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. 2023 Nov 15;24(22):16341.
doi: 10.3390/ijms242216341.

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

Colombe Otis  1 , Emilie Bouet  1 , Sokhna Keita-Alassane  1 , Marilyn Frezier  1 , Aliénor Delsart  1 , Martin Guillot  1 , Agathe Bédard  2 , Jean-Pierre Pelletier  3 , Johanne Martel-Pelletier  3 , Bertrand Lussier  1   3 , Francis Beaudry  1   3   4 , Eric Troncy  1   3   4
Affiliations

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

Colombe Otis et al. Int J Mol Sci. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
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
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
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)%).
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