Background & Aims

Chronic pain has been known as the most concerning symptom in patients with osteoarthritis (OA). Current treatments for OA-related pain are often inadequate and, in some cases, worsen disease progression overtime. In clinical trials using specific inhibitors, the voltage-dependent sodium channel subtype, NaV1.8, has been identified as a potential target to treat human acute pain. Effects were considered modest however, and these inhibitors must be given systemically which might be contraindicated in certain patient populations. Previously, we identified WW and PDZ domain containing scaffold protein Magi-1 as an NaV1.8 interactor at the plasma membrane of nociceptive neurons. Our studies have shown that disrupting NaV1.8 and Magi-1 interaction facilitates degradation of channels, resulting in attenuation of pain behavior in multiple animal models of pain.

Methods

Here we investigated the effect of disrupting NaV1.8 scaffolding on an animal model of OA pain using genetic and pharmacological approaches. Intraarticular injection of monoiodoacetate (MIA) was used as the OA pain animal model. Magi-1 knockdown in mice was performed using Magi-1-targeted shRNA and sciatic nerve transfection. We also intraarticularly injected an NaV1.8 WW binding domain peptidomimetic to pharmacologically target the NaV1.8-Magi-1 interaction in rats. Mechanical allodynia was measured using von Frey filaments, while dynamic weight bearing was used as a non-evoked pain behavior assay.

Results

Our results showed that genetic Magi-1 knockdown attenuated established OA pain behavior in mice. Additionally, a single intraarticular injection of an NaV1.8-based lipidated peptidomimetic inhibited pain behavior up to 21 days in animals with knee OA. Using microCT imaging, we surprisingly found that animals injected with the lipidated peptidomimetic presented minimal changes in subchondral bone remodeling compared to scrambled peptide-control animals. This suggested that the NaV1.8 peptidomimetic not only attenuated OA pain behavior, but also delayed joint degeneration in OA animals by improving mobility.

Conclusions

Our preclinical studies indicate that intraarticular injection of lipidated peptides to disrupt ion channel scaffolding can provide effective and sustained analgesia for many weeks after a single administration.

References

1- Pryce, K. D., Powell, R., Agwa, D., Evely, K. M., Sheehan, G. D., Nip, A., Tomasello, D. L.,
Gururaj, S., & Bhattacharjee, A. (2019). Magi-1 scaffolds NaV1.8 and Slack KNachannels in
dorsal root ganglion neurons regulating excitability and pain. FASEB Journal, 33(6), 7315–
7330.
2- ones, J., Correll, D. J., Lechner, S. M., Jazic, I., Miao, X., Shaw, D., Simard, C., Osteen, J. D., Hare, B., Beaton, A., Bertoch, T., Buvanendran, A., Habib, A. S., Pizzi, L. J., Pollak, R. A., Weiner, S. G., Bozic, C., Negulescu, P., White, P. F., & VX21-548-101 and VX21-548-102 Trial Groups (2023). Selective Inhibition of NaV1.8 with VX-548 for Acute Pain. The New England journal of medicine, 389(5), 393–405.

Presenting Author

Raider Rodriguez

Poster Authors

Raider Rodriguez

University At Buffalo, State University of New York

Lead Author

E-mail

Topics

  • Joint Pain