Abstract
Biological, genetic, and clinical data provide compelling proof for N-type voltage-gated calcium channels (CaV2.2) as therapeutic targets for chronic pain. While decreasing channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse effects. Targeting regulators of channel activity may facilitate improved analgesic properties associated with channel block and afford a broader therapeutic window. Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al., Nature Medicine 17:822–829 (2011)]. Rodents administered CBD3 intraperitoneally, fused to the HIV TAT protein cell penetrating domain, exhibited antinociception lasting ∼4 hours highlighting potential instability, limited oral bioavailability, and/or rapid elimination of peptide. This report focuses on improving upon the parental CBD3 peptide. Using SPOTScan analysis of synthetic versions of the parental CBD3 peptide, we identified peptides harboring single amino acid mutations that bound with greater affinity to CaV2.2. One such peptide, harboring a phenylalanine instead of glycine (G14F), was tested in rodent models of migraine and neuropathic pain. In vivo laser Doppler blood flowmetry measure of capsaicin-induced meningeal vascular responses related to headache pain was almost completely suppressed by dural application of the G14F peptide. The G14F mutant peptide, administered intraperitoneally, also exhibited greater antinociception in Stavudine (2′-3′-didehydro-2′-3′-dideoxythymidine (d4T)/Zerit®) model of AIDS therapy-induced peripheral neuropathy compared to the parent CBD3 peptide. These results demonstrate the patent translational value of small biologic drugs targeting CaV2.2 for management of clinical pain.
[1] Institute of medicine report from the committee on advancing pain research care and education, Relieving pain in America: A blueprint for transforming prevention, care, education and research, The National Academies Press, 2011 Search in Google Scholar
[2] Snutch T. P., Targeting chronic and neuropathic pain: the N-type calcium channel comes of age, NeuroRx, 2005, 2, 662–670 http://dx.doi.org/10.1602/neurorx.2.4.66210.1602/neurorx.2.4.662Search in Google Scholar
[3] Catterall W. A., Few A. P., Calcium channel regulation and presynaptic plasticity, Neuron, 2008, 59, 882–901 http://dx.doi.org/10.1016/j.neuron.2008.09.00510.1016/j.neuron.2008.09.005Search in Google Scholar
[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 Ca2+ channel, EMBO J., 2001, 20, 2349–2356 http://dx.doi.org/10.1093/emboj/20.10.234910.1093/emboj/20.10.2349Search in Google Scholar
[5] Cizkova D., Marsala J., Lukacova N., Marsala M., Jergova S., Orendacova J. et al., Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury, Exp. Brain Res., 2002, 147, 456–463 http://dx.doi.org/10.1007/s00221-002-1217-310.1007/s00221-002-1217-3Search in Google Scholar
[6] Bell T. J., Thaler C., Castiglioni A. J., Helton T. D., Lipscombe D., Cellspecific alternative splicing increases calcium channel current density in the pain pathway, Neuron, 2004, 41, 127–138 http://dx.doi.org/10.1016/S0896-6273(03)00801-810.1016/S0896-6273(03)00801-8Search in Google Scholar
[7] Altier C., Dale C. S., Kisilevsky A. E., Chapman K., Castiglioni A. J., Matthews E. A. et al., Differential role of N-type calcium channel splice isoforms in pain, J. Neurosci., 2007, 27, 6363–6373 http://dx.doi.org/10.1523/JNEUROSCI.0307-07.200710.1523/JNEUROSCI.0307-07.2007Search in Google Scholar PubMed PubMed Central
[8] Zamponi G. W., Feng Z. P., Zhang L., Pajouhesh H., Ding Y., Belardetti F. et al. Scaffold-based design and synthesis of potent N-type calcium channel blockers, Bioorg. Med. Chem. Lett., 2009, 19, 6467–6472 http://dx.doi.org/10.1016/j.bmcl.2009.09.00810.1016/j.bmcl.2009.09.008Search in Google Scholar PubMed
[9] Zamponi G. W., Lewis R. J., Todorovic S. M., Arneric S. P., Snutch T. P., Role of voltage-gated calcium channels in ascending pain pathways, Brain Res. Rev., 2009, 60, 84–89 http://dx.doi.org/10.1016/j.brainresrev.2008.12.02110.1016/j.brainresrev.2008.12.021Search in Google Scholar PubMed PubMed Central
[10] Swensen A. M., Herrington J., Bugianesi R. M., Dai G., Haedo R. J., Ratliff K. S. et al., Characterization of the substituted N-triazole oxindole, TROX-1, a small molecule, state-dependent inhibitor of CaV2 calcium channels, Mol. Pharmacol., 2011 epub ahead of print 10.1124/mol.111.075226Search in Google Scholar PubMed
[11] Abbadie C., McManus O. B., Sun S. Y., Bugianesi R. M., Dai G., Haedo R. J. et al., Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker, J. Pharmacol. Exp. Ther., 2010, 334, 545–555 http://dx.doi.org/10.1124/jpet.110.16636310.1124/jpet.110.166363Search in Google Scholar PubMed
[12] Bauer C. S., Nieto-Rostro M., Rahman W., Tran-Van-Minh A., Ferron L., Douglas L. et al., The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin, J. Neurosci., 2009, 29, 4076–4088 http://dx.doi.org/10.1523/JNEUROSCI.0356-09.200910.1523/JNEUROSCI.0356-09.2009Search in Google Scholar PubMed PubMed Central
[13] Brittain J. M., Piekarz A. D., Wang Y., Kondo T., Cummins T. R., Khanna R., An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltagegated Ca2+ channels, J. Biol. Chem., 2009, 284, 31375–31390 http://dx.doi.org/10.1074/jbc.M109.00995110.1074/jbc.M109.009951Search in Google Scholar PubMed PubMed Central
[14] Chi X. X., Schmutzler B. S., Brittain J. M., Hingtgen C. M., Nicol G. D., Khanna R., Regulation of N-type voltage-gated calcium (CaV2.2) channels and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons, J. Cell. Sci., 2009, 23, 4351–4362 http://dx.doi.org/10.1242/jcs.05328010.1242/jcs.053280Search in Google Scholar PubMed PubMed Central
[15] Hensley K., Venkova K., Christov A., Gunning W., Park J., Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications, Mol. Neurobiol., 2011, 43, 180–191 http://dx.doi.org/10.1007/s12035-011-8166-410.1007/s12035-011-8166-4Search in Google Scholar PubMed
[16] Inagaki N., Chihara K., Arimura N., Ménager C., Kawano Y., Matsuo N. et al., CRMP-2 induces axons in cultured hippocampal neurons, Nat. Neurosci., 2001, 4, 781–782 http://dx.doi.org/10.1038/9047610.1038/90476Search in Google Scholar PubMed
[17] Arimura N., Hattori A., Kimura T., Nakamuta S., Funahashi Y., Hirotsune S. et al., CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity, J. Neurochem., 2009, 111, 380–390 http://dx.doi.org/10.1111/j.1471-4159.2009.06317.x10.1111/j.1471-4159.2009.06317.xSearch in Google Scholar PubMed
[18] Morita T., Sobue K., Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway, J. Biol. Chem., 2009, 284, 27734–27745 http://dx.doi.org/10.1074/jbc.M109.00817710.1074/jbc.M109.008177Search in Google Scholar PubMed PubMed Central
[19] Yoshimura T., Kawano Y., Arimura N., Kawabata S., Kikuchi A., Kaibuchi K., GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity, Cell, 2005, 120, 137–149 http://dx.doi.org/10.1016/j.cell.2004.11.01210.1016/j.cell.2004.11.012Search in Google Scholar PubMed
[20] Wang Y., Brittain J. M., Wilson S. M., Khanna R., Emerging roles of collapsin response mediator proteins (CRMPs) as regulators of voltage-gated calcium channels and synaptic transmission, Commun. Integr. Biol., 2010, 3, 1–4 http://dx.doi.org/10.4161/cib.3.1.969410.4161/cib.3.1.9694Search in Google Scholar PubMed PubMed Central
[21] Brittain J. M., Duarte D. B., Wilson S. M., Zhu W., Ballard C., Johnson P. L. et al., Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2+) channel complex, Nat. Med., 2011, 17, 822–829 http://dx.doi.org/10.1038/nm.234510.1038/nm.2345Search in Google Scholar PubMed PubMed Central
[22] Wilson S. M., Brittain J. M., Piekarz A. D., Ballard C. J., Ripsch M. S., Cummins T. R. et al., Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex, Channels (Austin), 2011, 5, 449–456 http://dx.doi.org/10.4161/chan.5.5.1736310.4161/chan.5.5.17363Search in Google Scholar PubMed PubMed Central
[23] Kurosawa M., Messlinger K., Pawlak M., Schmidt R. F., Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene-related peptide, Br. J. Pharmacol., 1995, 114, 1397–1402 10.1111/j.1476-5381.1995.tb13361.xSearch in Google Scholar PubMed PubMed Central
[24] Gottselig R., Messlinger K., Noxious chemical stimulation of rat facial mucosa increases intracranial blood flow through a trigemino-parasympathetic reflex—an experimental model for vascular dysfunctions in cluster headache, Cephalalgia, 2004, 24, 206–214 http://dx.doi.org/10.1111/j.1468-2982.2004.00649.x10.1111/j.1468-2982.2004.00649.xSearch in Google Scholar PubMed
[25] Joseph E. K., Chen X., Khasar S. G., Levine J. D., Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat, Pain, 2004, 107, 147–158 http://dx.doi.org/10.1016/j.pain.2003.10.01010.1016/j.pain.2003.10.010Search in Google Scholar PubMed
[26] LaMotte R. H., Friedman R. M., Lu C., Khalsa P. S., Srinivasan M. A., Raised object on a planar surface stroked across the fingerpad: responses of cutaneous mechanoreceptors to shape and orientation, J. Neurophysiol., 1998, 80, 2446–2466 10.1152/jn.1998.80.5.2446Search in Google Scholar PubMed
[27] Ma C., Shu Y., Zheng Z., Chen Y., Yao H., Greenquist K. W. et al., Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons, J. Neurophysiol., 2003, 89, 1588–1602 http://dx.doi.org/10.1152/jn.00855.200210.1152/jn.00855.2002Search in Google Scholar PubMed
[28] Goadsby P. J., Calcitonin gene-related peptide (CGRP) antagonists and migraine: is this a new era?, Neurology, 2008, 70, 1300–1301 http://dx.doi.org/10.1212/01.wnl.0000309214.25038.fd10.1212/01.wnl.0000309214.25038.fdSearch in Google Scholar PubMed
[29] Olesen J., Diener H. C., Husstedt I. W., Goadsby P. J., Hall D., Meier U. et al., Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine, N. Engl. J. Med., 2004, 350, 1104–1110 http://dx.doi.org/10.1056/NEJMoa03050510.1056/NEJMoa030505Search in Google Scholar PubMed
[30] Xiao Y., Richter J. A., Hurley J. H., Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling, Mol. Pain, 2008, 4, 12 http://dx.doi.org/10.1186/1744-8069-4-1210.1186/1744-8069-4-12Search in Google Scholar PubMed PubMed Central
[31] Kunkler P. E., Ballard C. J., Oxford G. S., Hurley J. H., TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation, Pain, 2011, 152, 38–44 http://dx.doi.org/10.1016/j.pain.2010.08.02110.1016/j.pain.2010.08.021Search in Google Scholar PubMed PubMed Central
[32] Bhangoo S. K., Ripsch M. S., Buchanan D. J., Miller R. J., White F. A., Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy, Mol. Pain, 2009, 5, 48 http://dx.doi.org/10.1186/1744-8069-5-4810.1186/1744-8069-5-48Search in Google Scholar
[33] Westenbroek R. E., Hoskins L., Catterall W. A.. Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals, J. Neurosci., 1998, 18, 6319–6330 10.1523/JNEUROSCI.18-16-06319.1998Search in Google Scholar
[34] Kerr L. M., Filloux F., Olivera B. M., Jackson H., Wamsley J. K., Autoradiographic localization of calcium channels with [125I] omega-conotoxin in rat brain, Eur. J. Pharmacol., 1988, 146, 181–183 http://dx.doi.org/10.1016/0014-2999(88)90501-810.1016/0014-2999(88)90501-8Search in Google Scholar
[35] Heinke B., Balzer E., Sandkuhler J., Pre- and postsynaptic contributions of voltage-dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neurons, Eur. J. Neurosci., 2004, 19, 103–111 http://dx.doi.org/10.1046/j.1460-9568.2003.03083.x10.1046/j.1460-9568.2003.03083.xSearch in Google Scholar
[36] Akerman S., Williamson D. J., Goadsby P. J., Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism, Br. J. Pharmacol., 2003, 140, 558–566 http://dx.doi.org/10.1038/sj.bjp.070545610.1038/sj.bjp.0705456Search in Google Scholar
[37] Dux M., Santha P., Jancso G., Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat, J. Physiol., 2003, 552, 859–867 http://dx.doi.org/10.1113/jphysiol.2003.05063310.1113/jphysiol.2003.050633Search in Google Scholar
[38] Zimmermann K., Reeh P. W., Averbeck B., S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 release from isolated rat dura mater, Pain, 2003, 103, 313–320 http://dx.doi.org/10.1016/S0304-3959(02)00459-110.1016/S0304-3959(02)00459-1Search in Google Scholar
[39] Peitl B., Petho G., Porszasz R., Nemeth J., Szolcsanyi J., Capsaicininsensitive sensory-efferent meningeal vasodilatation evoked by electrical stimulation of trigeminal nerve fibres in the rat, Br. J. Pharmacol., 1999, 127, 457–467 http://dx.doi.org/10.1038/sj.bjp.070256110.1038/sj.bjp.0702561Search in Google Scholar PubMed PubMed Central
[40] Eikermann-Haerter K., Moskowitz M. A., Animal models of migraine headache and aura, Curr. Opin. Neurol., 2008, 21, 294–300 http://dx.doi.org/10.1097/WCO.0b013e3282fc25de10.1097/WCO.0b013e3282fc25deSearch in Google Scholar PubMed
[41] Reuter U., Sanchez del R. M., Moskowitz M. A., Experimental models of migraine, Funct. Neurol., 2000, 15(Suppl 3), 9–18 Search in Google Scholar
[42] Panconesi A., Bartolozzi M. L., Guidi L., Migraine pain: reflections against vasodilatation, J. Headache Pain, 2009, 10, 317–325 http://dx.doi.org/10.1007/s10194-009-0130-610.1007/s10194-009-0130-6Search in Google Scholar PubMed PubMed Central
[43] Strassman A. M., Levy D., Response properties of dural nociceptors in relation to headache, J. Neurophysiol., 2006, 95, 1298–1306 http://dx.doi.org/10.1152/jn.01293.200510.1152/jn.01293.2005Search in Google Scholar PubMed
[44] Moyle G. J., Sadler M., Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management, Drug Saf., 1998, 19, 481–494 http://dx.doi.org/10.2165/00002018-199819060-0000510.2165/00002018-199819060-00005Search in Google Scholar PubMed
[45] Deo R. C., Schmidt E. F., Elhabazi A., Togashi H., Burley S. K., Strittmatter S. M., Structural bases for CRMP function in plexin-dependent semaphorin3A signaling, EMBO J., 2004, 23, 9–22 http://dx.doi.org/10.1038/sj.emboj.760002110.1038/sj.emboj.7600021Search in Google Scholar PubMed PubMed Central
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