Background & Aims

Osteoarthritis (OA) is the most common musculoskeletal disease affecting millions of people worldwide. Pain is the dominant symptom of OA and the main reason for medical consultation. Current treatments are not very effective and/or associated with strong adverse effects. Therefore, new therapeutic approaches are needed. Among the low voltage activated T-type channels family, Cav3.2 calcium channels are known to participate to neuronal excitability through notably primary afferent fibers and dorsal horn. In different context of pain, inhibition of Cav3.2 has an anti-hyperalgesic action (1–3) and improves patients’ quality of life (4), both in mouse models and humans (5). Thus, the aim of this study was to evaluate the involvement of Cav3.2 channels, using genetic and pharmacological strategies, in a murine model of osteoarthritis.

Methods

Male and female C57BL/6 mice (10-week-old) underwent destabilization of the medial meniscus (DMM) surgery to induce OA (6). Mechanical hypersensitivity was assessed using the von Frey test during OA progression. The involvement of T-type calcium channels and Cav3.2 channels was assessed with different pharmacological (TTA-A2 and ethosuximide (ETX)) and genetic tools.

Results

After DMM surgery, a decrease in mechanical threshold was observed in mice. A unique intraperitoneal injection of T-type calcium channels inhibitors, TTA-A2 or ETX, led to a reduction in nociception. Furthermore, after DMM surgery, Cav3.2 KO mice exhibited a reduced nociception. Thus, Cav3.2 channels could be involved in OA-induced hypersensitivity in males and females. In order to assess the therapeutic repositioning of ETX, we evaluated its analgesic effect following chronic administration. When administered immediately following DMM surgery, ETX prevented the development of mechanical hypersensitivity. Finally, when administered after the establishment of OA, ETX reversed mechanical hypersensitivity.

Conclusions

These results demonstrate that, in DMM model, Cav3.2 calcium channels contribute to OA-induced hypersensitivity. Furthermore, these findings suggest that Cav3.2 inhibition could be a promising new therapeutic solution for the management of OA pain.

References

1.Fayad, S. L. et al. Centrally expressed Cav3.2 T-type calcium channel is critical for the initiation and maintenance of neuropathic pain. eLife 11, e79018 (2022).
2.Picard, E. et al. Inhibition of Ca v 3.2 calcium channels: A new target for colonic hypersensitivity associated with low?grade inflammation. Br. J. Pharmacol. 176, 950–963 (2019).
3.Picard, E. et al. Role of T CD4 + cells, macrophages, C?low threshold mechanoreceptors and spinal Ca v 3.2 channels in inflammation and related pain?like symptoms in murine inflammatory models. Br. J. Pharmacol. 180, 385–400 (2023).
4.Kerckhove, N. et al. Ethosuximide improves chronic pain-induced anxiety- and depression-like behaviors. Eur. Neuropsychopharmacol. 29, 1419–1432 (2019).
5.Kerckhove, N. et al. Efficacy and safety of a T?type calcium channel blocker in patients with neuropathic pain: A proof?of?concept, randomized, double?blind and controlled trial. Eur. J. Pain 22, 1321–1330 (2018).
6.Glasson, S. S., Blanchet, T. J. & Morris, E. A. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15, 1061–1069 (2007).

Presenting Author

Pauline Gousseau

Poster Authors

Pauline Gousseau

MSc

Neuro-Dol, Université Clermont Auvergne

Lead Author

Guillaume Ourties

PhD

Neuro-Dol, Inserm U1107, Université Clermont Auvergne (France)

Lead Author

Baptiste Jouffre

NeuroDol Université Clermont Auvergne

Lead Author

Laurence Daulhac-Terrail

PharmD PhD

Neuro-Dol, Inserm U1107, Université Clermont Auvergne (France)

Lead Author

Christophe Mallet

PhD

Neuro-Dol, Inserm U1107, Université Clermont Auvergne (France)

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Rheumatology, Arthritis, and Other