Uncoupling the CRMP2-Ca(V)2.2 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(V)2.2 modulators available for the treatment of pain. Although effective, drugs targeting Ca(V)2.2 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(V)2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate Ca(V)2.2 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(V)2.2. 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(V)2.2-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.