Pharmacological evaluation of the early and late phases of the mono-iodo-acetate (MIA)-induced osteoarthritic joint pain model in rats using an automated dynamic weight bearing system
Osteoarthritic (OA) knee joint pain affects millions of aged people world-wide, often leading to disability and eventual joint replacement. The rat mono-iodoacetate (MIA)-induced osteoarthritic joint pain model has been recognized as one of the most translatable OA pain models. The model is extensively used by researchers to evaluate novel therapeutics targeted for chronic joint pain. In the present study, we have utilized the automated dynamic weight bearing (DWB) system from Bioseb to pharmacologically validate the early and late phase of the MIA-induced OA joint pain model in rats.
To induce the model, a single intra-articular injection of MIA into the right knee joint of rats was performed on Day 1. Joint pain evaluation was performed from Day 2 to Day 26. As a glycolytic inhibitor, MIA causes cartilage damage and induces monoarthritic joint pain. To assess joint pain, the advanced automated DWB-2 system was used. To assess joint swelling, joint diameter was measured using a caliper. Synovial fluids were also collected for proinflammatory cytokines evaluation. Effects of two analgesic drugs, naproxen and dexamethasone were evaluated in the model.
In the first experiment, we assessed the dose-response effects of MIA (2 mg and 3 mg) in inducing joint pain. Intra-articular saline injection didn’t cause any weight bearing changes or any joint swelling in the rats. On the other hand, significant weight bearing deficit in the injected limb and swelling of the injected joint were observed with both 2 mg and 3 mg of MIA. Joint swelling and weight bearing deficits were MIA dose dependent. Weight bearing deficits in MIA-injected limb showed a biphasic pattern with an early and a late phase. Joint pain reactions were more pronounced between Day 2-7 and Day 22-26 with relatively lower pain level in between. Joint swelling was more pronounced in the first week after MIA injection. Afterwards, it mostly resolved with a small window in later phase.
In a follow-up experiment to examine effects of analgesic drugs, 3 mg MIA was chosen to induce the model based on higher window and lower variability compared with 2 mg MIA model. Effects of the drugs were assessed in early and late phase of the model. In the early phase, both naproxen and dexamethasone significantly attenuated joint pain and joint swelling in the MIA rats. In the late phase, only dexamethasone attenuated the joint pain as well as joint swelling. These results suggest that the early phase of the MIA model is NSAID-sensitive while the late phase is less sensitive to NSAIDs. Currently, cytokines analysis in synovial fluids is being performed to further evaluate the inflammatory nature of the two phases of the rat MIA model.