ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1416–1418 DOI 10.1002/art.39092 C 2015, American College of Rheumatology V
EDITORIAL
Voltage-Gated Calcium 2.2 Channels: Therapeutic Target for Chronic Arthritic Pain? Sadaf Ashraf Arthritis is a debilitating multifactorial disease process that mainly affects the aging population. Arthritic conditions place a huge burden on the health care system. An estimated 50 million adults in the US alone and an estimated 175 million adults worldwide have some form of arthritic condition (1). Patients with rheumatoid arthritis (RA) account for 1–2% of this worldwide estimate. RA is characterized by severe cartilage damage, persistent synovitis, and subchondral bone remodeling, leading to disability and loss of function of the affected joints. Pain is the main clinical symptom in RA. Current treatments offer symptomatic relief, focusing on reducing pain and inflammation, but fail to halt disease progression. Because of the low efficacy and serious side effects associated with current antiinflammatory and analgesic treatments, further improved therapeutic strategies in RA are warranted. RA pain has nociceptive and neuropathic components (2). Central and peripheral sensitization, altered processing of noxious input, and dysfunction of descending inhibitory control play crucial roles in the intensity and chronicity of RA pain. Abnormal cellular mechanisms at both the peripheral and central levels of the nervous system result in increased nociceptive input from the arthritic joint. Symptoms such as hyperalgesia and allodynia are a result of the increased sensitivity of neurones to noxious and innocuous stimuli as well as hyperexcitability. Due to the complexity of the mechanisms involved, chronic RA pain is still not fully understood. Although significant progress has been made, current treatments used in clinics to manage RA pain are
inadequate. In the search for improved and safe analgesics, many targets of chronic pain in RA have been suggested; however, sufficient data on their efficacy and safety in relevant preclinical models of RA are not available. Among the targets are inhibitors of voltage-gated calcium (CaV) channels. Transmission of pain relies on CaV channels, one of which is the N-type calcium channel CaV2.2. The lure of this channel as a novel pain target lies in its critical location in nerve terminals within the central and peripheral nervous systems and its important role in the release of neurotransmitters and proinflammatory mediators. Several groups of investigators have indicated the potential benefit of targeting CaV2.2 channels and controlling chronic pain disease states (3–5), including osteoarthritis pain (6). CaV2.2 channels can be specifically blocked by the v-conotoxins CVID, FVIA, GVIA, and MVIIA (7,8). The synthetic forms of the v-conotoxins (gabapentin, pregabalin, and ziconotide) are available to treat chronic pain states associated with inflammation and neuropathies (9), and in certain situations, they are even more effective than opioids for treating pain. In order to investigate whether blocking CaV2.2 channel activity could offer a new strategy for managing inflammatory pain such as that in RA, the contribution of the CaV2.2 channel to the development of RA pathology and possible associated side effects were investigated by Baddack et al and are reported in this issue of Arthritis & Rheumatology (10). This study provides innovative information for scientists and clinicians. The authors decided to use the most widely studied v-conotoxin, MVIIA (ziconotide), which is administered using intrathecal microinfusion pumps to minimize side effects on the central nervous system. To overcome the potential difficulty with using intrathecal microinfusion pumps, Baddack et al used a paininsensitive transgenic mouse model (MVIIA-transgenic mice) (11), in which arthritis was induced using a
Sadaf Ashraf, PhD: Queen’s University Belfast, Belfast, UK. Address correspondence to Sadaf Ashraf, PhD, Centre for Experimental Medicine, Queen’s University Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast BT12-6BA, UK. E-mail: s.ashraf@ qub.ac.uk. Submitted for publication January 26, 2015; accepted in revised form February 24, 2015. 1416
EDITORIAL
combination of antigen and collagen. The authors recognized that the ACIA model more effectively mimicked human RA, displaying chronic erosive synovitis and autoimmune anti–citrullinated protein antibodies. After selecting the most clinically relevant animal model to test their hypothesis, the next step was to explore a mechanistic link whereby CaV2.2 channels could potentially alleviate inflammatory arthritis pain and pathology. Was there a link between the main mediator of joint inflammation, tumor necrosis factor a (TNFa), which also regulates the expression of RANKL (the main mediator of osteoclastogenesis), and inflammatory bone resorption? In RA, RANKL is expressed by synovial fibroblasts and T cells. The theory that there is a link between the pain-sensing pathways of the peripheral nervous system and the immune system is quickly gaining momentum. Baddack et al, however, demonstrated that blocking CaV2.2 channels reduced arthritis pain but surprisingly exacerbated joint inflammation and joint damage via upregulation of the osteoclast activator RANKL (10). Could this be due to the use of MVIIA, which is less selective compared with other v-conotoxins? This study highlights not only the importance of using the relevant preclinical disease model but also the need for potent and selective CaV2.2 inhibitors that might be more beneficial for chronic pain states such as RA, in which a definite link between the peripheral nervous system and the immune system exists to form an integrated protective mechanism. In light of this evidence, can blocking CaV2.2 achieve pain relief in inflammatory conditions such as RA? Imperative for the success of such an endeavor will be identification of not only the compounds that are selective only for CaV2.2 channels but also compounds that demonstrate effective blockade in pathologic pain states in which increased neuronal firing/excitability is seen, without compromising the channel activity associated with normal physiologic functions (12). It should be noted, however, that in arthritis, the intensity of pain does not necessary reflect disease progression. Although the pain-insensitive transgenic mouse model might not provide the perfect pathophysiologically relevant backdrop for testing the effects of pathologic CaV2.2 blockade in RA pathology and pain, it nevertheless points to the devastating consequences of general CaV2.2 inhibition. The findings of Baddack et al echo the risks and benefits observed with anti– nerve growth factor (anti-NGF) treatment in patients with knee osteoarthritis; in these patients, anti-NGF treatment resulted in sustained pain relief, but it exacerbated joint pathology (13). In comparison, orally
1417
active small-molecule CaV2.2 inhibitors that block the channel in a voltage-dependent manner may provide selective and effective pain management (12,14). Similarly, selective inhibition of the NGF receptor tropomyosin receptor kinase A instead of the NGF molecule may yield better pain management without the added adverse effects. Is there a link between the peripheral nervous system, the immune system, and RA pathology? Indeed, joint inflammation causes peripheral and central sensitization, encouraging a broader appreciation of the heterogeneity of chronic pain etiology. Similar to the findings in the study by Baddack et al, emerging data suggest that nociceptors not only are sensitive to immune mediators but also can release immune-acting modulators (15). Local release of proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from peripheral nerve endings contributes to the development of neurogenic inflammation. Along with TNFa, interleukin-1b (IL-1b), IL-15, and IL-17 increase osteoclastogenesis via RANKL activation. IL-23 stimulates IL17 production by and RANKL expression on CD41 T cells, and the IL-23/IL-17 axis is critical for bone destruction in RA (16). Baddack et al showed for the first time that analgesic treatment by CaV2.2 blockade enhanced RANKL-mediated joint destruction and progressive arthritis. CaV2.2 is involved in regulating monocyte chemotactic protein 1, a cytokine that recruits monocytes, memory T cells, and dendritic cells to sites of inflammation; thus, general CaV2.2 blockade can cause upregulation of RANKL and severe joint damage. In conclusion, although safety is still a concern, further insights into the role of CaV2.2 channel activity and the complex interaction between the immune system and pain pathways need to be analyzed in various relevant models of preclinical arthritis. This approach might pave the way for specific and targeted analgesic alternatives to relieve chronic arthritis pain in the future. Based on the findings by Baddack et al, we should not rule out the potential therapeutic significance of CaV2.2 channels in combating inflammatory arthritic pain. Yes, blocking the channel causes adverse effects, but the way forward in getting closer to an effective analgesic is to test the specificity of the target site and route of administration, trying to tease the physiologic mechanism of actions from the pathologic ones, so that we target only the pathologic functions of that target site. AUTHOR CONTRIBUTIONS Dr. Ashraf drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
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REFERENCES 1. World Health Organization. The global burden of disease. 2004. URL: http://www.cdc.gov/arthritis/data_statistics/disabilitieslimita tions.html. 2. Ahmed S, Magan T, Vargas M, Harrison A, Sofat N. Use of the painDETECT tool in rheumatoid arthritis suggests neuropathic and sensitization components in pain reporting. J Pain Res 2014; 7:579–88. 3. Snutch TP. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx 2005;2:662–70. 4. Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, et al. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca21 channel. EMBO J 2001;20:2349–56. 5. Saegusa H, Tanabe T. N-type voltage-dependent Ca21 channel in non-excitable microglial cells in mice is involved in the pathophysiology of neuropathic pain. Biochem Biophys Res Commun 2014;450:142–7. 6. Dray A, Read SJ. Arthritis and pain: future targets to control osteoarthritis pain. Arthritis Res Ther 2007;9:212. 7. Scott DA, Wright CE, Angus JA. Actions of intrathecal vconotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol 2002;451:279–86. 8. Lee S, Kim Y, Back SK, Choi HW, Lee JY, Jung HH, et al. Analgesic effect of highly reversible v-conotoxin FVIA on N type Ca21 channels. Mol Pain 2010;6:97.
9. Pexton T, Moeller-Bertram T, Schilling JM, Wallace MS. Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert Opin Investig Drugs 2011;20:1277–84. 10. Baddack U, Frahm S, Antolin-Fontes B, Grobe J, Lipp M, Muller G, et al. 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. Arthritis Rheumatol 2015;67:1657–67. 11. Auer S, Sturzebecher AS, Juttner R, Santos-Torres J, Hanack C, Frahm S, et al. Silencing neurotransmission with membranetethered toxins. Nat Methods 2010;7:229–36. 12. Winquist RJ, Pan JQ, Gribkoff VK. Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. Biochem Pharmacol 2005;70:489–99. 13. Seidel MF, Lane NE. Control of arthritis pain with anti-nervegrowth factor: risk and benefit. Curr Rheumatol Rep 2012;14: 583–8. 14. Lee S. Pharmacological inhibition of voltage-gated Ca21 channels for chronic pain relief. Curr Neuropharmacol 2013;11:606–20. 15. Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 2012;15:1063–7. 16. Ju JH, Cho ML, Moon YM, Oh HJ, Park JS, Jhun JY, et al. IL23 induces receptor activator of NF-kB ligand expression on CD41 T cells and promotes osteoclastogenesis in an autoimmune arthritis model. J Immunol 2008;181:1507–18.
Copyright of Arthritis & Rheumatology is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
EDITORIAL
Voltage-Gated Calcium 2.2 Channels: Therapeutic Target for Chronic Arthritic Pain? Sadaf Ashraf Arthritis is a debilitating multifactorial disease process that mainly affects the aging population. Arthritic conditions place a huge burden on the health care system. An estimated 50 million adults in the US alone and an estimated 175 million adults worldwide have some form of arthritic condition (1). Patients with rheumatoid arthritis (RA) account for 1–2% of this worldwide estimate. RA is characterized by severe cartilage damage, persistent synovitis, and subchondral bone remodeling, leading to disability and loss of function of the affected joints. Pain is the main clinical symptom in RA. Current treatments offer symptomatic relief, focusing on reducing pain and inflammation, but fail to halt disease progression. Because of the low efficacy and serious side effects associated with current antiinflammatory and analgesic treatments, further improved therapeutic strategies in RA are warranted. RA pain has nociceptive and neuropathic components (2). Central and peripheral sensitization, altered processing of noxious input, and dysfunction of descending inhibitory control play crucial roles in the intensity and chronicity of RA pain. Abnormal cellular mechanisms at both the peripheral and central levels of the nervous system result in increased nociceptive input from the arthritic joint. Symptoms such as hyperalgesia and allodynia are a result of the increased sensitivity of neurones to noxious and innocuous stimuli as well as hyperexcitability. Due to the complexity of the mechanisms involved, chronic RA pain is still not fully understood. Although significant progress has been made, current treatments used in clinics to manage RA pain are
inadequate. In the search for improved and safe analgesics, many targets of chronic pain in RA have been suggested; however, sufficient data on their efficacy and safety in relevant preclinical models of RA are not available. Among the targets are inhibitors of voltage-gated calcium (CaV) channels. Transmission of pain relies on CaV channels, one of which is the N-type calcium channel CaV2.2. The lure of this channel as a novel pain target lies in its critical location in nerve terminals within the central and peripheral nervous systems and its important role in the release of neurotransmitters and proinflammatory mediators. Several groups of investigators have indicated the potential benefit of targeting CaV2.2 channels and controlling chronic pain disease states (3–5), including osteoarthritis pain (6). CaV2.2 channels can be specifically blocked by the v-conotoxins CVID, FVIA, GVIA, and MVIIA (7,8). The synthetic forms of the v-conotoxins (gabapentin, pregabalin, and ziconotide) are available to treat chronic pain states associated with inflammation and neuropathies (9), and in certain situations, they are even more effective than opioids for treating pain. In order to investigate whether blocking CaV2.2 channel activity could offer a new strategy for managing inflammatory pain such as that in RA, the contribution of the CaV2.2 channel to the development of RA pathology and possible associated side effects were investigated by Baddack et al and are reported in this issue of Arthritis & Rheumatology (10). This study provides innovative information for scientists and clinicians. The authors decided to use the most widely studied v-conotoxin, MVIIA (ziconotide), which is administered using intrathecal microinfusion pumps to minimize side effects on the central nervous system. To overcome the potential difficulty with using intrathecal microinfusion pumps, Baddack et al used a paininsensitive transgenic mouse model (MVIIA-transgenic mice) (11), in which arthritis was induced using a
Sadaf Ashraf, PhD: Queen’s University Belfast, Belfast, UK. Address correspondence to Sadaf Ashraf, PhD, Centre for Experimental Medicine, Queen’s University Belfast, Royal Victoria Hospital, Grosvenor Road, Belfast BT12-6BA, UK. E-mail: s.ashraf@ qub.ac.uk. Submitted for publication January 26, 2015; accepted in revised form February 24, 2015. 1416
EDITORIAL
combination of antigen and collagen. The authors recognized that the ACIA model more effectively mimicked human RA, displaying chronic erosive synovitis and autoimmune anti–citrullinated protein antibodies. After selecting the most clinically relevant animal model to test their hypothesis, the next step was to explore a mechanistic link whereby CaV2.2 channels could potentially alleviate inflammatory arthritis pain and pathology. Was there a link between the main mediator of joint inflammation, tumor necrosis factor a (TNFa), which also regulates the expression of RANKL (the main mediator of osteoclastogenesis), and inflammatory bone resorption? In RA, RANKL is expressed by synovial fibroblasts and T cells. The theory that there is a link between the pain-sensing pathways of the peripheral nervous system and the immune system is quickly gaining momentum. Baddack et al, however, demonstrated that blocking CaV2.2 channels reduced arthritis pain but surprisingly exacerbated joint inflammation and joint damage via upregulation of the osteoclast activator RANKL (10). Could this be due to the use of MVIIA, which is less selective compared with other v-conotoxins? This study highlights not only the importance of using the relevant preclinical disease model but also the need for potent and selective CaV2.2 inhibitors that might be more beneficial for chronic pain states such as RA, in which a definite link between the peripheral nervous system and the immune system exists to form an integrated protective mechanism. In light of this evidence, can blocking CaV2.2 achieve pain relief in inflammatory conditions such as RA? Imperative for the success of such an endeavor will be identification of not only the compounds that are selective only for CaV2.2 channels but also compounds that demonstrate effective blockade in pathologic pain states in which increased neuronal firing/excitability is seen, without compromising the channel activity associated with normal physiologic functions (12). It should be noted, however, that in arthritis, the intensity of pain does not necessary reflect disease progression. Although the pain-insensitive transgenic mouse model might not provide the perfect pathophysiologically relevant backdrop for testing the effects of pathologic CaV2.2 blockade in RA pathology and pain, it nevertheless points to the devastating consequences of general CaV2.2 inhibition. The findings of Baddack et al echo the risks and benefits observed with anti– nerve growth factor (anti-NGF) treatment in patients with knee osteoarthritis; in these patients, anti-NGF treatment resulted in sustained pain relief, but it exacerbated joint pathology (13). In comparison, orally
1417
active small-molecule CaV2.2 inhibitors that block the channel in a voltage-dependent manner may provide selective and effective pain management (12,14). Similarly, selective inhibition of the NGF receptor tropomyosin receptor kinase A instead of the NGF molecule may yield better pain management without the added adverse effects. Is there a link between the peripheral nervous system, the immune system, and RA pathology? Indeed, joint inflammation causes peripheral and central sensitization, encouraging a broader appreciation of the heterogeneity of chronic pain etiology. Similar to the findings in the study by Baddack et al, emerging data suggest that nociceptors not only are sensitive to immune mediators but also can release immune-acting modulators (15). Local release of proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from peripheral nerve endings contributes to the development of neurogenic inflammation. Along with TNFa, interleukin-1b (IL-1b), IL-15, and IL-17 increase osteoclastogenesis via RANKL activation. IL-23 stimulates IL17 production by and RANKL expression on CD41 T cells, and the IL-23/IL-17 axis is critical for bone destruction in RA (16). Baddack et al showed for the first time that analgesic treatment by CaV2.2 blockade enhanced RANKL-mediated joint destruction and progressive arthritis. CaV2.2 is involved in regulating monocyte chemotactic protein 1, a cytokine that recruits monocytes, memory T cells, and dendritic cells to sites of inflammation; thus, general CaV2.2 blockade can cause upregulation of RANKL and severe joint damage. In conclusion, although safety is still a concern, further insights into the role of CaV2.2 channel activity and the complex interaction between the immune system and pain pathways need to be analyzed in various relevant models of preclinical arthritis. This approach might pave the way for specific and targeted analgesic alternatives to relieve chronic arthritis pain in the future. Based on the findings by Baddack et al, we should not rule out the potential therapeutic significance of CaV2.2 channels in combating inflammatory arthritic pain. Yes, blocking the channel causes adverse effects, but the way forward in getting closer to an effective analgesic is to test the specificity of the target site and route of administration, trying to tease the physiologic mechanism of actions from the pathologic ones, so that we target only the pathologic functions of that target site. AUTHOR CONTRIBUTIONS Dr. Ashraf drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
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REFERENCES 1. World Health Organization. The global burden of disease. 2004. URL: http://www.cdc.gov/arthritis/data_statistics/disabilitieslimita tions.html. 2. Ahmed S, Magan T, Vargas M, Harrison A, Sofat N. Use of the painDETECT tool in rheumatoid arthritis suggests neuropathic and sensitization components in pain reporting. J Pain Res 2014; 7:579–88. 3. Snutch TP. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx 2005;2:662–70. 4. Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, et al. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca21 channel. EMBO J 2001;20:2349–56. 5. Saegusa H, Tanabe T. N-type voltage-dependent Ca21 channel in non-excitable microglial cells in mice is involved in the pathophysiology of neuropathic pain. Biochem Biophys Res Commun 2014;450:142–7. 6. Dray A, Read SJ. Arthritis and pain: future targets to control osteoarthritis pain. Arthritis Res Ther 2007;9:212. 7. Scott DA, Wright CE, Angus JA. Actions of intrathecal vconotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol 2002;451:279–86. 8. Lee S, Kim Y, Back SK, Choi HW, Lee JY, Jung HH, et al. Analgesic effect of highly reversible v-conotoxin FVIA on N type Ca21 channels. Mol Pain 2010;6:97.
9. Pexton T, Moeller-Bertram T, Schilling JM, Wallace MS. Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert Opin Investig Drugs 2011;20:1277–84. 10. Baddack U, Frahm S, Antolin-Fontes B, Grobe J, Lipp M, Muller G, et al. 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. Arthritis Rheumatol 2015;67:1657–67. 11. Auer S, Sturzebecher AS, Juttner R, Santos-Torres J, Hanack C, Frahm S, et al. Silencing neurotransmission with membranetethered toxins. Nat Methods 2010;7:229–36. 12. Winquist RJ, Pan JQ, Gribkoff VK. Use-dependent blockade of Cav2.2 voltage-gated calcium channels for neuropathic pain. Biochem Pharmacol 2005;70:489–99. 13. Seidel MF, Lane NE. Control of arthritis pain with anti-nervegrowth factor: risk and benefit. Curr Rheumatol Rep 2012;14: 583–8. 14. Lee S. Pharmacological inhibition of voltage-gated Ca21 channels for chronic pain relief. Curr Neuropharmacol 2013;11:606–20. 15. Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci 2012;15:1063–7. 16. Ju JH, Cho ML, Moon YM, Oh HJ, Park JS, Jhun JY, et al. IL23 induces receptor activator of NF-kB ligand expression on CD41 T cells and promotes osteoclastogenesis in an autoimmune arthritis model. J Immunol 2008;181:1507–18.
Copyright of Arthritis & Rheumatology is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
