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. Issue 6 (June 2015)

• Record Type: Journal Article
• Authors: Baddack, Uta; Frahm, Silke; Antolin‐Fontes, Beatriz; Grobe, Jenny; Lipp, Martin; Müller, Gerd; Ibañez‐Tallon, Ines
• Is Part Of: Arthritis & rheumatology. Volume 67:Issue 6(2015)
• Page Start: 1657
• Page End: 1667
• Publication Date: 2015-06
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39094
• Languages: English
• ISSNs: 2326-5191

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="art39094-sec-0001" sec-type="section"> <title>Objective</title> <p>A hallmark of rheumatoid arthritis (RA) is the chronic pain that accompanies inflammation and joint deformation. Patients with RA rate pain relief as the highest priority; however, few studies have addressed the efficacy and safety of therapies directed specifically toward pain pathways. The ω‐conotoxin MVIIA (ziconotide) is used in humans to alleviate persistent pain syndromes, because it specifically blocks the voltage‐gated calcium 2.2 (Ca<sub>V</sub>2.2) channel, which mediates the release of neurotransmitters and proinflammatory mediators from peripheral nociceptor nerve terminals. The aims of this study were to investigate whether blockade of Ca<sub>V</sub>2.2 can suppress arthritis pain, and to examine the progression of induced arthritis during persistent Ca<sub>V</sub>2.2 blockade.</p> </sec> <sec id="art39094-sec-0002" sec-type="section"> <title>Methods</title> <p>Transgenic mice expressing a membrane‐tethered form of MVIIA under the control of a nociceptor‐specific gene (MVIIA‐transgenic mice) were used in the experiments. The mice were subjected to unilateral induction of joint inflammation using a combination of antigen and collagen.</p> </sec> <sec id="art39094-sec-0003" sec-type="section"> <title>Results</title> <p>Ca<sub>V</sub>2.2 blockade mediated by tethered MVIIA effectively suppressed arthritis‐induced pain; however, in contrast to their wild‐type littermates, which ultimately regained use of their injured joint as inflammation subsided, MVIIA‐transgenic mice showed continued inflammation, with up‐regulation of the osteoclast activator RANKL and concomitant joint and bone destruction.</p> </sec> <sec id="art39094-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Taken together, our results indicate that alleviation of peripheral pain by blockade of Ca<sub>V</sub>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 Ca<sub>V</sub>2.2 channel blockers as analgesics during inflammation.</p> </sec> </abstract>