Uta Baddack1, Silke Frahm2, Beatriz Antolin-Fontes3, Jenny Grobe4, Martin Lipp4, Gerd Müller4, Ines Ibañez-Tallon3. 1. Max Delbrück Centre for Molecular Medicine, Berlin, Germany, and Centre National de la Recherche Scientifique, Toulouse, France. 2. Charité-Universitätsmedizin, Berlin, Germany. 3. The Rockefeller University, New York, New York. 4. Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
Abstract
OBJECTIVE: 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 (CaV 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 CaV 2.2 can suppress arthritis pain, and to examine the progression of induced arthritis during persistent CaV 2.2 blockade. METHODS: 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. RESULTS: CaV 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. CONCLUSION: Taken together, 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.
OBJECTIVE: 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 (CaV 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 CaV 2.2 can suppress arthritis pain, and to examine the progression of induced arthritis during persistent CaV 2.2 blockade. METHODS: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. RESULTS:CaV 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. CONCLUSION: Taken together, 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.
Authors: Y Y Kong; U Feige; I Sarosi; B Bolon; A Tafuri; S Morony; C Capparelli; J Li; R Elliott; S McCabe; T Wong; G Campagnuolo; E Moran; E R Bogoch; G Van; L T Nguyen; P S Ohashi; D L Lacey; E Fish; W J Boyle; J M Penninger Journal: Nature Date: 1999-11-18 Impact factor: 49.962
Authors: Jose A Caparros-Martin; Mona S Aglan; Samia Temtamy; Ghada A Otaify; Maria Valencia; Julián Nevado; Elena Vallespin; Angela Del Pozo; Carmen Prior de Castro; Lucia Calatrava-Ferreras; Pilar Gutierrez; Ana M Bueno; Belen Sagastizabal; Encarna Guillen-Navarro; Maria Ballesta-Martinez; Vanesa Gonzalez; Sarenur Y Basaran; Ruksan Buyukoglan; Bilge Sarikepe; Cecilia Espinoza-Valdez; Francisco Cammarata-Scalisi; Victor Martinez-Glez; Karen E Heath; Pablo Lapunzina; Victor L Ruiz-Perez Journal: Mol Genet Genomic Med Date: 2016-12-20 Impact factor: 2.183