Department of Pharmacology Pain, Global Biomedical Sciences, Grünenthal GmbH, Aachen, Germany.
Eur J Pain. 2014 Feb;18(2):204-12. doi: 10.1002/j.1532-2149.2013.00358.x. Epub 2013 Jul 12.
Innate responses against spontaneous pain are proposed to improve the predictive validity of preclinical analgesia models. Therefore, development and validation of novel readouts is necessary. To investigate whether innate rodent burrowing is a useful alternative behavioural readout for assessment of analgesic efficacy, a complete Freund's adjuvant (CFA)-induced model of sub-chronic inflammation was used to compare the effects of naproxen, ibuprofen and pregabalin in weight-bearing (WB), open-field (OF) and burrowing assays.
Male Sprague Dawley rats were injected with 150 μL of CFA (2 mg/mL) into the knee (hind leg) 3 days before testing. Naproxen, ibuprofen and pregabalin were administered at different doses 30, 90 and 60 min, respectively, before testing. WB was determined using a rat incapacitance tester; horizontal distance moved and vertical rearings were recorded in an OF; and burrowing was measured by the weight of gravel remaining in a hollow tube after 60 min.
CFA-induced arthritis reduced WB, OF activity and burrowing. Naproxen, pregabalin and ibuprofen treatment normalized WB; however, horizontal OF activity was not improved by any treatment; rearing behaviour was moderately reinstated by ibuprofen (100 mg/kg). In burrowing, naproxen (100 mg/kg), ibuprofen (31.6 and 100 mg/kg) and pregabalin (10 mg/kg) reversed CFA-induced deficits.
Burrowing performance is an alternative non-reflex readout relying on innate rodent behaviour that is affected by nociceptive behaviour and can be pharmacologically manipulated. The burrowing assay appears to be more sensitive than OF assays and is as sensitive as WB assays at distinguishing between analgesic doses and doses that impair locomotion.
针对自发性疼痛的先天反应被提议提高临床前镇痛模型的预测有效性。因此，有必要开发和验证新的检测方法。为了研究先天啮齿动物的洞穴行为是否是评估镇痛效果的有用替代行为检测方法，本研究使用完全弗氏佐剂（CFA）诱导的亚慢性炎症模型，比较了萘普生、布洛芬和普瑞巴林在负重（WB）、旷场（OF）和洞穴试验中的作用。
雄性 Sprague Dawley 大鼠在测试前 3 天将 150 μL 的 CFA（2mg/mL）注射到膝关节（后腿）。在测试前 30、90 和 60 分钟分别给予萘普生、布洛芬和普瑞巴林不同剂量。用大鼠失能测试仪测定 WB；在 OF 中记录水平移动距离和垂直后肢站立次数；60 分钟后通过测量空心管中剩余砾石的重量来测量洞穴行为。
CFA 诱导的关节炎降低了 WB、OF 活动和洞穴行为。萘普生、普瑞巴林和布洛芬治疗使 WB 正常化；然而，任何治疗都没有改善 OF 活动；布洛芬（100mg/kg）中等程度地恢复了后肢站立行为。在洞穴行为中，萘普生（100mg/kg）、布洛芬（31.6 和 100mg/kg）和普瑞巴林（10mg/kg）逆转了 CFA 引起的缺陷。
洞穴行为是一种替代非反射性的检测方法，依赖于受伤害感受行为影响的先天啮齿动物行为，并且可以通过药理学进行操纵。洞穴行为检测似乎比 OF 检测更敏感，与 WB 检测一样，能够区分镇痛剂量和影响运动的剂量。
