Anderson Laura M, Samineni Sridhar, Wilder Donna M, Lara Marisela, Eken Ondine, Urioste Rodrigo, Long Joseph B, Arun Peethambaran
Veterinary Services Program, Center for Enabling Capabilities, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States.
Front Neurol. 2021 Oct 12;12:746370. doi: 10.3389/fneur.2021.746370. eCollection 2021.
Previous findings have indicated that pain relieving medications such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs) may be neuroprotective after traumatic brain injury in rodents, but only limited studies have been performed in a blast-induced traumatic brain injury (bTBI) model. In addition, many pre-clinical TBI studies performed in rodents did not use analgesics due to the possibility of neuroprotection or other changes in cognitive, behavioral, and pathology outcomes. To examine this in a pre-clinical setting, we examined the neurobehavioral changes in rats given a single pre-blast dose of meloxicam, buprenorphine, or no pain relieving medication and exposed to tightly-coupled repeated blasts in an advanced blast simulator and evaluated neurobehavioral functions up to 28 days post-blast. A 16.7% mortality rate was recorded in the rats treated with buprenorphine, which might be attributed to the physiologically depressive side effects of buprenorphine in combination with isoflurane anesthesia and acute brain injury. Rats given buprenorphine, but not meloxicam, took more time to recover from the isoflurane anesthesia given just before blast. We found that treatment with meloxicam protected repeated blast-exposed rats from vestibulomotor dysfunctions up to day 14, but by day 28 the protective effects had receded. Both pain relieving medications seemed to promote short-term memory deficits in blast-exposed animals, whereas vehicle-treated blast-exposed animals showed only a non-significant trend toward worsening short-term memory by day 27. Open field exploratory behavior results showed that blast exposed rats treated with meloxicam engaged in significantly more locomotor activities and possibly a lesser degree of responses thought to reflect anxiety and depressive-like behaviors than any of the other groups. Rats treated with analgesics to alleviate possible pain from the blast ate more than their counterparts that were not treated with analgesics, which supports that both analgesics were effective in alleviating some of the discomfort that these rats potentially experienced post-blast injury. These results suggest that meloxicam and, to a lesser extent buprenorphine alter a variety of neurobehavioral functions in a rat bTBI model and, because of their impact on these neurobehavioral changes, may be less than ideal analgesic agents for pre-clinical studies evaluating these neurobehavioral responses after TBI.
先前的研究结果表明，阿片类药物和非甾体抗炎药（NSAIDs）等止痛药物在啮齿动物创伤性脑损伤后可能具有神经保护作用，但在爆炸所致创伤性脑损伤（bTBI）模型中的研究还很有限。此外，许多在啮齿动物身上进行的临床前TBI研究未使用镇痛药，因为担心其可能具有神经保护作用，或者会对认知、行为和病理学结果产生其他影响。为了在临床前环境中对此进行研究，我们检测了在高级爆炸模拟器中预先单次给予美洛昔康、丁丙诺啡或不给予任何止痛药物，然后暴露于紧密耦合的重复爆炸中的大鼠的神经行为变化，并在爆炸后长达28天评估其神经行为功能。接受丁丙诺啡治疗的大鼠死亡率为16.7%，这可能归因于丁丙诺啡与异氟烷麻醉和急性脑损伤联合产生的生理抑制副作用。接受丁丙诺啡而非美洛昔康治疗的大鼠，从爆炸前给予的异氟烷麻醉中恢复所需的时间更长。我们发现，美洛昔康治疗可保护重复暴露于爆炸的大鼠直至第14天不出现前庭运动功能障碍，但到第28天，保护作用消退。两种止痛药物似乎都促使暴露于爆炸的动物出现短期记忆缺陷，而未接受药物治疗的暴露于爆炸的动物在第27天时短期记忆仅有不显著的恶化趋势。旷场探索行为结果显示，与其他任何组相比，接受美洛昔康治疗的暴露于爆炸的大鼠进行的自发活动明显更多，可能反映焦虑和抑郁样行为的反应程度也较低。接受镇痛药治疗以减轻爆炸可能带来的疼痛的大鼠比未接受镇痛药治疗的大鼠进食更多，这支持两种镇痛药在减轻这些大鼠爆炸后可能经历的一些不适方面均有效。这些结果表明，美洛昔康以及在较小程度上丁丙诺啡会改变大鼠bTBI模型中的多种神经行为功能，并且由于它们对这些神经行为变化的影响，对于评估TBI后这些神经行为反应的临床前研究而言，可能并非理想的镇痛药物。
