Role of Voltage-Gate Calcium Channels in Pain Pathophysiology

Year 2018, , 140 - 148, 01.08.2018

Mustafa Emre

https://doi.org/10.5505/kjms.2018.43925

Abstract

The perception and processing of painful stimuli in afferent sensory neurons depends on the variety of voltage, ligand-gated and
receptor-controlled calcium channels, including sodium, calcium,
P2X class purinergic receptors, transient receptor potential (TRP)
channels and G-protein coupled receptor (GPCR) channels. The
pathophysiology of the pain is quite complex, and the fact that,
nowadays there are some difficulties on identification of exact reason of pain, developing right therapeutic approaches and effective continuity of the approaches. Calcium channels in the afferent
pathway are thought to play a role in cell signaling beyond electrical activity. A large number of voltage-gated calcium channels are
involved in primer afferent pain signal transduction. Among the calcium channel family, N and T-type calcium channels play the most
critical role. For this reason, they have been very strongly involved
in therapeutic targets. In this review, the role of voltage-gated calcium ion channels in pain physiopathology has been reviewed.

Keywords

pain; voltage-gated calcium channels; pathophysiology

Ağrı Patofizyolojisinde Voltaj Kapılı Kalsiyum Kanallarının Rolü

Abstract

Afferent duyu nöronlarında ağrılı uyarıların algılanıp işlenilmesi,
sodyum, kalsiyum, P2X sınıfı purinerjik reseptörler, geçici reseptör
potansiyel (TRP) kanalları ve G-protein bağlı reseptör (GPCR) kanallarının dâhil olduğu voltaj, ligand kapılı ve reseptör kontrollü kalsiyum kanallarının çeşitliliğine bağlıdır. Ağrının patofizyolojisi oldukça
karmaşıktır, günümüzde ağrının nedeninin belirlenmesi, doğru tedavi
yaklaşımlarının bulunması ve uygulanan tedavilerin etkin bir şekilde
sürdürülebilmesinde zorluklar yaşandığı bir gerçektir. Afferent ağrı
yolunda yer alan kalsiyum kanallarının, hücre sinyalleşmesinde elektriksel aktivitenin de ötesinde rol üstlendiği düşünülmektedir. Primer
afferent ağrı sinyal iletiminde çok sayıda voltaj kapılı kalsiyum kanalı
yer alır. Kalsiyum kanal ailesi arasında N ve T-tipi kalsiyum kanalları
en kritik role sahiptir. Bu nedenle, çok güçlü bir şekilde terapötik
hedefler arasında yer almışlardır. Bu derlemede, ağrı fizyopatolojisin
de voltaj kapılı kalsiyum iyon kanallarının rolü gözden geçirilmiştir. 

Keywords

ağrı; voltaj kapılı kalsiyum kanalları; patofizyoloji

References

• 1. Emre M. Voltaj kapılı kalsiyum kanalları ve moleküller özellikleri. Arşiv Kaynak Tarama Dergisi 2018;27(1):1–17. 2. Ibrahim HS, Maryam IU, Nasir Mohamad, Mahadeva R, Adzim K, Nor Hidayah AB. Reviews on calcium mediated secondary messengers in chronic opioids exposure/addiction. Journal of Applied Pharmaceutical Science 2015;5(01), 114–119. 3. William AC, Edward PR, Terrance PS, Joerg S. International union of pharmacology. XLVIII. Nomenclature and structurefunction relationships of voltage-gated calcium channels. Pharmacol Rev 2005;57(4):411–25. 4. Thomas L. Pallone, Sandeep Khurana, Chunhua Cao. Voltage-Gated Calcium Channels: Structure and Function (CACNA)2017;5942–49. 5. Simms BA, Zamponi GW. Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction. Neuron 2014;82(1):24–45. 6. Sümer Turanlıgil NC, Uyanıkgil Y. Hücre İçi Sinyal Yolakları ve Klinik Yansımaları. Arşiv 2010;19:180–191. 7. Zhang Z, Xu Y, Song H, Rodriguez J, Tuteja D, Namkung Y, et al. Functional roles of Ca (v)1 3(alpha(1D))calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice. Circ Res 2002;90:981–87. 8. Triggle DJ. L-type calcium channels. Curr Pharm Des 2006;12(4):443–57. 9. Safa P, Boulter J, and Hales TG. Functional properties of Cav1 3(alpha1D) L-type Ca2+ channel splice variants expressed by rat brain and neuroendocrine GH3 cells. J Biol Chem 2001;276:38727–37. 10. Xu W and Lipscombe D. Neuronal Ca (V)1 3alpha(1)L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci 2001;21:5944–51. 11. Thomas DH, Weifeng Xu, and Diane Lipscombe. Neuronal L-type calcium channels open quickly and are inhibited slowly. The Journal of Neuroscience 2005;25(44):10247–51. 12. Platzer J, Engel J, Schrott-Fischer A, Stephan K, Bova S, Chen H, et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 2000;102:89–97. 13. Valentin KG. The role of voltage-gated calcium channels in pain and nociception. Seminars in Cell & Developmental Biology 2006;17:555–64. 14. Gruner W, Silva LR. Omega-conotoxin sensitivity and presynaptic inhibition of glutamatergic sensory neurotransmission in vitro. J Neurosci1994;14:2800–2808. 15. Mills LR, Niesen CE, So AP, Carlen PL, Spigelman I, Jones OT. N-type Ca2+ channels are located on somata, dendrites, and a subpopulation of dendritic spines on live hippocampal pyramidal neurons. J Neurosci 1994;14(11):6815–24. 16. Jason E Pope, Timothy R. Deer. Ziconotide: a clinical update and pharmacologic review. Journal Expert Opinion on Pharmacotherapy 2013;14(7):957–966. 17. Emilie P, Michel V, Jean M, Valerie R. Peptide Neurotoxins That Affect Voltage-Gated Calcium Channels: A Close-Up on ω-Agatoxins. Toxins 2011, 3(1), 17–42. 18. Wallace MS, Kosek PS, Staats P, Fisher R, Schultz DM, Leong M. Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain. Pain Med 2008;9(3):271–81. 19. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS. J Am Med Assoc 2004;291(1):64–70. 20. Dray A, Read SJ. Arthritis and pain. Future targets to control osteoarthritis pain. Arthritis Research & Therapy 2007;9(212):1–14. 21. Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Therapeutic Advances in Chronic Disease 2015;6(1):15–28. 22. Bruel BM, Burton AW. Intrathecal Therapy for Cancer-Related Pain. Pain Medicine 2016;17(12):2404–21. 23. Webster LR, Fakata KL, Charapata S, Robert F, Michael MH. Open-label, multicenter study of combined intrathecal morphine and ziconotide: Addition of morphine in patients receiving ziconotide for severe chronic pain. Pain Med 2008;9:282–90. 24. Dupoiron D, Bore F, Lefebvre-Kuntz D, Brenet O, Debourmont S, Dixmerias F, et al. Ziconotide Adverse Events in Patients with Cancer Pain: A Multicenter Observational Study of a Slow Titration, Multidrug Protocol. Pain Physician 2012;15:395–403. 25. McGuire D, Bowersox S, Fellmann JD, Luther RR. Sympatholysis after neuron-specific, N-type, voltagesensitive calcium channel blockade: first demonstration of N-channel function in humans. J Cardiovasc Pharmaco 1997;30:400–403. 26. Kolosov A, Aurini L, Williams ED, Cooke I, Goodchild CS. Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain. Pain Medicine 2011;12(6), 923–941. 27. Williams ME, Brust PF, Feldman DH, Patthi S, Simerson S, Maroufi A, et al. Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science 1992;257:389–395. 28. Weber AM, Wong FK, Tufford AR, Schlichter LC, Matveev V, Stanley EF. N-type Ca2+ channels carry the largest current: implications for nanodomains and transmitter release. Nature Neuroscience 2010;13(11):1348–50. 29. Valentin KG and Leonard KK (Eds). Structure, Function, and Modulation of Neuronal Voltage-Gated Ion Channels. Elizabeth T and Terrance PS. Voltage-gated N-type and T-type calcium channels and excitability disorders 2009;35–66, John Wiley & Sons, Inc. doi:10 1002/9780470429907. ch2. 30. Alles SRA, Smith PA. Etiology and Pharmacology of Neuropathic Pain. Pharmacol Rev 2018;70(2):315–347. 31. Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel α2 δ-1 subunit upregulation contributes to peripheral nevre injury-induced tactile allodynia. J Neurosci 2004;29(39):8494–99. 32. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2 delta subunit of a calcium channel. J Biol Chem 1996;271:5768–76. 33. Kavoussi R. Pregabalin: From molecule to medicine. Eur Neuropsychopharmacol 2006;16:28–33. 34. Shneker BF, McAuley JW. Pregabalin: a new neuromodulator with broad therapeutic indications. Ann Pharmacother 2005;39(12):2029–37. 35. Dworkin RH, O’Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, at al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007;132:237–251. 36. Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP Jr, Martin SA, et al. A randomized, double-blind, placebocontrolled, phase III trial of Pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 2008;35:502–14. 37. Olivera BM, McIntosh JM, Cruz LJ, Luque FA, Gray WR. Purification and sequence of a presynaptic peptide toxin from Conus geographus venom. Biochemistry 1984;23:5087–90. 38. Ryan M. Brady, Jonathan B. Baell and Raymond S. Norton. Strategies for the development of conotoxins as new therapeutic leads. Mar. Drugs 2013;11:2293–2313. 39. Olivera BM, Cruz LJ, de Santos V, LeCheminant GW, Griffin D, Zeikus R, et al. Neuronal calcium channel antagonists Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry 1987;26:2086–90. 40. Wang YX, Pettus M, Gao D, Phillips C, Scott Bowersox S. Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain 2000;84:151–8. 41. Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS. a randomized controlled trial. JAMA 2004;291:63–70. 42. Ver Donck A, Collins R, Rauck RL, Nitescu P. An open-label, multicenter study of the safety and efficacy of intrathecal ziconotide for severe chronic pain when delivered via an external pump. Neuromodulation 2008;11:103–11. 43. Richard JL, Se´bastien Dutertre, Irina Vetter, and MacDonald J. Conus Venom Peptide Pharmacology. Pharmacological Reviews 2012;64(2):259–298. 44. Peter D. Anderson, Gyula Bokor. Conotoxins: Potential Weapons from the Sea. J Bioterr Biodef 2012;3(3), 1–4. 45. Thomas D. Helton, Weifeng Xu, and Diane Lipscombe. Neuronal L-type calcium channels open quickly and are inhibited slowly. The Journal of Neuroscience 2005;25(44):10247–51. 46. Martinello K, Huang Z, Lujan R, Tran B, Watanabe M, et al. Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells. Neuron 2015;85:346–63. 47. Perez-Reyes E. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 2003;83:117–161. 48. McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Baillie DL, et al. Molecular and functional characterization of a family of rat brain T-type calcium channels. J Biol Chem 2001;276:3999–4011. 49. Heron SE, Phillips HA, Mulley JC, Mazarib A, Neufeld MY, Berkovic SF, et al. Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann Neurol 2004;55:595–596. 50. Yue J, Liu L, Liu Z, Shu B, Zhang Y. Upregulation of T-type Ca2+ channels in primary sensory neurons in spinal nerve injury. Spine 2013;38:463–70. 51. Messinger RB, Naik AK, Jagodic MM, Nelson MT, Lee WY, Choe WJ, et al. In vivo silencing of the Cav3 2 T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocininduced diabetic neuropathy. Pain 2009;145:184–195. 52. Wen XJ, Xu SY, Chen ZX, Yang CX, Liang H, Li H. The roles of T-type calcium channel in the development of neuropathic pain following chronic compression of rat dorsal root ganglia. Pharmacology 2010;85:295–300. 53. Chen WK, Liu IY, Chang YT, Chen YC, Chen CC, Yen CT, et al, Ca (v)3 2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J Neurosci 2010;30:10360–68. 54. Engbers JD, Anderson D, Asmara H, Rehak R, Mehaffey WH, Hameed S, et al. Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells. Proc Natl Acad Sci USA 2012;109:2601–06. 55. E. Bourinet, A Francois, S Laffray. T-type calcium channels in neuropathic pain. Pain 2016;157 S15-S22. 56. Barton ME, Eberle EL, Shannon HE. The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil. Eur J Pharmacol 2005;521:79–85. 57. Jagodic MM, Pathirathna S, Joksovic PM, Lee W, Nelson MT, Naik AK, et al. Up-regulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol 2008;99:3151–56. 58. Michael E. Hildebrand, Terrance P. Snutch. Contributions of T-type calcium channels to the pathophysiology of pain signaling. Pain 2006:3(3):335–341. 59. Haitao Y, Vinicius MG, Ravil RP, Gerald WZ, Philippe D. Functional characterization and analgesic effects of mixed cannabinoid receptor/T-type channel ligands. Molecular Pain 2011;7(89):1–12. 60. Huc S, Monteil A, Bidaud I, Barbara G, Chemin J, Lory P. Regulation of T-type calcium channels: signalling pathways and functional implications. Biochim Biophys Acta 2009;1793:947–952. 61. Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P. Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J 2001;20:7033–40. 62. Park JY, Remy S, Varela J, Cooper DC, Chung S, Kang HW, et al. A post-burst after depolarization is mediated by group I metabotropic glutamate receptor- dependent upregulation of Ca (v)2 3 R-type calcium channels in CA1 pyramidal neurons. PLoS Biol 2010;8(11):1–17. 63. Naidoo V, Dai X, Galligan JJ. R-type Ca2+ channels contribute to fast synaptic excitation and action potentials in subsets of myenteric neurons in the guinea pig intestine. Neurogastroenterol Motil 2010;22: e353–363. 64. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol 2013;75:365–391. 65. Nebe J, Vanegas H, Neugebauer V, Schaible HG. Omegaagatoxin IVA, a P-type calcium channel antagonist, reduces nociceptive processing in spinal cord neurons with input from the inflamed but not from the normal knee joint-an electrophysiological study in the rat in vivo. Eur J Neurosci 1997;9:2193–2201. 66. Charles P Taylor. Mechanisms of analgesia by gabapentin and pregabalin Calcium channel α2-δ (Cavα2-δ) ligands. Pain 2009;142(1–2):13–6. 67. Ebersberger A, Portz S, Meissner W, Schaible HG, Richter F. Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura. Cephalalgia 2004 Apr; 24(4):250–61. 68. Gurkoff G, Shahlaie K, Lyeth B, Berman R. Calcium Channel Antagonists and traumatic Brain Injury. Pharmaceuticals 2013, 6(7), 788–812.