓毒症模型中，安乃近是一种安全有效的非阿片类镇痛替代药物。
