Bryden L A, Nicholson J R, Doods H, Pekcec A
Boehringer Ingelheim Pharma GmbH & Co. KG, Div. Research Germany, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany.
Osteoarthritis Cartilage. 2015 Sep;23(9):1605-12. doi: 10.1016/j.joca.2015.05.001. Epub 2015 May 9.
To characterize deficits in burrowing behavior - an ethologically-relevant rodent behavior - in the monosodium iodoacetate (MIA) rat model of osteoarthritis (OA), and the sensitivity of these deficits to reversal by analgesic drugs of both prototypical and novel mechanisms of action. A second objective was to compare the burrowing assay to a spontaneous locomotor activity (sLA) assay.
Male Wistar Han rats (200-220 g) received intrarticular (i.a.) injections of MIA or saline for sham animals. A deficit in the amount of sand burrowed from steel tubes filled with 2.5 kg of sand was used as a measure of pain-related behavior, and sensitivity to reversal of these deficits by analgesic drugs was assessed in bilaterally MIA-injected rats.
Bilateral MIA injections induced a significant impairment of burrowing behavior, which was concentration-dependent. The temporal pattern of the deficits was biphasic: a large deficit at 3 days post-injection, resolving by day 14 and returning at the 21 and 28 day time points. At the 3 day time point ibuprofen, celecoxib and an anti-nerve growth factor (NGF) monoclonal antibody (mAb) were able to significantly reinstate burrowing behavior, whereas the fatty acid amide hydrolase (FAAH) inhibitor PF-04457845 and morphine displayed no reversal effect. Morphine impaired burrowing behavior at 3 mg/kg in sham animals. Deficits in rearing frequency in the locomotor activity assay proved irreversible by analgesics.
Burrowing behavior provides an objective, non-reflexive read-out for pain-related behavior in the MIA model that has predictive validity in detecting analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and an anti-NGF mAb.
在骨关节炎（OA）的碘乙酸钠（MIA）大鼠模型中，描述打洞行为（一种与行为学相关的啮齿动物行为）的缺陷，以及这些缺陷对具有典型和新型作用机制的镇痛药逆转的敏感性。第二个目的是将打洞试验与自发运动活动（sLA）试验进行比较。
雄性Wistar Han大鼠（200 - 220克）接受关节内（i.a.）注射MIA或给假手术动物注射生理盐水。从装有2.5千克沙子的钢管中挖出的沙子量的减少作为疼痛相关行为的指标，并在双侧注射MIA的大鼠中评估镇痛药对这些缺陷逆转的敏感性。
双侧注射MIA导致打洞行为显著受损，且呈浓度依赖性。缺陷的时间模式是双相的：注射后3天有较大缺陷，到第14天恢复，在第21天和28天时间点又再次出现。在第3天时间点，布洛芬、塞来昔布和抗神经生长因子（NGF）单克隆抗体（mAb）能够显著恢复打洞行为，而脂肪酸酰胺水解酶（FAAH）抑制剂PF - 04457845和吗啡没有显示出逆转作用。在假手术动物中，3毫克/千克的吗啡会损害打洞行为。运动活动试验中竖毛频率的缺陷被证明不能被镇痛药逆转。
打洞行为为MIA模型中与疼痛相关的行为提供了一种客观、非反射性的读数，在检测非甾体抗炎药（NSAIDs）和抗NGF mAb的镇痛效果方面具有预测效度。
