Uncoupling the CRMP2-Ca_V2.2 Interaction Reduces Pain-Like Behavior in a Preclinical Joint-Pain Model

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple Food and Drug Administration-approved Ca_V2.2 modulators available for the treatment of pain. Although effective, drugs targeting Ca_V2.2 are complicated by the same obstacles facing other pain therapeutics—invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of Ca_V2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate Ca_V2.2 expression and function. We previously developed a peptidomimetic modulator of collapsin response mediator protein 2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of Ca_V2.2. The potent analgesic properties of CBD3063, combined with the lack of negative side effects, prompted us to assess the efficacy of CBD3063 in a rodent model of OA pain. Here, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and nonevoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest that CBD3063 is an effective analgesic for OA pain. Perspective: Despite the high prevalence of OA pain worldwide, current treatment options remain limited. We demonstrate that CBD3063-mediated disruption of the Ca_V2.2-collapsin response mediator protein 2 interaction alleviates pain in a preclinical joint pain model, providing a promising basis for the development of new OA pain treatments.