Kuo A, Raboczyj A, Nicholson J R, Corradini L, Smith M T
School of Biomedical Sciences, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, St Lucia, QLD, Australia.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Front Pharmacol. 2025 Apr 16;16:1560265. doi: 10.3389/fphar.2025.1560265. eCollection 2025.
Unrelenting osteoarthritis (OA) knee pain is the primary reason patients seek treatment that may ultimately result in knee replacement surgery. Although the anterior cruciate ligament transection (ACLT) and the ACLT plus medial meniscectomy (MMx) induced rat models of OA knee pain are well-characterized histologically, reports on changes in pain-like behaviors that persist longterm, are scant and so this is a knowledge gap.
We conducted a 40-week longitudinal study using these models in male Sprague-Dawley rats. Hindlimb static weight-bearing asymmetry was assessed using the incapacitance test. Von Frey filaments and an Analgesy-Meter were used to measure paw withdrawal thresholds (PWTs) and paw pressure thresholds (PPTs) respectively in the hindpaws.
Our findings show significant, reproducible and long-lasting static weight-bearing asymmetry in the hindlimbs of both models (but not the sham-control group) for the 40-week study duration. Significant mechanical hypersensitivity developed in the ipsilateral hindpaws of the ACLT + MMx model (PWTs ≤8 g) which reversed spontaneously by ∼8-12-weeks. In the ACLT and the sham-groups, significant mechanical hypersensitivity did not develop in the ipsilateral hindpaws. In conclusion, hindlimb static weight-bearing asymmetry is a long-lasting, significant pain behavioral endpoint in these models suitable for assessing novel disease-modifying OA therapeutics and/or analgesic drug candidates aimed at alleviating unrelenting chronic OA knee pain in patients.
持续性骨关节炎（OA）膝关节疼痛是患者寻求治疗的主要原因，而这种治疗最终可能导致膝关节置换手术。尽管前交叉韧带切断术（ACLT）以及ACLT联合内侧半月板切除术（MMx）诱导的OA膝关节疼痛大鼠模型在组织学上已得到充分表征，但关于长期持续的疼痛样行为变化的报道却很少，因此这是一个知识空白。
我们使用这些模型对雄性Sprague-Dawley大鼠进行了一项为期40周的纵向研究。使用失能测试评估后肢静态负重不对称性。分别使用von Frey细丝和镇痛仪测量后爪的爪撤离阈值（PWTs）和爪压力阈值（PPTs）。
我们的研究结果表明，在为期40周的研究期间，两种模型（而非假手术对照组）的后肢均出现了显著、可重复且持久的静态负重不对称。ACLT + MMx模型同侧后爪出现了显著的机械性超敏反应（PWTs≤8克），并在约8 - 12周时自发逆转。在ACLT组和假手术组中，同侧后爪未出现显著的机械性超敏反应。总之，后肢静态负重不对称是这些模型中一个持久、显著的疼痛行为终点，适用于评估旨在减轻患者持续性慢性OA膝关节疼痛的新型疾病修饰性OA治疗药物和/或镇痛候选药物。
