Background & Aims

Monoiodoacetate (MIA) model is a commonly used rodent model to study osteoarthritis (OA) pain and efficacy of novel analgesics in vivo. However, to understand the mode of action behind the behavioral findings, deeper understanding of the model and the mechanisms are needed. Aim of this study was to broadly characterize MIA rat model by combining behavioral data with immunological and molecular biology techniques to find OA and pain specific changes on cellular and molecular levels in injury site and peripheral nervous system.

Methods

Pain behavior was assessed at acute and chronic pain phases (3-4 days or 3 weeks, respectively) after injection (i.a. knee) of 0, 1, 2 or 3 mg of MIA, and after analgesic treatment with naproxen (7.6 mg/kg, p.o.) or pregabalin (30 mg/kg). Tactile allodynia (with von Frey filaments), weight bearing (with Catwalk) and knee hyperalgesia (Pressure Application Method) of injured hind paw were used as readouts for pain behavior. Whole knee joints, knee surrounding tissue and DRG were collected at chronic pain phase for histology, immune cell analysis, and for single-cell RNA sequencing, respectively.

Results

MIA injection with all doses (1, 2 and 3 mg) induced mechanical hypersensitivity and knee hyperalgesia, and impaired weight bearing of the injured paw when compared to sham treated animals. Treatment with pregabalin alleviated mechanical hypersensitivity with no effect on other pain behaviors. Toluidine blue staining showed severe end state OA induced by 2 mg of MIA. Immune cell infiltration in the joints were analyzed with flow cytometric analysis, displaying significant changes in number of leukocyte and macrophage populations between MIA and Sham treated animals. Transcriptomic analysis of collected DRGs from Sham vs MIA tissue showed the presence of numerous cell type clusters, including satellite glial, Schwann, immune and subsets of neuronal cell types. Differential gene expression analysis displayed changes, particularly in non-neuronal cell subtypes between MIA and Sham treated animals.

Conclusions

In this study, we show, how combining a battery of technologies to traditional pharmacological assessments of pain behavior can help in understanding the pain models, which are commonly used in development of new analgesics. Selection of the correct model and understanding the changes on the cellular and molecular level in specific cell types of the target tissues are necessary to increase the successful translatability of rodent pain models to human chronic pain. Gaining these insights may aid in the successful development of novel analgesics to treat OA pain.

References

de Sousa Valente J. The Pharmacology of Pain Associated With the Monoiodoacetate Model of Osteoarthritis. Front Pharmacol. 2019 Sep 18;10:974. doi: 10.3389/fphar.2019.00974. PMID: 31619987; PMCID: PMC6759799.

Presenting Author

Liisa Ailanen

Poster Authors

Lauri Louhivuori, Ph.D.

PhD

Orion Pharma

Lead Author

Liisa Ailanen

Orion Oyj, Orion Pharma

Lead Author

Kaisa Auvinen

Orion Pharma

Lead Author

Nea Korvenlaita

PhD

Orion Pharma

Lead Author

Topics

  • Models: Chronic Pain - Inflammatory