NeuroRX

, Volume 2, Issue 4, pp 662–670 | Cite as

Targeting chronic and neuropathic pain: The N-type calcium channel comes of age

Article

Summary

The rapid entry of calcium into cells through activation of voltage-gated calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals, calcium entry is the initial trigger mediating the release of neurotransmitters via the calcium-dependent fusion of synaptic vesicles and involves interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release proteins. Physiological factors or drugs that affect either presynaptic calcium channel activity or the efficacy of calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating pain signaling. The N-type calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic peptide Priait for the treatment of intractable pain. Priait is the first N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for chronic pain intervention in many years. The present review discusses the rationale behind targeting the N-type calcium channel, some of the limitations confronting the widespread clinical application of Priait, and outlines possible strategies to improve upon Prialt’s relatively narrow therapeutic window.

Key Words

N-type calcium channel Prialt chronic pain neuropathic pain ω-conotoxin 

References

  1. 1.
    Snutch TP, Peloquin J, Mathews E, McRory J. Molecular properties of voltage-gated calcium channels. In: Voltage-gated calcium (Zamponi G, ed), pp 61–94. New York: Landes Bioscience, 2005.CrossRefGoogle Scholar
  2. 2.
    Catterall WA. Biochemical studies of Ca2+ channels. In: Voltage-gated calcium (Zamponi G, ed), pp 48–60. New York: Landes Bioscience, 2005.CrossRefGoogle Scholar
  3. 3.
    Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, Catterall WA. Biochemical properties and subcellular distribution of an N-type calcium channel α1 subunit. Neuron 9: 1099–1115, 1992.PubMedCrossRefGoogle Scholar
  4. 4.
    Dunlap K, Luebke JI, Turner TJ. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci 18: 89–98, 1995.PubMedCrossRefGoogle Scholar
  5. 5.
    Janis RJ, Triggle DJ. In: Calcium channels: their properties, functions, regulation and clinical relevance. London: CRC, 1991.Google Scholar
  6. 6.
    Cahill AL, Hurley JH, Fox AP. Coexpression of cloned α(1B), β(2a), and α(2)/δ subunits produces non-inactivating calcium currents similar to those found in bovine chromaffin cells. J Neurosci 20: 1685–1693, 2000.PubMedGoogle Scholar
  7. 7.
    Stea A, Soong TW, Snutch TP. Determinants of PKC-dependent modulation of a family of neuronal calcium channels. Neuron 15: 929–940, 1995.PubMedCrossRefGoogle Scholar
  8. 8.
    Bourinet E, Soong TW, Stea A, Snutch TP. Determinants of the G-protein-dependent opioid modulation of neuronal calcium channels. Proc Natl Acad Sci USA 93: 1486–1491, 1996.PubMedCrossRefGoogle Scholar
  9. 9.
    Artalejo CR, Perlman RL, Fox AP. ω-Conotoxin GVIA blocks a Ca2+ current in bovine chromaffin cells that is not the “classic” N-type. Neuron 8: 85–95, 1992.PubMedCrossRefGoogle Scholar
  10. 10.
    Dubel SJ, Starr TVB, Hell J, Ahlijanian MK, Enyeart JJ, Catterall WA, Snutch TP. Molecular cloning of the α-1 subunit of an (ω-conotoxin-sensitive calcium channel. Proc Natl Acad Sci USA 89: 5058–5062, 1992.PubMedCrossRefGoogle Scholar
  11. 11.
    Lin Z, Haus S, Edgerton J, Lipscombe D. Identification of functionally distinct isoforms of the N-type Ca2+ channel in rat sympathetic ganglia and brain. Neuron 18: 153–166, 1997.PubMedCrossRefGoogle Scholar
  12. 12.
    Lin Z, Lin T, Schorge S, Pan JQ, Beierlein M, Lipscombe D. Alternative splicing of a short cassette exon in α1B generates functionally distinct N-type calcium channels in central and peripheral neurons. J Neurosci 19: 5322–3531, 1999.PubMedGoogle Scholar
  13. 13.
    Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, Zamponi GW, Nargeot J, Snutch TP. Phenotypic variants of P- and Q-type calcium channels are generated by alternative splicing of the α1A subunit gene. Nat Neurosci 2: 407–415, 1999.PubMedCrossRefGoogle Scholar
  14. 14.
    Kerr LM, Filloux F, Olivera BM, Jackson H, Wamsley JK. Autoradiographic localization of calcium channels with [125I] ω-conotoxin in rat brain. Eur J Pharmacol 146: 181–183, 1988.PubMedCrossRefGoogle Scholar
  15. 15.
    Beedle AM, Zamponi GW. Modulation of high voltage-activated calcium channels by G protein coupled receptors. In: Calcium channel pharmacology (McDonough SI, ed), pp 331–367. New York: Kluwer Academic/Plenum Publishers, 2004.CrossRefGoogle Scholar
  16. 16.
    Soldo BL, Moises HC. μ-Opioid receptor activation inhibits N- and P-type Ca2+ channel currents in magnocellular neurones of the rat supraoptic nucleus. J Physiol (Lond) 513: 787–804, 1998.CrossRefGoogle Scholar
  17. 17.
    Pan X, Ikeda SR, Lewis DL. Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system. Mol Pharmacol 49: 707–714, 1996.PubMedGoogle Scholar
  18. 18.
    Sun L, Miller RJ. Multiple neuropeptides Y receptors regulate K+ and Ca2+ channels in acutely isolated neurons from the rat arcuate nucleus. J Neurophysiol 81: 1391–1403, 1999.PubMedGoogle Scholar
  19. 19.
    Shapiro MS, Hille B. Substance P and somatostatin inhibit calcium currents in rat sympathetic neurons via different G protein pathways. Neuron 10: 11–20, 1993.PubMedCrossRefGoogle Scholar
  20. 20.
    Zamponi GW, Bourinet E, Nelson D, Nargeot J, Snutch TP. Crosstalk between G-proteins and protein kinase C mediated by the calcium channel α1 subunit. Nature 385: 442–446, 1997.PubMedCrossRefGoogle Scholar
  21. 21.
    Zamponi GW, Snutch TP. Decay of prepulse facilitation during G-protein inhibition of N-type calcium channels involves binding of a single Gβγ subunit. Proc Natl Acad Sci USA 95: 4035–4039, 1998.PubMedCrossRefGoogle Scholar
  22. 22.
    Patil PG, de Leon M, Reed RR, Dubel SJ, Snutch TP, Yue DT. Elementary events underlying voltage-dependent G-protein inhibition of N-type calcium channels. Biophys J 71: 2509–2521, 1996.PubMedCrossRefGoogle Scholar
  23. 23.
    Sheng ZH, Rettig J, Takahashi M, Catterall WA. Identification of a syntaxin-binding site on N-type calcium channels. Neuron 13: 1303–1313, 1994.PubMedCrossRefGoogle Scholar
  24. 24.
    Jarvis SE, Zamponi GW. Distinct molecular determinants govern syntaxin 1A-mediated inactivation and G-protein inhibition of N-type calcium channels. J Neurosci 21: 2939–2948, 2001.PubMedGoogle Scholar
  25. 25.
    Jarvis SE, Barr W, Feng Z-P, Hamid J, Zamponi GW. Molecular determinants of syntaxin 1 modulation of N-type calcium channels. J Biol Chem 277: 44399–44407, 2002.PubMedCrossRefGoogle Scholar
  26. 26.
    Cruz LJ, Olivera BM. Calcium channel antagonists. (ω-Conotoxin defines a new high affinity site. J Biol Chem 261: 6230–6233, 1986.PubMedGoogle Scholar
  27. 27.
    Olivera BM, Cruz LJ, de Santos V, LeCheminant GW, Griffin D, Zeikus R, McIntosh JM, Galyean R, Varga J, Gray WR. Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using ω-conotoxin from Conus magus venom. Biochemistry 26: 2086–2090, 1987.PubMedCrossRefGoogle Scholar
  28. 28.
    Gohil K, Bell JR, Ramachandran J, Miljanich GP. Neuroanatomical distribution of receptors for a novel voltage-sensitive calcium channel antagonist, SNX-230 (ω-conopeptide MVIIC). Brain Res 653: 258–266, 1994.PubMedCrossRefGoogle Scholar
  29. 29.
    Maggi CA, Giuliani S, Santicioli P, Tramontana M, Meli A. Effects of ω conotoxin on reflex responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder and peptide release from rat spinal cord. Neurosci 34: 243–250, 1990.CrossRefGoogle Scholar
  30. 30.
    Santicioli P, Del Biaanco E, Tramontana M, Geppetti P, Maggi CA. Release of calcitonin gene-related peptide-like immunoreactivity induced by electrical field stimulation from rat spinal afferents is mediated by conotoxin sensitive calcium channels. Neurosci Lett 136: 161–164, 1992.PubMedCrossRefGoogle Scholar
  31. 31.
    Evans AR, Nicol GD, Vasko MR. Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res 712: 265–273, 1996.PubMedCrossRefGoogle Scholar
  32. 32.
    Vanegas H, Schaible H-G. Effects of antagonists to high-threshold Ca channels upon spinal mechanisms of pain, hyperalgesia and allodynia. Pain 85: 9–18, 2000.PubMedCrossRefGoogle Scholar
  33. 33.
    Wang Y-X, Pettus M, Gao D, Phillips C, Bowersox SS. Effects of intrathecal administration of ziconotide, a selective neuronal N-type Ca channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain 84: 151–158, 2000.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang Y-X, Gao D, Pettus M, Phillips C, Bowersox SS. Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive Ca channels, with morphine on nociception in rats. Pain 84: 271–281, 2000.PubMedCrossRefGoogle Scholar
  35. 35.
    Ino M, Yoshinaga T, Wakamori M, Miyamoto N, Takahashi E, Sonoda J, Kagaya T, Oki T, Nagasu T, Nishizawa Y, Tanaka I, Imoto K, Aizawa S, Koch S, Schwartz A, Niidome T, Sawada K, Mori Y. Functional disorders of the sympathetic nervous system in mice lacking the α 1B subunit (Cav 2.2) of N-type calcium channels. Proc Natl Acad Sci USA 98: 5323–5328, 2001.PubMedCrossRefGoogle Scholar
  36. 36.
    Kim C, Jun K, Lee T, Kim S-S, McEnery MW, Chin H, Kim H-L, Park JM, Kim DW, Jung SJ, Kim J, Shin H-S. Altered nociceptive response in mice deficient in the α1B subunit of the voltage-dependent Ca channel. Mol Cell Neurosci 18: 235–245, 2001.PubMedCrossRefGoogle Scholar
  37. 37.
    Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, Han W, Toriyama H, Tanabe T. Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca channel. EMBO J 20: 2349–2356, 2001.PubMedCrossRefGoogle Scholar
  38. 38.
    Saegusa H, Matsuda Y, Tanabe T. Effects of ablation of N- and R-type Ca(2+) channels on pain transmission. Neurosci Res 43: 1–7, 2002.PubMedCrossRefGoogle Scholar
  39. 39.
    Brose WG, Gutlove DP, Luther RR, Bowersox SS, McGuire D. Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain. Clin J Pain 13: 256–259, 1997.PubMedCrossRefGoogle Scholar
  40. 40.
    Mathur VS. Ziconotide: a new pharmacological class of drug for the management of pain. Semin Anesthesia Perioperative Med Pain 19: 67–75, 2000.CrossRefGoogle Scholar
  41. 41.
    Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce D, Mangieri EA, Luther RR, Mayo M, McGuire D, Ellis D. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA 291: 63–70, 2004.PubMedCrossRefGoogle Scholar
  42. 42.
    Ridgeway B, Wallace M, Gerayli A. Ziconotide for the treatment of severe spasticity after spinal cord injury. Pain 85: 287–289, 2000.PubMedCrossRefGoogle Scholar
  43. 43.
    McGuire D, Bowersox S, Fellmann JD, Luther RR. Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium channel blockade: first demonstration of N-channel function in humans. J Cardiovasc Pharmacol 30: 400–403, 1997.PubMedCrossRefGoogle Scholar
  44. 44.
    Malmberg AB, Yaksh TL. Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception. J Neurosci 14: 4882–4890, 1994.PubMedGoogle Scholar
  45. 45.
    Schroeder JE, McCleskey EW. Inhibition of Ca2+ currents by a μ-opiod in a defined subset of rat sensory neurons. J Neurosci 13: 867–873, 1993.PubMedGoogle Scholar
  46. 46.
    Westenbroek RE, Hoskins L, Catterall WA. Localization of Ca2+ channel subtypes on rat spinal motor neurons, intemeurons, and nerve terminals. J Neurosci 18: 6319–6330, 1998.PubMedGoogle Scholar
  47. 47.
    Murakami M, Nakagawasai O, Suzuki T, Mobarakeh II, Sakurada Y, Murata A, Yamadera F, Miyoshi I, Yanai K, Tan-No K, Sasano H, Tadano T, Iijima T. Antinociceptive effect of different types of Ca channel inhibitors and the distribution of various Ca channel α1 subunits in the dorsal horn of spinal cord in mice. Brain Res 1024: 122–129, 2004.PubMedCrossRefGoogle Scholar
  48. 48.
    Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci 25: 319–325, 2002.PubMedCrossRefGoogle Scholar
  49. 49.
    Urban MO, Ren K, Sablad M, Park KT. Medullary N-type and P/Q-type Ca channels contribute to neuropathy-induced allodynia. Neuroreport 16: 563–566, 2005.PubMedCrossRefGoogle Scholar
  50. 50.
    Hille B. Ionic channels of excitable membranes. Sunderland, MA: Sinauer Associates, 2001.Google Scholar
  51. 51.
    Bean BP. Nitrendipine block of cardiac calcium channels: high-affinity binding to the inactivated state. Proc Natl Acad Sci USA 81: 6388–6392, 1984.PubMedCrossRefGoogle Scholar
  52. 52.
    Stocker JW, Nadasdi L, Aldrich RW, Tsien RW. Preferential interaction of (ω-conotoxins with inactivated N-type Ca2+ channels. J Neurosci 17: 3002–3013, 1997.PubMedGoogle Scholar
  53. 53.
    Feng Z-P, Doering CJ, Winkfein RJ, Beedle AM, Spafford JD, Zamponi GW. Determinants of inhibition of transiently expressed voltage-gated calcium channels by (ω-conotoxins GVIA and MVIIA. J Biol Chem 278: 20171–20178, 2003.PubMedCrossRefGoogle Scholar
  54. 54.
    Lewis RJ, Nielsen KJ, Craik DJ, Loughnan ML, Adams DA, Sharpe IA, Luchian T, Adams DJ, Bond T, Thomas L, Jones A, Matheson JL, Drinkwater R, Andrews PR, Alewood PF. Novel (ω-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. J Biol Chem 275: 35335–35344, 2000.PubMedCrossRefGoogle Scholar
  55. 55.
    Scott DA, Wright CE, Angus JA. Actions of intrathecal ω-conotoxins CVID, GVIA, MVIIA, and morphine in acute and neuropathic pain in the rat. Eur J Pharmacol 451: 279–286, 2002.PubMedCrossRefGoogle Scholar
  56. 56.
    Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain 96: 119–127, 2002.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen J-Q, Zhang Y-Q, Dai J, Luo Z-M, Liang S-P. Antinociceptive effects of intrathecally administered huwentoxin-I, a selective N-type Ca channel blocker, in the formalin test in conscious rats. Toxicon 45: 15–20, 2005.PubMedCrossRefGoogle Scholar
  58. 58.
    Uhrenholt TR, Nedergaard OV. Involvement of different calcium channels in the depolarization-evoked release of noradrenaline from sympathetic neurones in rabbit carotid artery. Basic Clin Pharm Tox 97: 109–114, 2005.CrossRefGoogle Scholar
  59. 59.
    Morris JL, Ozols DI, Lewis RJ, Gibbins IL, Jobling P. Differential involvement of N-type Ca channels in transmitter release from vasoconstrictor and vasodilator neurons. Br J Pharmacol 141: 961–970, 2004.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2005

Authors and Affiliations

  1. 1.Michael Smith LaboratoriesUniversity of British ColumbiaVancouverCanada

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