Face and Predictive Validity of MI-RAT (M ontreal I nduction of R at A rthritis T esting), a Surgical Model of Osteoarthritis Pain in Rodents Combined with Calibrated Exercise

Abstract

Validating animal pain models is crucial to enhancing translational research and response to pharmacological treatment. This study investigated the effects of a calibrated slight exercise protocol alone or combined with multimodal analgesia on sensory sensitivity, neuroproteomics, and joint structural components in the MI-RAT model. Joint instability was induced surgically on day (D) 0 in female rats (N = 48) distributed into sedentary-placebo, exercise-placebo, sedentary-positive analgesic (PA), and exercise-PA groups. Daily analgesic treatment (D3-D56) included pregabalin and carprofen. Quantitative sensory testing was achieved temporally (D-1, D7, D21, D56), while cartilage alteration (modified Mankin's score (mMs)) and targeted spinal pain neuropeptide were quantified upon sacrifice. Compared with the sedentary-placebo (presenting allodynia from D7), the exercise-placebo group showed an increase in sensitivity threshold (p < 0.04 on D7, D21, and D56). PA treatment was efficient on D56 (p = 0.001) and presented a synergic anti-allodynic effect with exercise from D21 to D56 (p < 0.0001). Histological assessment demonstrated a detrimental influence of exercise (mMs = 33.3%) compared with sedentary counterparts (mMs = 12.0%; p < 0.001), with more mature transformations. Spinal neuropeptide concentration was correlated with sensory sensitization and modulation sites (inflammation and endogenous inhibitory control) of the forced mobility effect. The surgical MI-RAT OA model coupled with calibrated slight exercise demonstrated face and predictive validity, an assurance of higher clinical translatability.

Keywords: animal model; exercise; nociception; osteoarthritis; pain.

Figure 1

Static QST of ipsilateral RHP PWT after surgically induced OA pain in rats (N = 12/group). Allodynia (ipsilateral paw) was present as soon as D7 in all groups and was maintained up to D56 in sedentary–placebo rats with a lower PWT compared with exercise rats (p < 0.05). Exercise counteracted it in both placebo and PA groups (p < 0.04). PA treatment alone was efficient on D56 only (p = 0.001) but presented an additive anti-allodynic effect to exercise (D21; D56; p < 0.0001). * Significant statistical inter-group differences for each time point. Least squares mean ± 95% confidence limit intervals are represented. The horizontal gray zone represents baseline values (D–1) and naïve rats (mean (standard deviation)) for RHP PWT static QST (76.85 (2.42) g).

Figure 2

Static QST of contralateral LHP PWT over time following surgically induced osteoarthritis pain in rats (N = 12/group). Lower PWT of LHP was noted on D7 in sedentary rats compared with exercise rats (p < 0.004). Allodynia continued to develop in sedentary–placebo rats until the end of the experiment (p < 0.039). No effect of PA treatment was noted in the contralateral hind limb. * Significant statistical inter-group differences for each time point. Least squares mean ± 95% confidence limit intervals are represented. The horizontal gray zone represents baseline values (D–1) and naïve rats (mean (standard deviation)) for LHP PWT static QST (78.61 (2.90) g).

Figure 3

Temporal evolution of static QST asymmetry index between ipsilateral and contralateral hind limbs over time. On the QST asymmetry index, all groups (N = 12 rats/group) presented marked contralateral transfer on D7, with a mean of −41.73 (3.95)%, which disappeared in all groups on D56 (p < 0.018) but as soon as D21 in the exercise–PA group (p = 0.013). * Significant statistical inter-group differences for each time point. Least squares mean ± 95% confidence limit intervals are represented. The horizontal gray zone represents the QST asymmetry index at baseline (D–1) and naïve rats (–1.45 (3.11)%).