Cheatham Stanley M, Muchhala Karan H, Koseli Eda, Jacob Joanna C, Komla Essie, Negus S Stevens, Akbarali Hamid I
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
Front Pain Res (Lausanne). 2021 Dec 13;2:738499. doi: 10.3389/fpain.2021.738499. eCollection 2021.
Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are excellent analgesics, but recent clinical evidence suggests that these drugs might worsen disease severity in Crohn's disease patients, limiting their clinical utility for treating Inflammatory Bowel Disease (IBD). One indicator of change in well-being from conditions such as IBD is behavioral depression and disruption to activities of daily living. Preclinical measures of behavioral depression can provide an indicator of changes in quality of life and subsequent modification by candidate analgesics. In mice, nesting is an adaptive unconditioned behavior that is susceptible to disruption by noxious stimuli, and some types of pain related nesting depression are responsive to opioid and NSAID analgesics. Here we show that a 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) model of experimental colitis depresses nesting behavior in mice, and we evaluated effects of morphine, an opioid, and ketoprofen, a NSAID, on TNBS-induced nesting depression. In Swiss Webster mice, TNBS significantly reduced nesting that peaked on Day 3 and recovered in a time-dependent manner with complete recovery by Day 7. In the absence of colonic inflammation, daily treatment with morphine (1-10 mg/kg) did not decrease nesting except at 10mg/kg/day. However, in TNBS-treated mice 3.2 mg/kg/day morphine significantly exacerbated TNBS-induced nesting depression and delayed recovery. While 3.2 mg/kg/day morphine alone did not alter locomotor activity and TNBS-induced depression of locomotion recovered, the combination of TNBS and 3.2 mg/kg/day morphine significantly attenuated locomotion and prevented recovery. Daily treatment with 3.2 or 10 mg/kg ketoprofen in TNBS-treated mice did not prevent depression of nesting. These data suggest that opioid analgesics but not NSAIDS worsen colonic inflammation-induced behavioral depression. Furthermore, these findings highlight the importance of evaluating analgesic effects in models of colonic inflammation induced depression of behavior.
阿片类药物和非甾体抗炎药（NSAIDs）是有效的镇痛药，但最近的临床证据表明，这些药物可能会加重克罗恩病患者的疾病严重程度，限制了它们在治疗炎症性肠病（IBD）中的临床应用。IBD等疾病导致的幸福感变化的一个指标是行为抑郁和日常生活活动的紊乱。行为抑郁的临床前测量可以提供生活质量变化以及候选镇痛药后续调整的指标。在小鼠中，筑巢是一种适应性的非条件行为，容易受到有害刺激的干扰，某些类型的与疼痛相关的筑巢抑郁对阿片类药物和NSAIDs镇痛药有反应。在这里，我们表明，2,4,6-三硝基苯磺酸（TNBS）诱导的实验性结肠炎模型会抑制小鼠的筑巢行为，并且我们评估了阿片类药物吗啡和NSAIDs酮洛芬对TNBS诱导的筑巢抑郁的影响。在瑞士韦伯斯特小鼠中，TNBS显著降低了筑巢行为，在第3天达到峰值，并随时间依赖性恢复，到第7天完全恢复。在没有结肠炎症的情况下，每天用吗啡（1-10mg/kg）治疗，除了10mg/kg/天时，不会降低筑巢行为。然而，在TNBS处理的小鼠中，3.2mg/kg/天的吗啡显著加剧了TNBS诱导的筑巢抑郁并延迟了恢复。虽然单独使用3.2mg/kg/天的吗啡不会改变运动活动，并且TNBS诱导的运动抑制会恢复，但TNBS和3.2mg/kg/天的吗啡联合使用会显著减弱运动并阻止恢复。在TNBS处理的小鼠中，每天用3.2或10mg/kg的酮洛芬治疗并不能预防筑巢行为的抑制。这些数据表明，阿片类镇痛药而非NSAIDs会加重结肠炎症诱导的行为抑郁。此外，这些发现突出了在结肠炎症诱导行为抑郁模型中评估镇痛效果的重要性。
