Nociceptive mechanisms driving pain in a post-traumatic osteoarthritis mouse model

In osteoarthritis (OA), pain is the dominant clinical symptom, yet the therapeutic approaches remain inadequate. The knowledge of the nociceptive mechanisms in OA, which will allow to develop effective therapies for OA pain, is of utmost need. In this study, we investigated the nociceptive mechanisms involved in post-traumatic OA pain, using the destabilization of the medial meniscus (DMM) mouse model. Our results revealed the development of peripheral pain sensitization, reflected by augmented mechanical allodynia. Along with the development of pain behaviour, we observed an increase in the expression of calcitonin gene-related peptide (CGRP) in both the sensory nerve fibers of the periosteum and the dorsal root ganglia. Interestingly, we also observed that other nociceptive mechanisms commonly described in non-traumatic OA phenotypes, such as infiltration of the synovium by immune cells, neuropathic mechanisms and also central sensitization were not present. Overall, our results suggest that CGRP in the sensory nervous system is underlying the peripheral sensitization observed after traumatic knee injury in the DMM model, highlighting the CGRP as a putative therapeutic target to treat pain in post-traumatic OA. Moreover, our findings suggest that the nociceptive mechanisms involved in driving pain in post-traumatic OA are considerably different from those in non-traumatic OA. This work was financed by the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). CJA was supported by the project NORTE-01-0145-FEDER-000008 financed by NORTE 2020, under the PORTUGAL 2020 Partnership Agreement, through the ERDF. DMS is recipient of Fundação para a Ciência e a Tecnologia (FCT) Post-Doc fellowship (SFRH/BPD/115341/2016). LL and FC are recipients of FCT Ph.D. fellowships (SFRH/BD/109686/2015 and SFRH/BD/128771/2017, respectively). The authors acknowledge the support of the i3S Scientific Platforms Bioimaging, and Histology and Electron Microscopy (HEMS), members of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122), and Cláudia Machado (Instituto de Investigação e Inovação em Saúde) for helping with histology procedures.