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.
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.


CONCLUSIONS
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.
Max Delbrück Centre for Molecular Medicine, Berlin, Germany, and Centre National de la Recherche Scientifique, Toulouse, France.
Uta
U
Baddack
Charité-Universitätsmedizin, Berlin, Germany.
Silke
S
Frahm
The Rockefeller University, New York, New York.
Beatriz
B
Antolin-Fontes
Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
Jenny
J
Grobe
Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
Martin
M
Lipp
Max Delbrück Centre for Molecular Medicine, Berlin, Germany.
Gerd
G
Müller
The Rockefeller University, New York, New York.
Ines
I
Ibañez-Tallon
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D059226:Nociceptive Pain / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D013264:Stifle / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D020960:omega-Conotoxins / Q000235:genetics* / Q000627:therapeutic use
C500963:Cacna1b protein, mouse; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020960:omega-Conotoxins; C078452:ziconotide