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*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

1 Citation (Scopus)

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 Food and Drug Administration-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 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 CaV2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate CaV2.2 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 CaV2.2. 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.
Original languageEnglish
Article number104664
JournalThe Journal of Pain
Volume25
Issue number12
ISSN1526-5900
DOIs
Publication statusPublished - 2024

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