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T-type Calcium Channels in Basic and Clinical Science pp 129–136Cite as

T-Type Calcium Channels and Management of Pain

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Abstract

T-type Ca2+ channels exhibit small, transient currents that are relatively insensitive to dihydropyridines and exhibit “window current” in the physiological range for voltage. A role for T-type Ca2+ channels in nociceptor sensitization was reported in 2001, an effect confirmed in studies using Cav3.1 and Cav3.2 knockout animals. The Cav3.2 channel is involved in both central and peripheral termini of primary afferent neurons and is now considered an important player in the processing of pain. The analgesic effect of T-type calcium channels has been tested in different pain models. In addition to neuropathic pain reduction, the inhibition of T-type calcium channels is efficacious in formalin injection into the hind paw, which models an acute inflammatory pain. T-type Ca2+ channel blockers also produce a dose-dependent reduction in IBS-induced pain in a rat model of irritable bowel syndrome (IBS). T-type Ca2+ channel antagonists present obvious advantages over opioid analgesics; they directly act on the cytoplasmic membrane of neurons and most likely from the extracellular side. Therefore their antinociceptive effect may not cause profound drug tolerance and dependence.

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References

  • Atreja A, Bellam N, Levy SR (2005) Strategies to enhance patient adherence: making it simple. Med Gen Med 7:4

    Google Scholar 

  • Belardetti F, Zamponi GW (2008) Linking calcium-channel isoforms to potential therapies. Curr Opin Investig Drugs 9:707–715

    CAS  PubMed  Google Scholar 

  • Bie B, Peng Y, Zhang Y, Pan ZZ (2005) cAMP-mediated mechanisms for pain sensitization during opioid withdrawal. J Neurosci 25:3824–3832

    Article  CAS  PubMed  Google Scholar 

  • Bourinet E, Alloui A, Monteil A, Barrere C, Couette B, Poirot O, Pages A, McRory J, Snutch TP, Eschalier A, Nargeot J (2005) Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J 24:315–324

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brogden RN, Markham A (1997) Mibefradil—a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris. Drugs 54:774–793

    Article  CAS  PubMed  Google Scholar 

  • Calcutt NA (2013) Location, location, location?: Is the pain of diabetic neuropathy generated by hyperactive sensory neurons? Diabetes 62:3658–3660

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen WK, Liu IY, Chang YT, Chen YC, Chen CC, Yen CT, Shin HS, Chen CC (2010) Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J Neurosci 30:10360–10368

    Article  CAS  PubMed  Google Scholar 

  • Choe W, Messinger RB, Leach E, Eckle VS, Obradovic A, Salajegheh R, Jevtovic-Todorovic V, Todorovic SM (2011) TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol Pharmacol 80:900–910

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Choi S, Na HS, Kim J, Lee J, Lee S, Kim D, Park J, Chen CC, Campbell KP, Shin HS (2007) Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels. Genes Brain Behav 6:425–431

    Article  CAS  PubMed  Google Scholar 

  • Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F (2003) Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain 105:159–168

    Article  CAS  PubMed  Google Scholar 

  • Dziegielewska B, Gray LS, Dziegielewski J (2014) T-type calcium channels blockers as new tools in cancer therapies. Pflugers Arch 466:801–810

    Article  CAS  PubMed  Google Scholar 

  • Flatters SJ, Bennett GJ (2004) Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109:150–161

    Article  CAS  PubMed  Google Scholar 

  • Francois A, Kerckhove N, Meleine M, Alloui A, Barrere C, Gelot A, Uebele VN, Renger JJ, Eschalier A, Ardid D, Bourinet E (2013) State-dependent properties of a new T-type calcium channel blocker enhance Ca(V)3.2 selectivity and support analgesic effects. Pain 154:283–293

    Article  CAS  PubMed  Google Scholar 

  • Gray LS, Schiff D, Macdonald TL (2013) A model for the regulation of T-type Ca(2+) channels in proliferation: roles in stem cells and cancer. Expert Rev Anticancer Ther 13:589–595

    Article  CAS  PubMed  Google Scholar 

  • Huc S, Monteil A, Bidaud I, Barbara G, Chemin J, Lory P (2009) Regulation of T-type calcium channels: signaling pathways and functional implications. Biochem Biophys Acta 1793:947–952

    Article  CAS  PubMed  Google Scholar 

  • Iftinca MC (2011) Neuronal T-type calcium channels: what’s new? Iftinca: T-type channel regulation. J Med Life 4:126–138

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jacus MO, Uebele VN, Renger JJ, Todorovic SM (2012) Presynaptic Cav3.2 channels regulate excitatory neurotransmission in nociceptive dorsal horn neurons. J Neurosci 32:9374–9382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jagodic MM, Pathirathna S, Nelson MT, Mancuso S, Joksovic PM, Rosenberg ER, Bayliss DA, Jevtovic-Todorovic V, Todorovic SM (2007) Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons. J Neurosci 27:3305–3316

    Article  CAS  PubMed  Google Scholar 

  • Jagodic MM, Pathirathna S, Joksovic PM, Lee W, Nelson MT, Naik AK, Su P, Jevtovic-Todorovic V, Todorovic SM (2008) Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol 99:3151–3156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jarvis MF, Scott VE, McGaraughty S, Chu KL, Xu J, Niforatos W, Milicic I, Joshi S, Zhang Q, Xia Z (2014) A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats. Biochem Pharmacol 89:536–544

    Article  CAS  PubMed  Google Scholar 

  • Kam YL, Rhee HK, Rhim H, Back SK, Na HS, Choo HY (2010) Synthesis and T-type calcium channel blocking activity of novel diphenylpiperazine compounds, and evaluation of in vivo analgesic activity. Bioorg Med Chem 18:5938–5944

    Article  CAS  PubMed  Google Scholar 

  • Keyser BM, Taylor JT, Choi S-K, Lu Y, Bhattacharjee A, Huang L, Pottle J, Matrougui K, Xu Z, Li M (2014) Role of T-type Ca2+ channels in basal [Ca2+]i regulation and basal insulin secretion in rat islet cells. Curr Trend Endocrinol

    Google Scholar 

  • Khomula EV, Viatchenko-Karpinski VY, Borisyuk AL, Duzhyy DE, Belan PV, Voitenko NV (2013) Specific functioning of Cav3.2 T-type calcium and TRPV1 channels under different types of STZ-diabetic neuropathy. Biochim Biophys Acta 1832:636–649

    Article  CAS  PubMed  Google Scholar 

  • Latham JR, Pathirathna S, Jagodic MM, Choe WJ, Levin ME, Nelson MT, Lee WY, Krishnan K, Covey DF, Todorovic SM, Jevtovic-Todorovic V (2009) Selective T-type calcium channel blockade alleviates hyperalgesia in ob/ob mice. Diabetes 58:2656–2665

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee MJ, Shin TJ, Lee JE, Choo H, Koh HY, Chung HJ, Pae AN, Lee SC, Kim HJ (2010) KST5468, a new T-type calcium channel antagonist, has an antinociceptive effect on inflammatory and neuropathic pain models. Pharmacol Biochem Behav 97:198–204

    Article  CAS  PubMed  Google Scholar 

  • Li W, Zhang SL, Wang N, Zhang BB, Li M (2011) Blockade of T-type Ca2+ channels inhibits human ovarian cancer cell proliferation. Cancer Invest 29:339–346

    Article  CAS  PubMed  Google Scholar 

  • Liao YF, Tsai ML, Chen CC, Yen CT (2011) Involvement of the Cav3.2 T-type calcium channel in thalamic neuron discharge patterns. Mol Pain 7:43

    Article  PubMed Central  PubMed  Google Scholar 

  • Maeda Y, Aoki Y, Sekiguchi F, Matsunami M, Takahashi T, Nishikawa H, Kawabata A (2009) Hyperalgesia induced by spinal and peripheral hydrogen sulfide: evidence for involvement of Cav3.2 T-type calcium channels. Pain 142:127–132

    Article  CAS  PubMed  Google Scholar 

  • Marcantoni A, Carabelli V, Comunanza V, Hoddah H, Carbone E (2008) Calcium channels in chromaffin cells: focus on L and T types. Acta Physiol 192:233–246

    Article  CAS  Google Scholar 

  • Marger F, Gelot A, Alloui A, Matricon J, Ferrer JF, Barrere C, Pizzoccaro A, Muller E, Nargeot J, Snutch TP, Eschalier A, Bourinet E, Ardid D (2011) T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. Proc Natl Acad Sci USA 108:11268–11273

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Messinger RB, Naik AK, Jagodic MM, Nelson MT, Lee WY, Choe WJ, Orestes P, Latham JR, Todorovic SM, Jevtovic-Todorovic V (2009) In vivo silencing of the Ca(V)3.2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy. Pain 145:184–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Na HS, Choi S, Kim J, Park J, Shin HS (2008) Attenuated neuropathic pain in Cav3.1 null mice. Mol Cells 25:242–246

    CAS  PubMed  Google Scholar 

  • National Research Council (2009) Recognition and alleviation of pain in laboratory animals. The National Academies Press, Washington, DC

    Google Scholar 

  • Obradovic A, Hwang SM, Scarpa J, Hong SJ, Todorovic SM, Jevtovic-Todorovic V (2014) CaV3.2 T-type calcium channels in peripheral sensory neurons are important for mibefradil-induced reversal of hyperalgesia and allodynia in rats with painful diabetic neuropathy. PLoS One 9:e91467

    Article  PubMed Central  PubMed  Google Scholar 

  • Ohkubo T, Yamazaki J (2012) T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells. Int J Oncol 41:267–275

    CAS  PubMed  Google Scholar 

  • Okubo K, Takahashi T, Sekiguchi F, Kanaoka D, Matsunami M, Ohkubo T, Yamazaki J, Fukushima N, Yoshida S, Kawabata A (2011) Inhibition of T-type calcium channels and hydrogen sulfide-forming enzyme reverses paclitaxel-evoked neuropathic hyperalgesia in rats. Neuroscience 188:148–156

    Article  CAS  PubMed  Google Scholar 

  • Pottle J, Sun C, Gray L, Li M (2013) Exploiting MCF-7 cells’ calcium dependence with interlaced therapy. J Cancer Ther 4:32–40

    Article  Google Scholar 

  • Pradhan AA, Walwyn W, Nozaki C, Filliol D, Erbs E, Matifas A, Evans C, Kieffer BL (2010) Ligand-directed trafficking of the δ-opioid receptor in vivo: two paths toward analgesic tolerance. J Neurosci 30:16459–16468

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ripamonti CI, Bandieri E, Roila F, Group EGW (2011) Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol 22(Suppl 6):vi69–77

    Google Scholar 

  • Rupp T, Delaney KA (2004) Inadequate analgesia in emergency medicine. Ann Emerg Med 43:494–503

    Article  PubMed  Google Scholar 

  • Sekiguchi F, Kawabata A (2013) T-type calcium channels: functional regulation and implication in pain signaling. J Pharmacol Sci 122:244–250

    Article  CAS  PubMed  Google Scholar 

  • Shin HS, Cheong EJ, Choi S, Lee J, Na HS (2008) T-type Ca2+ channels as therapeutic targets in the nervous system. Curr Opin Pharmacol 8:33–41

    Article  CAS  PubMed  Google Scholar 

  • Smith GF, Toonen TR (2007) Primary care of the patient with cancer. Am Fam Physician 75:1207–1214

    PubMed  Google Scholar 

  • Takahashi T, Aoki Y, Okubo K, Maeda Y, Sekiguchi F, Mitani K, Nishikawa H, Kawabata A (2010) Upregulation of Ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain. Pain 150:183–191

    Article  CAS  PubMed  Google Scholar 

  • Taylor JT, Huang L, Pottle JE, Liu K, Yang Y, Zeng X, Keyser BM, Agrawal KC, Hansen JB, Li M (2008a) Selective blockade of T-type Ca2+ channels suppresses human breast cancer cell proliferation. Cancer Lett 267:116–124

    Article  CAS  PubMed  Google Scholar 

  • Taylor JT, Zeng XB, Pottle JE, Lee K, Wang AR, Yi SG, Scruggs JA, Sikka SS, Li M (2008b) Calcium signaling and T-type calcium channels in cancer cell cycling. World J Gastroenterol 14:4984–4991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Todorovic SM, Jevtovic-Todorovic V, Meyenburg A, Mennerick S, Perez-Reyes E, Romano C, Olney JW, Zorumski CF (2001) Redox modulation of T-type calcium channels in rat peripheral nociceptors. Neuron 31:75–85

    Article  CAS  PubMed  Google Scholar 

  • Todorovic SM, Meyenburg A, Jevtovic-Todorovic V (2002) Mechanical and thermal antinociception in rats following systemic administration of mibefradil, a T-type calcium channel blocker. Brain Res 951:336–340

    Article  CAS  PubMed  Google Scholar 

  • Weiss N, Hameed S, Fernandez-Fernandez JM, Fablet K, Karmazinova M, Poillot C, Proft J, Chen L, Bidaud I, Monteil A, Huc-Brandt S, Lacinova L, Lory P, Zamponi GW, De Waard M (2012) A Ca(v)3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis. J Biol Chem 287:2810–2818

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wen XJ, Xu SY, Chen ZX, Yang CX, Liang H, Li H (2010) The roles of T-type calcium channel in the development of neuropathic pain following chronic compression of rat dorsal root ganglia. Pharmacology 85:295–300

    Article  CAS  PubMed  Google Scholar 

  • Yang SN, Berggren PO (2006) The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology. Endocr Rev 27:621–676

    Article  CAS  PubMed  Google Scholar 

  • Yue J, Liu L, Liu Z, Shu B, Zhang Y (2013) Upregulation of T-type Ca2+ channels in primary sensory neurons in spinal nerve injury. Spine 38:463–470

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cellular and Molecular Biology Branch, U.S. Army Medical Research Institute of Chemical Defense Research Division, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD, 21015, USA

    Brian M. Keyser

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  1. Brian M. Keyser
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Editors and Affiliations

  1. Dept. Pharmacology, University of South Alabama School of Medicine, Mobile, Alabama, USA

    Stephen W. Schaffer

  2. Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, USA

    Ming Li

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Keyser, B.M. (2015). T-Type Calcium Channels and Management of Pain. In: Schaffer, S., Li, M. (eds) T-type Calcium Channels in Basic and Clinical Science. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1413-1_9

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