A small lipidated peptide targeting Na_V1.8 channels attenuates osteoarthritic pain behavior and prevents bone erosion

Objective: In clinical practice, intra-articular therapies are commonly used for the management of osteoarthritis (OA) pain. However, these current treatments for OA-related pain are recognized for compromising joint integrity over time. Previously, we demonstrated that disrupting the interaction between Na_V1.8 channels and the Magi-1 scaffold protein facilitated channel degradation in nociceptors, thereby reducing pain behavior in multiple animal models. In this study, we sought to investigate the effects of our small lipidated peptide targeting Na_V1.8 on OA-associated pain in rodents. Methods: In vivo shRNA plasmid transfection was used to knock down Magi-1 in mouse DRG neurons to assess its effects on MIA-induced osteoarthritis (OA) pain behavior. Subsequently, a lipidated Na_V1.8 WW binding domain decoy peptide (PY(A)) was used to pharmacologically target the Na_V1.8-Magi-1 interaction and evaluate its effects on OA pain behavior in rats. A single intra-articular peptide injection (50 μL, 200 μM) was administered to each animal, and a scrambled peptide was used as a control. Histopathology analysis assessed MIA-induced cartilage degradation, and microCT imaging evaluated subchondral bone integrity. Results: Magi-1 knockdown effectively reduced established OA pain in mice. An intra-articular injection of the PY(A) peptide inhibited pain for multiple weeks in rats. MicroCT imaging showed minimal changes in subchondral bone remodeling in the PY(A) peptide group compared to the scrambled peptide group. Conclusions: The PY(A) peptide targeting the Na_V1.8-Magi-1 interaction alleviated OA pain and attenuated subchrondal bone remodeling. Intra-articular injection of lipidated peptides disrupting ion channel scaffolding in neurons provides effective and sustained analgesia for several weeks after a single administration.