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| Item Type: | Article |
|---|---|
| Title: | Suppression of peripheral pain by blockade of voltage-gated calcium 2.2 channels in nociceptors induces RANKL and impairs recovery from inflammatory arthritis in a mouse model |
| Creators Name: | Baddack, U., Frahm, S., Antolin-Fontes, B., Grobe, J., Lipp, M., Mueller, G. and Ibanez-Tallon, I. |
| Abstract: | Objective: A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies the inflammation and joint deformation. Patients with RA rate pain relief with highest priority, however, few studies have addressed the efficacy and safety of therapies directed specifically towards pain pathways. The conotoxin MVIIA (Prialt/Ziconotide) is used in humans to alleviate persistent pain syndromes because it specifically blocks the CaV 2.2 voltage-gated calcium channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The purpose of this study was to investigate whether block of CaV 2.2 can suppress arthritic pain, and to examine the progression of induced arthritis during persistent CaV 2.2 blockade. Methods: Transgenic mice (Tg-MVIIA) expressing a membrane-tethered form of the {Omega}-conotoxin MVIIA, under the control of a nociceptor-specific gene, were employed. These mice were subjected to unilateral induction of joint inflammation using the Antigen- and Collagen-Induced Arthritis (ACIA) model. Results: We observed that CaV 2.2-blockade mediated by t-MVIIA effectively suppressed arthritis-induced pain; however, in contrast to their wild-type littermates, which ultimately regained use of their injured joint as inflammation subsides, Tg-MVIIA mice showed continued inflammation with an up-regulation of the osteoclast activator RANKL and concomitant joint and bone destruction. Conclusion: Altogether, our results indicate that alleviation of peripheral pain by blockade of CaV 2.2- mediated calcium influx and signaling in nociceptor sensory neurons, impairs recovery from induced arthritis and point to the potentially devastating effects of using CaV 2.2 channel blockers as analgesics during inflammation. |
| Keywords: | Animal Disease Models, Calcium Channel Blockers, Experimental Arthritis, N-Type Calcium Channels, Nociceptive Pain, Nociceptors, {omega}-Conotoxins, RANK Ligand, Rheumatoid Arthritis, Stifle, Transgenic Mice, Tumor Necrosis Factor-{alpha}, Up-Regulation, Animals, Mice |
| Source: | Arthritis & Rheumatology |
| ISSN: | 2326-5191 |
| Publisher: | Wiley-Blackwell |
| Volume: | 67 |
| Number: | 6 |
| Page Range: | 1657-1667 |
| Date: | June 2015 |
| Official Publication: | https://doi.org/10.1002/art.39094 |
| PubMed: | View item in PubMed |
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