Uncoupling the CRMP2-CaV2.2 interaction reduces pain-like behavior in a preclinical joint-pain model

Heather N Allen; Sara Hestehave; Paz Duran; Tyler S Nelson; Rajesh Khanna

doi:10.1016/j.jpain.2024.104664

Uncoupling the CRMP2-Ca_V2.2 interaction reduces pain-like behavior in a preclinical joint-pain model

J Pain. 2024 Sep 2:104664. doi: 10.1016/j.jpain.2024.104664. Online ahead of print.

Authors

Heather N Allen¹, Sara Hestehave², Paz Duran³, Tyler S Nelson¹, Rajesh Khanna⁴

Affiliations

¹ Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
² Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York 10010, USA; Current address: Department of Experimental Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
³ Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York 10010, USA.
⁴ Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida 32610, USA. Electronic address: r.khanna@ufl.edu.

PMID: 39233208
DOI: 10.1016/j.jpain.2024.104664

Abstract

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 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, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate Ca_V2.2 expression and function. We previously developed a peptidomimetic modulator of CRMP2, 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 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. PERSPECTIVE: Despite the high prevalence of osteoarthritis pain worldwide, current treatment options remain limited. We demonstrate that CBD3063-mediated disruption of the Ca_V2.2-CRMP2 interaction alleviates pain in a preclinical joint pain model, providing a promising basis for the development of new osteoarthritis pain treatments.

Keywords: CRMP2; Ca(V)2.2; Osteoarthritis pain; collapsin response mediator protein 2; voltage gated calcium channel 2.2.