Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis

Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis.

化疗诱导性肠黏膜炎（Chemotherapy-induced intestinal mucositis）以疼痛与促炎性组织反应为主要特征。大鼠模型常被应用于肠黏膜炎的疾病研究中，但目前对于该类动物是否存在疼痛、镇痛药（analgesics）能否缓解病症，以及镇痛给药对研究结局可能产生的影响仍知之甚少。本研究针对不同类别镇痛药展开探究，旨在明确其镇痛效果，以及对肠黏膜炎大鼠模型中目标研究结局的影响。将雌性DA大鼠随机分为8组，包含生理盐水对照组与化疗对照组（每组n=8）。受试镇痛药包括阿片类衍生物（opioid derivatives）：丁丙诺啡（0.05mg/kg）与曲马多（12.5mg/kg），以及非甾体抗炎药（NSAID）类的卡洛芬（carprofen：15mg/kg）；给药方案为分别联合生理盐水或5-氟尿嘧啶（5-Fluorouracil，5-FU：150mg/kg）。研究结局指标包括每日临床参数、疼痛评分与肠道组织病理学检查结果。通过髓过氧化物酶（Myeloperoxidase）检测法评估肠道炎症程度。在所采用的给药剂量下，基于行为学疼痛评分结果，所有受试药物均表现出镇痛效果。与5-FU对照组大鼠相比，丁丙诺啡与曲马多可显著降低空肠髓过氧化物酶活性（分别下降53%，p=0.0004；下降58%，p=0.0001）。卡洛芬对髓过氧化物酶水平无显著改善作用。所有受试药物均未缓解5-FU给药引发的组织病理学损伤，不过即便在健康大鼠中给药，曲马多也可一定程度上增加肠绒毛长度。本研究数据表明，鉴于卡洛芬的镇痛效果以及对各项检测参数的影响极小，其在该动物模型中具备作为镇痛药的应用潜力。本研究同时支持针对阿片类药物治疗化疗诱导性肠黏膜炎的作用机制与应用价值开展进一步探究。