A small lipidated peptide targeting Na _V 1.8 channels attenuates osteoarthritic pain behavior and prevents bone erosion

Chronic pain is a major concern for patients with osteoarthritis (OA). Current treatments for OA-related pain often fail and may worsen the disease. The sodium channel subtype Na _V 1.8 has emerged as a potential target for treating pain, leading to the development of Na _V 1.8 inhibitors in clinical trials. We previously identified Magi-1, a WW domain-containing scaffold protein, as a regulator of Na _V 1.8 at the plasma membrane of nociceptive neurons. Disrupting the interaction between Na _V 1.8 and Magi-1 facilitated channel degradation in neurons, reducing pain behavior in multiple animal models. In this study, we investigated the impact of disrupting Na _V 1.8 scaffolding on an animal model of OA pain using genetic and pharmacological approaches. Genetic Magi-1 knockdown effectively attenuated established OA pain in mice. Pharmacological targeting of the Na _V 1.8-Magi-1 interaction in rats with a lipidated Na _V 1.8 WW binding domain decoy peptide inhibited pain behavior for multiple weeks. MicroCT imaging revealed minimal alterations in subchondral bone remodeling in animals injected with the lipidated decoy peptide compared to those receiving scrambled peptide-control animals. This suggested that the Na _V 1.8 peptidomimetic not only alleviated OA pain but also delayed joint degeneration. Our preclinical studies indicate that intraarticular injection of lipidated peptides capable of disrupting ion channel scaffolding in neurons can provide effective and sustained analgesia for several weeks after a single administration.