{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T12:28:08Z","timestamp":1764332888763,"version":"3.37.3"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T00:00:00Z","timestamp":1589155200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T00:00:00Z","timestamp":1589155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["1R01NS098772"],"award-info":[{"award-number":["1R01NS098772"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA90265"],"award-info":[{"award-number":["R01CA90265"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Brain"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium\u00a0channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the <jats:italic>ent<\/jats:italic>-kaurane diterpenoid, geopyxin A, 1-<jats:italic>O<\/jats:italic>-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of\u00a0voltage-gated sodium and calcium channels, 1-<jats:italic>O<\/jats:italic>-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-<jats:italic>O<\/jats:italic>-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.<\/jats:p>","DOI":"10.1186\/s13041-020-00616-2","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T13:02:55Z","timestamp":1589202175000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain"],"prefix":"10.1186","volume":"13","author":[{"given":"Yuan","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E. M. Kithsiri","family":"Wijeratne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingshi","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shreya S.","family":"Bellampalli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shizhen","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aubin","family":"Moutal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. A. Leslie","family":"Gunatilaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9066-2969","authenticated-orcid":false,"given":"Rajesh","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,5,11]]},"reference":[{"issue":"9169","key":"616_CR1","doi-asserted-by":"publisher","first-page":"2051","DOI":"10.1016\/S0140-6736(99)03313-9","volume":"353","author":"DB Carr","year":"1999","unstructured":"Carr DB, Goudas LC. Acute pain. Lancet. 1999;353(9169):2051\u20138.","journal-title":"Lancet."},{"key":"616_CR2","volume-title":"Relieving pain in America: a blueprint for transforming prevention, care, education, and research","author":"Institute of Medicine (US) Committee on Advancing Pain Research Cr, and Education","year":"2011","unstructured":"Institute of Medicine (US) Committee on Advancing Pain Research Cr, and Education. Relieving pain in America: a blueprint for transforming prevention, care, education, and research; 2011."},{"issue":"11","key":"616_CR3","doi-asserted-by":"publisher","first-page":"3742","DOI":"10.1172\/JCI45178","volume":"120","author":"CJ Woolf","year":"2010","unstructured":"Woolf CJ. What is this thing called pain? J Clin Invest. 2010;120(11):3742\u20134.","journal-title":"J Clin Invest"},{"issue":"1","key":"616_CR4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr6501e1","volume":"65","author":"D Dowell","year":"2016","unstructured":"Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1\u201349.","journal-title":"MMWR Recomm Rep"},{"issue":"3","key":"616_CR5","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1021\/np200769q","volume":"75","author":"EM Wijeratne","year":"2012","unstructured":"Wijeratne EM, Bashyal BP, Liu MX, Rocha DD, Gunaherath GM, U'Ren JM, et al. Geopyxins A-E, ent-kaurane diterpenoids from endolichenic fungal strains Geopyxis aff. Majalis and Geopyxis sp. AZ0066: structure-activity relationships of geopyxins and their analogues. J Nat Prod. 2012;75(3):361\u20139.","journal-title":"J Nat Prod"},{"issue":"5","key":"616_CR6","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1021\/np9903705","volume":"63","author":"AJ Hou","year":"2000","unstructured":"Hou AJ, Li ML, Jiang B, Lin ZW, Ji SY, Zhou YP, et al. New 7,20:14,20-diepoxy ent-kauranoids from Isodon xerophilus. J Nat Prod. 2000;63(5):599\u2013601.","journal-title":"J Nat Prod"},{"issue":"3","key":"616_CR7","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1021\/np060504w","volume":"70","author":"S Rosselli","year":"2007","unstructured":"Rosselli S, Bruno M, Maggio A, Bellone G, Chen TH, Bastow KF, et al. Cytotoxic activity of some natural and synthetic ent-kauranes. J Nat Prod. 2007;70(3):347\u201352.","journal-title":"J Nat Prod"},{"issue":"2","key":"616_CR8","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1055\/s-0029-1186002","volume":"76","author":"N Bai","year":"2010","unstructured":"Bai N, He K, Zhou Z, Tsai ML, Zhang L, Quan Z, et al. Ent-kaurane diterpenoids from Rabdosia rubescens and their cytotoxic effects on human cancer cell lines. Planta Med. 2010;76(2):140\u20135.","journal-title":"Planta Med"},{"key":"616_CR9","doi-asserted-by":"publisher","unstructured":"Aimond A, Calabro K, Audoin C, et al. Cytotoxic and Anti-Inflammatory Effects of Ent-Kaurane Derivatives Isolated from the Alpine Plant Sideritis hyssopifolia. Molecules (Basel, Switzerland). 2020;25(3). https:\/\/doi.org\/10.3390\/molecules25030589.","DOI":"10.3390\/molecules25030589"},{"issue":"10","key":"616_CR10","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1055\/s-2005-871234","volume":"71","author":"SH Yeh","year":"2005","unstructured":"Yeh SH, Chang FR, Wu YC, Yang YL, Zhuo SK, Hwang TL. An anti-inflammatory ent-kaurane from the stems of Annona squamosa that inhibits various human neutrophil functions. Planta Med. 2005;71(10):904\u20139.","journal-title":"Planta Med"},{"issue":"5","key":"616_CR11","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1055\/s-2001-15808","volume":"67","author":"BY Hwang","year":"2001","unstructured":"Hwang BY, Lee JH, Koo TH, Kim HS, Hong YS, Ro JS, et al. Kaurane diterpenes from Isodon japonicus inhibit nitric oxide and prostaglandin E2 production and NF-kappaB activation in LPS-stimulated macrophage RAW264.7 cells. Planta Med. 2001;67(5):406\u201310.","journal-title":"Planta Med"},{"issue":"1","key":"616_CR12","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1021\/np0304114","volume":"67","author":"LC Meade-Tollin","year":"2004","unstructured":"Meade-Tollin LC, Wijeratne EM, Cooper D, Guild M, Jon E, Fritz A, et al. Ponicidin and oridonin are responsible for the antiangiogenic activity of Rabdosia rubescens, a constituent of the herbal supplement PC SPES. J Nat Prod. 2004;67(1):2\u20134.","journal-title":"J Nat Prod"},{"issue":"7","key":"616_CR13","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1055\/s-0029-1240683","volume":"76","author":"S Saepou","year":"2010","unstructured":"Saepou S, Pohmakotr M, Reutrakul V, Yoosook C, Kasisit J, Napaswad C, et al. Anti-HIV-1 diterpenoids from leaves and twigs of Polyalthia sclerophylla. Planta Med. 2010;76(7):721\u20135.","journal-title":"Planta Med"},{"issue":"3","key":"616_CR14","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1021\/np800671p","volume":"72","author":"A Erta\u015f","year":"2009","unstructured":"Erta\u015f A, Ozt\u00fcrk M, Bo\u011fa M, Top\u00e7u G. Antioxidant and anticholinesterase activity evaluation of ent-kaurane diterpenoids from Sideritis arguta. J Nat Prod. 2009;72(3):500\u20132.","journal-title":"J Nat Prod"},{"issue":"11","key":"616_CR15","doi-asserted-by":"publisher","first-page":"1930","DOI":"10.1021\/np800564z","volume":"71","author":"HH Ko","year":"2008","unstructured":"Ko HH, Chang WL, Lu TM. Antityrosinase and antioxidant effects of ent-kaurane diterpenes from leaves of Broussonetia papyrifera. J Nat Prod. 2008;71(11):1930\u20133.","journal-title":"J Nat Prod"},{"issue":"1","key":"616_CR16","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1097\/j.pain.0000000000001385","volume":"160","author":"SS Bellampalli","year":"2019","unstructured":"Bellampalli SS, Ji Y, Moutal A, Cai S, Wijeratne EMK, Gandini MA, et al. Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury-associated peripheral sensory neuropathy via block of N- and T-type calcium channels. Pain. 2019;160(1):117\u201335.","journal-title":"Pain."},{"issue":"3","key":"616_CR17","doi-asserted-by":"publisher","first-page":"1716","DOI":"10.1021\/acschemneuro.8b00617","volume":"10","author":"S Cai","year":"2019","unstructured":"Cai S, Bellampalli SS, Yu J, Li W, Ji Y, Wijeratne EMK, et al. (\u2212)-Hardwickiic acid and Hautriwaic acid induce Antinociception via blockade of Tetrodotoxin-sensitive voltage-dependent sodium channels. ACS Chem Nerosci. 2019;10(3):1716\u201328.","journal-title":"ACS Chem Nerosci"},{"issue":"6","key":"616_CR18","doi-asserted-by":"publisher","first-page":"2939","DOI":"10.1021\/acschemneuro.9b00166","volume":"10","author":"Z Shan","year":"2019","unstructured":"Shan Z, Cai S, Yu J, Zhang Z, Vallecillo TGM, Serafini MJ, et al. Reversal of peripheral neuropathic pain by the small-molecule natural product Physalin F via block of CaV2.3 (R-type) and CaV2.2 (N-type) voltage-gated calcium channels. ACS Chem Nerosci. 2019;10(6):2939\u201355.","journal-title":"ACS Chem Nerosci"},{"issue":"5","key":"616_CR19","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1016\/j.cell.2012.03.041","volume":"149","author":"DG Wheeler","year":"2012","unstructured":"Wheeler DG, Groth RD, Ma H, Barrett CF, Owen SF, Safa P, et al. Ca(V)1 and ca(V)2 channels engage distinct modes of ca (2+) signaling to control CREB-dependent gene expression. Cell. 2012;149(5):1112\u201324.","journal-title":"Cell."},{"issue":"24","key":"616_CR20","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1042\/CS20160041","volume":"130","author":"AH Kanellopoulos","year":"2016","unstructured":"Kanellopoulos AH, Matsuyama A. Voltage-gated sodium channels and pain-related disorders. Clin Sci (Lond). 2016;130(24):2257\u201365.","journal-title":"Clin Sci (Lond)"},{"issue":"52","key":"616_CR21","doi-asserted-by":"publisher","first-page":"E8443","DOI":"10.1073\/pnas.1610531113","volume":"113","author":"ET Dustrude","year":"2016","unstructured":"Dustrude ET, Moutal A, Yang X, Wang Y, Khanna M, Khanna R. Hierarchical CRMP2 posttranslational modifications control NaV1.7 function. Proc Natl Acad Sci U S A. 2016;113(52):E8443\u2013E52.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"616_CR22","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.neulet.2014.12.056","volume":"596","author":"JG Hoeijmakers","year":"2015","unstructured":"Hoeijmakers JG, Faber CG, Merkies IS, Waxman SG. Painful peripheral neuropathy and sodium channel mutations. Neurosci Lett. 2015;596:51\u20139.","journal-title":"Neurosci Lett"},{"issue":"11","key":"616_CR23","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1016\/S1474-4422(14)70150-4","volume":"13","author":"SG Waxman","year":"2014","unstructured":"Waxman SG, Merkies ISJ, Gerrits MM, Dib-Hajj SD, Lauria G, Cox JJ, et al. Sodium channel genes in pain-related disorders: phenotype-genotype associations and recommendations for clinical use. Lancet Neurol. 2014;13(11):1152\u201360.","journal-title":"Lancet Neurol"},{"issue":"2","key":"616_CR24","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/sj.emboj.7600515","volume":"24","author":"E Bourinet","year":"2005","unstructured":"Bourinet E, Alloui A, Monteil A, Barr\u00e8re C, Couette B, Poirot O, et al. Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception. EMBO J. 2005;24(2):315\u201324.","journal-title":"EMBO J"},{"issue":"6","key":"616_CR25","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1152\/jn.01031.2007","volume":"99","author":"MM Jagodic","year":"2008","unstructured":"Jagodic MM, Pathirathna S, Joksovic PM, Lee W, Nelson MT, Naik AK, et al. Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve. J Neurophysiol. 2008;99(6):3151\u20136.","journal-title":"J Neurophysiol"},{"issue":"3","key":"616_CR26","first-page":"1117","volume":"269","author":"SR Chaplan","year":"1994","unstructured":"Chaplan SR, Pogrel JW, Yaksh TL. Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther. 1994;269(3):1117\u201323.","journal-title":"J Pharmacol Exp Ther"},{"issue":"6","key":"616_CR27","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1002\/ana.24139","volume":"75","author":"SB Yuan","year":"2014","unstructured":"Yuan SB, Shi Y, Chen J, Zhou X, Li G, Gelman BB, et al. Gp120 in the pathogenesis of human immunodeficiency virus-associated pain. Ann Neurol. 2014;75(6):837\u201350.","journal-title":"Ann Neurol"},{"issue":"8","key":"616_CR28","doi-asserted-by":"publisher","first-page":"2808","DOI":"10.1523\/JNEUROSCI.21-08-02808.2001","volume":"21","author":"ED Milligan","year":"2001","unstructured":"Milligan ED, O'Connor KA, Nguyen KT, Armstrong CB, Twining C, Gaykema RP, et al. Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci. 2001;21(8):2808\u201319.","journal-title":"J Neurosci"},{"key":"616_CR29","doi-asserted-by":"publisher","first-page":"e48118","DOI":"10.7554\/eLife.48118","volume":"8","author":"S Lee","year":"2019","unstructured":"Lee S, Jo S, Talbot S, Zhang HB, Kotoda M, Andrews NA, et al. Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation. Elife. 2019;8:e48118.","journal-title":"Elife."},{"issue":"2","key":"616_CR30","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0920-1211(93)90023-Z","volume":"16","author":"DM Rock","year":"1993","unstructured":"Rock DM, Kelly KM, Macdonald RL. Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons. Epilepsy Res. 1993;16(2):89\u201398.","journal-title":"Epilepsy Res"},{"issue":"2","key":"616_CR31","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.cell.2009.09.025","volume":"139","author":"C Eroglu","year":"2009","unstructured":"Eroglu C, Allen NJ, Susman MW, O'Rourke NA, Park CY, Ozkan E, et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139(2):380\u201392.","journal-title":"Cell."},{"issue":"9","key":"616_CR32","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1016\/j.celrep.2018.02.021","volume":"22","author":"J Chen","year":"2018","unstructured":"Chen J, Li L, Chen SR, Chen H, Xie JD, Sirrieh RE, et al. The alpha2delta-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions. Cell Rep. 2018;22(9):2307\u201321.","journal-title":"Cell Rep"},{"issue":"6","key":"616_CR33","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.neuron.2008.09.005","volume":"59","author":"WA Catterall","year":"2008","unstructured":"Catterall WA, Few AP. Calcium channel regulation and presynaptic plasticity. Neuron. 2008;59(6):882\u2013901.","journal-title":"Neuron."},{"issue":"6","key":"616_CR34","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1016\/0896-6273(92)90069-P","volume":"9","author":"RE Westenbroek","year":"1992","unstructured":"Westenbroek RE, Hell JW, Warner C, Dubel SJ, Snutch TP, Catterall WA. Biochemical properties and subcellular distribution of an N-type calcium channel alpha 1 subunit. Neuron. 1992;9(6):1099\u2013115.","journal-title":"Neuron."},{"issue":"3","key":"616_CR35","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/S0896-6273(03)00430-6","volume":"39","author":"D Dietrich","year":"2003","unstructured":"Dietrich D, Kirschstein T, Kukley M, Pereverzev A, von der Brelie C, Schneider T, et al. Functional specialization of presynaptic Cav2.3 Ca2+ channels. Neuron. 2003;39(3):483\u201396.","journal-title":"Neuron."},{"issue":"4","key":"616_CR36","doi-asserted-by":"publisher","first-page":"2810","DOI":"10.1074\/jbc.M111.290882","volume":"287","author":"N Weiss","year":"2012","unstructured":"Weiss N, Hameed S, Fernandez-Fernandez JM, Fablet K, Karmazinova M, Poillot C, et al. A ca(v)3.2\/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis. J Biol Chem. 2012;287(4):2810\u20138.","journal-title":"J Biol Chem"},{"issue":"1","key":"616_CR37","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.tips.2008.10.004","volume":"30","author":"MC Iftinca","year":"2009","unstructured":"Iftinca MC, Zamponi GW. Regulation of neuronal T-type calcium channels. Trends Pharmacol Sci. 2009;30(1):32\u201340.","journal-title":"Trends Pharmacol Sci"},{"issue":"3","key":"616_CR38","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1523\/JNEUROSCI.3145-09.2010","volume":"30","author":"P Fossat","year":"2010","unstructured":"Fossat P, Dobremez E, Bouali-Benazzouz R, Favereaux A, Bertrand SS, Kilk K, et al. Knockdown of L calcium channel subtypes: differential effects in neuropathic pain. J Neurosci. 2010;30(3):1073\u201385.","journal-title":"J Neurosci"},{"issue":"4","key":"616_CR39","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1007\/s00221-002-1217-3","volume":"147","author":"D Cizkova","year":"2002","unstructured":"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(4):456\u201363.","journal-title":"Exp Brain Res"},{"issue":"6","key":"616_CR40","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1523\/JNEUROSCI.21-06-01868.2001","volume":"21","author":"ZD Luo","year":"2001","unstructured":"Luo ZD, Chaplan SR, Higuera ES, Sorkin LS, Stauderman KA, Williams ME, et al. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 2001;21(6):1868\u201375.","journal-title":"J Neurosci"},{"issue":"1\u20132","key":"616_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0169-328X(01)00188-7","volume":"95","author":"RA Newton","year":"2001","unstructured":"Newton RA, Bingham S, Case PC, Sanger GJ, Lawson SN. Dorsal root ganglion neurons show increased expression of the calcium channel alpha2delta-1 subunit following partial sciatic nerve injury. Brain Res Mol Brain Res. 2001;95(1\u20132):1\u20138.","journal-title":"Brain Res Mol Brain Res"},{"issue":"13","key":"616_CR42","doi-asserted-by":"publisher","first-page":"4076","DOI":"10.1523\/JNEUROSCI.0356-09.2009","volume":"29","author":"CS Bauer","year":"2009","unstructured":"Bauer CS, 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(13):4076\u201388.","journal-title":"J Neurosci"},{"issue":"1","key":"616_CR43","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.pain.2010.04.022","volume":"150","author":"T Takahashi","year":"2010","unstructured":"Takahashi T, Aoki Y, Okubo K, Maeda Y, Sekiguchi F, Mitani K, et al. Upregulation of ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain. Pain. 2010;150(1):183\u201391.","journal-title":"Pain."},{"issue":"2","key":"616_CR44","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1523\/JNEUROSCI.0181-19.2019","volume":"40","author":"K Gomez","year":"2020","unstructured":"Gomez K, Calder\u00f3n-Rivera A, Sandoval A, Gonz\u00e1lez-Ram\u00edrez R, Vargas-Parada A, Ojeda-Alonso J, et al. Cdk5-dependent phosphorylation of ca. J Neurosci. 2020;40(2):283\u201396.","journal-title":"J Neurosci"},{"issue":"7\u20138","key":"616_CR45","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1345\/aph.1G584","volume":"40","author":"SS Lynch","year":"2006","unstructured":"Lynch SS, Cheng CM, Yee JL. Intrathecal ziconotide for refractory chronic pain. Ann Pharmacother. 2006;40(7\u20138):1293\u2013300.","journal-title":"Ann Pharmacother"},{"issue":"5","key":"616_CR46","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1124\/mol.111.073205","volume":"80","author":"W Choe","year":"2011","unstructured":"Choe W, Messinger RB, Leach E, Eckle VS, Obradovic A, Salajegheh R, et al. TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. Mol Pharmacol. 2011;80(5):900\u201310.","journal-title":"Mol Pharmacol"},{"issue":"10","key":"616_CR47","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1016\/j.pain.2012.04.022","volume":"153","author":"SD Shields","year":"2012","unstructured":"Shields SD, Ahn HS, Yang Y, Han C, Seal RP, Wood JN, et al. Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain. 2012;153(10):2017\u201330.","journal-title":"Pain."},{"issue":"5","key":"616_CR48","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/S0166-2236(02)02150-1","volume":"25","author":"S Dib-Hajj","year":"2002","unstructured":"Dib-Hajj S, Black JA, Cummins TR, Waxman SG. NaN\/Nav1.9: a sodium channel with unique properties. Trends Neurosci. 2002;25(5):253\u20139.","journal-title":"Trends Neurosci"},{"issue":"Pt 3","key":"616_CR49","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1113\/jphysiol.2003.047357","volume":"551","author":"RI Herzog","year":"2003","unstructured":"Herzog RI, Cummins TR, Ghassemi F, Dib-Hajj SD, Waxman SG. Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J Physiol. 2003;551(Pt 3):741\u201350.","journal-title":"J Physiol"},{"issue":"11","key":"616_CR50","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/j.tins.2007.08.004","volume":"30","author":"SD Dib-Hajj","year":"2007","unstructured":"Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Na v 1.7 and human pain disorders. Trends Neurosci. 2007;30(11):555\u201363.","journal-title":"Trends Neurosci"},{"issue":"2","key":"616_CR51","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1152\/jn.2001.86.2.629","volume":"86","author":"M Renganathan","year":"2001","unstructured":"Renganathan M, Cummins TR, Waxman SG. Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol. 2001;86(2):629\u201340.","journal-title":"J Neurophysiol"},{"issue":"34","key":"616_CR52","doi-asserted-by":"publisher","first-page":"12706","DOI":"10.1073\/pnas.0404915101","volume":"101","author":"MA Nassar","year":"2004","unstructured":"Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci U S A. 2004;101(34):12706\u201311.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"26","key":"616_CR53","doi-asserted-by":"publisher","first-page":"9382","DOI":"10.1073\/pnas.0501549102","volume":"102","author":"BT Priest","year":"2005","unstructured":"Priest BT, Murphy BA, Lindia JA, Diaz C, Abbadie C, Ritter AM, et al. Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proc Natl Acad Sci U S A. 2005;102(26):9382\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"616_CR54","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1097\/j.pain.0000000000000147","volume":"156","author":"L Fran\u00e7ois-Moutal","year":"2015","unstructured":"Fran\u00e7ois-Moutal L, Wang Y, Moutal A, Cottier KE, Melemedjian OK, Yang X, et al. A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors. Pain. 2015;156(7):1247\u201364.","journal-title":"Pain."},{"issue":"11","key":"616_CR55","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1097\/j.pain.0000000000001026","volume":"158","author":"A Moutal","year":"2017","unstructured":"Moutal A, Wang Y, Yang X, Ji Y, Luo S, Dorame A, et al. Dissecting the role of the CRMP2-neurofibromin complex on pain behaviors. Pain. 2017;158(11):2203\u201321.","journal-title":"Pain."},{"issue":"1","key":"616_CR56","first-page":"54","volume":"8","author":"AD Piekarz","year":"2012","unstructured":"Piekarz AD, Due MR, Khanna M, Wang B, Ripsch MS, Wang R, et al. CRMP-2 peptide mediated decrease of high and low voltage-activated calcium channels, attenuation of nociceptor excitability, and anti-nociception in a model of AIDS therapy-induced painful peripheral neuropathy. Mol Pain. 2012;8(1):54.","journal-title":"Mol Pain"},{"key":"616_CR57","doi-asserted-by":"publisher","first-page":"4351","DOI":"10.1242\/jcs.053280","volume":"23","author":"XX Chi","year":"2009","unstructured":"Chi XX, Schmutzler BS, Brittain JM, Hingtgen CM, Nicol GD, 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\u201362.","journal-title":"J Cell Sci"},{"issue":"7","key":"616_CR58","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1038\/nm.2345","volume":"17","author":"JM Brittain","year":"2011","unstructured":"Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex. Nat Med. 2011;17(7):822\u20139.","journal-title":"Nat Med"},{"issue":"34","key":"616_CR59","doi-asserted-by":"publisher","first-page":"24316","DOI":"10.1074\/jbc.M113.474924","volume":"288","author":"ET Dustrude","year":"2013","unstructured":"Dustrude ET, Wilson SM, Ju W, Xiao Y, Khanna R. CRMP2 protein SUMOylation modulates NaV1.7 channel trafficking. J Biol Chem. 2013;288(34):24316\u201331.","journal-title":"J Biol Chem"},{"issue":"12","key":"616_CR60","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1111\/bph.13737","volume":"175","author":"A Moutal","year":"2018","unstructured":"Moutal A, Li W, Wang Y, Ju W, Luo S, Cai S, et al. Homology-guided mutational analysis reveals the functional requirements for antinociceptive specificity of collapsin response mediator protein 2-derived peptides. Br J Pharmacol. 2018;175(12):2244\u201360.","journal-title":"Br J Pharmacol"},{"issue":"6","key":"616_CR61","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1523\/JNEUROSCI.12-06-02104.1992","volume":"12","author":"ML Roy","year":"1992","unstructured":"Roy ML, Narahashi T. Differential properties of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in rat dorsal root ganglion neurons. J Neurosci. 1992;12(6):2104\u201311.","journal-title":"J Neurosci"},{"issue":"12","key":"616_CR62","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1097\/j.pain.0000000000001002","volume":"158","author":"A Moutal","year":"2017","unstructured":"Moutal A, Yang X, Li W, Gilbraith KB, Luo S, Cai S, et al. CRISPR\/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide. Pain. 2017;158(12):2301\u201319.","journal-title":"Pain."},{"issue":"6","key":"616_CR63","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1016\/0031-9384(76)90029-9","volume":"17","author":"TL Yaksh","year":"1976","unstructured":"Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976;17(6):1031\u20136.","journal-title":"Physiol Behav"},{"issue":"1","key":"616_CR64","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/0165-0270(94)90144-9","volume":"53","author":"SR Chaplan","year":"1994","unstructured":"Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55\u201363.","journal-title":"J Neurosci Methods"}],"container-title":["Molecular Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-020-00616-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13041-020-00616-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13041-020-00616-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T23:55:41Z","timestamp":1620690941000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularbrain.biomedcentral.com\/articles\/10.1186\/s13041-020-00616-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,11]]},"references-count":64,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["616"],"URL":"https:\/\/doi.org\/10.1186\/s13041-020-00616-2","relation":{},"ISSN":["1756-6606"],"issn-type":[{"type":"electronic","value":"1756-6606"}],"subject":[],"published":{"date-parts":[[2020,5,11]]},"assertion":[{"value":"3 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 May 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.<b>Ethics approval for use of animals<\/b>The University of Arizona\u2019s College of Medicine Institutional Animal Care and Use Committee (IACUC) sanctioned all experiments.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"R. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna has patents US10287334 and US10441586 issued to Regulonix LLC. The other\u00a0authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"73"}}