Uncoupling the CRMP2-Ca2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis 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 FDA-approved Ca2.2 modulators available for the treatment of pain. Although effective, drugs targeting Ca2.2 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 Ca2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate Ca2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of Ca2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked 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 CBD3063 is an effective analgesic for OA pain.