{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:20:21Z","timestamp":1790500821370,"version":"4.1.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T00:00:00Z","timestamp":1605657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente 2020"],"award-info":[{"award-number":["Ricerca Corrente 2020"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007514","name":"Universit\u00e0 di Pisa","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007514","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurotox Res"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson\u2019s disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5\u00a0mg\/kg\/X2, daily, for 21\u00a0days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alpha-synuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD.<\/jats:p>","DOI":"10.1007\/s12640-020-00313-x","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T08:03:22Z","timestamp":1605686602000},"page":"156-169","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Chronic MPTP in Mice Damage-specific Neuronal Phenotypes within Dorsal Laminae of the Spinal Cord"],"prefix":"10.1007","volume":"39","author":[{"given":"Francesca","family":"Biagioni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Vivacqua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Lazzeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosangela","family":"Ferese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Iannacone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Onori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Morini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"D\u2019Este","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Fornai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,18]]},"reference":[{"key":"313_CR1","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nrn1868","volume":"7","author":"PM Abou-Sleiman","year":"2006","unstructured":"Abou-Sleiman PM, Muqit MMK, Wood NW (2006) Expanding insights of mitochondrial dysfunction in Parkinson\u2019s disease. Nat Rev Neurosci 7:207\u2013219. https:\/\/doi.org\/10.1038\/nrn1868","journal-title":"Nat Rev Neurosci"},{"key":"313_CR2","doi-asserted-by":"publisher","first-page":"5661","DOI":"10.1523\/JNEUROSCI.2469-15.2016","volume":"36","author":"Z Aira","year":"2016","unstructured":"Aira Z, Barrenetxea T, Buesa I, Garc\u00eda Del Ca\u00f1o G, Azkue JJ (2016) Dopamine D1-like receptors regulate constitutive, \u03bc-opioid receptor-mediated repression of use-dependent synaptic plasticity in dorsal horn neurons: More harm than good? J Neurossci 36:5661\u20135673. https:\/\/doi.org\/10.1523\/JNEUROSCI.2469-15.2016","journal-title":"J Neurossci"},{"key":"313_CR3","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1002\/cne.903140111","volume":"314","author":"M Antal","year":"1991","unstructured":"Antal M, Polg\u00e1r E, Chalmers J, Minson JB, Llewellyn-Smith I, Heizmann CW, Somogyi P (1991) Different populations of parvalbumin- and calbindin-D28k-immunoreactive neurons contain GABA and accumulate 3H-D-aspartate in the dorsal horn of the rat spinal cord. J Comp Neurol 314:114\u2013124. https:\/\/doi.org\/10.1002\/cne.903140111","journal-title":"J Comp Neurol"},{"key":"313_CR4","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1016\/S1474-4422","volume":"15","author":"A Ascherio","year":"2016","unstructured":"Ascherio A, Schwarzschild MA (2016) The epidemiology of Parkinson\u2019s disease: Risk factors and prevention. Lancet Neurol 15:1257\u20131272. https:\/\/doi.org\/10.1016\/S1474-4422","journal-title":"Lancet Neurol"},{"key":"313_CR5","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/S0304-3959(01)00443-2","volume":"96","author":"B Berglund","year":"2002","unstructured":"Berglund B, Harju EL, Kosek E, Lindblom U (2002) Quantitative and qualitative perceptual analysis of cold dysesthesia and hyperalgesia in fibromyalgia. Pain 96:177\u2013187. https:\/\/doi.org\/10.1016\/S0304-3959(01)00443-2","journal-title":"Pain"},{"key":"313_CR6","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1007\/s00401-007-0193-x","volume":"113","author":"H Braak","year":"2007","unstructured":"Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson\u2019s disease: Lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421\u2013429. https:\/\/doi.org\/10.1007\/s00401-007-0193-x","journal-title":"Acta Neuropathol"},{"key":"313_CR7","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s004010000247","volume":"101","author":"E Braak","year":"2001","unstructured":"Braak E, Sandmann-Keil D, R\u00fcb U, Gai WP, de Vos RA, Steur EN, Arai K, Braak H (2001) Alpha-synuclein immunopositive Parkinson\u2019s disease-related inclusion bodies in lower brain stem nuclei. Acta Neuropathol 101:195\u2013201. https:\/\/doi.org\/10.1007\/s004010000247","journal-title":"Acta Neuropathol"},{"key":"313_CR8","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/0006-291x(84)91293-2","volume":"120","author":"K Chiba","year":"1984","unstructured":"Chiba K, Trevor A, Castagnoli N Jr (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys Res Commun 120:574\u2013578. https:\/\/doi.org\/10.1016\/0006-291x(84)91293-2","journal-title":"Biochem. Biophys Res Commun"},{"key":"313_CR9","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1016\/S0140-6736(19)30430-1","volume":"393","author":"LA Colvin","year":"2019","unstructured":"Colvin LA, Bull F, Hales TG (2019) Perioperative opioid analgesia-when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 393:1558\u20131568. https:\/\/doi.org\/10.1016\/S0140-6736(19)30430-1","journal-title":"Lancet"},{"key":"313_CR10","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/372770a0","volume":"372","author":"AD Craig","year":"1994","unstructured":"Craig AD, Bushnell MC, Zhang ET, Blomqvist A (1994) A thalamic nucleus specific for pain and temperature sensation. Nat 372:770\u2013773. https:\/\/doi.org\/10.1038\/372770a0","journal-title":"Nat"},{"key":"313_CR11","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/s0304-3959(02)00009-x","volume":"97","author":"AD Craig","year":"2002","unstructured":"Craig AD, Zhang ET, Blomqvist A (2002) Association of spinothalamic lamina I neurons and their ascending axons with calbindin-immunoreactivity in monkey and human. Pain 97:105\u2013115. https:\/\/doi.org\/10.1016\/s0304-3959(02)00009-x","journal-title":"Pain"},{"key":"313_CR12","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s00401-012-1028-y","volume":"124","author":"K Del Tredici","year":"2012","unstructured":"Del Tredici K, Braak H (2012) Spinal cord lesions in sporadic Parkinson\u2019s disease. Acta Neuropathol 124:643\u2013664. https:\/\/doi.org\/10.1007\/s00401-012-1028-y","journal-title":"Acta Neuropathol"},{"key":"313_CR13","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/j.cell.2014.11.003","volume":"159","author":"B Duan","year":"2014","unstructured":"Duan B, Cheng L, Bourane S, Britz O, Padilla C, Garcia-Campmany L, Krashes M, Knowlton W, Velasquez T, Ren X, Ross SE, Lowell BB, Wang Y, Goulding M, Ma Q (2014) Identification of spinal circuits transmitting and gating mechanical pain. Cell 159:1417\u20131432","journal-title":"Cell"},{"key":"313_CR14","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1113\/jphysiol.1960.sp006565","volume":"154","author":"JC Eccles","year":"1960","unstructured":"Eccles JC, Eccles RM, Magni F (1960) Monosynaptic excitatory action on motoneurones regenerated to antagonistic muscles. J Physiol 154:68\u201388. https:\/\/doi.org\/10.1113\/jphysiol.1960.sp006565","journal-title":"J Physiol"},{"key":"313_CR15","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1113\/jphysiol.1961.sp006798","volume":"159","author":"JC Eccles","year":"1961","unstructured":"Eccles JC, Eccles RM, Magni F (1961) Central inhibitory action attributable to presynaptic depolarization produced by muscle afferent volleys. J Physiol 159:147\u2013166. https:\/\/doi.org\/10.1113\/jphysiol.1961.sp006798","journal-title":"J Physiol"},{"key":"313_CR16","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1113\/jphysiol.1961.sp006797","volume":"159","author":"JC Eccles","year":"1961","unstructured":"Eccles JC, Kozak W, Magni F (1961) Dorsal root reflexes of muscle group I afferent fibres. J Physiol 159:128\u2013146. https:\/\/doi.org\/10.1113\/jphysiol.1961.sp006797","journal-title":"J Physiol"},{"key":"313_CR17","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1113\/jphysiol.1962.sp006835","volume":"160","author":"JC Eccles","year":"1962","unstructured":"Eccles JC, Magni F, Willis WD (1962) Depolarization of central terminals of Group I afferent fibres from muscle. J Physiol 160:62\u201393. https:\/\/doi.org\/10.1113\/jphysiol.1962.sp006835","journal-title":"J Physiol"},{"key":"313_CR18","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/s1353-8020(98)00012-1","volume":"4","author":"H Ehringer","year":"1998","unstructured":"Ehringer H, Hornykiewicz O (1998) Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Parkinsonism Relat Disord 4:53\u201357. https:\/\/doi.org\/10.1016\/s1353-8020(98)00012-1","journal-title":"Parkinsonism Relat Disord"},{"key":"313_CR19","doi-asserted-by":"publisher","unstructured":"Ehringer H, Hornykiewicz O (1960) [Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system]. Klin Wochenschr 38:1236-1239. German.\u00a0https:\/\/doi.org\/10.1007\/BF01485901","DOI":"10.1007\/BF01485901"},{"key":"313_CR20","first-page":"219","volume":"15","author":"M Ferrucci","year":"2013","unstructured":"Ferrucci M, Biagioni F, Vivacqua G, Busceti CL, Bartalucci A, Soldani P, D\u2019Este L, Fumagalli L, Fornai F (2013) The neurobiology of the spinal cord in experimental parkinsonism and Parkinson\u2019s disease. Arch Ital Biol 15:219\u2013234","journal-title":"Arch Ital Biol"},{"key":"313_CR21","doi-asserted-by":"publisher","first-page":"S180","DOI":"10.1016\/j.parkreldis.2008.04.025","volume":"14","author":"M Ferrucci","year":"2008","unstructured":"Ferrucci M, Pasquali L, Ruggieri S, Paparelli A, Fornai F (2008) Alpha-synuclein and autophagy as common steps in neurodegeneration. Parkinsonism Relat Disord 14:S180-184. https:\/\/doi.org\/10.1016\/j.parkreldis.2008.04.025","journal-title":"Parkinsonism Relat Disord"},{"key":"313_CR22","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.brainresbull.2005.02.022","volume":"65","author":"F Fornai","year":"2005","unstructured":"Fornai F, Lenzi P, Ferrucci M, Lazzeri G, di Poggio AB, Natale G, Busceti CL, Biagioni F, Giusiani M, Ruggieri S, Paparelli A (2005) Occurrence of neuronal inclusions combined with increased nigral expression of alpha-synuclein within dopaminergic neurons following treatment with amphetamine derivatives in mice. Brain Res Bull 65:405\u2013413. https:\/\/doi.org\/10.1016\/j.brainresbull.2005.02.022","journal-title":"Brain Res Bull"},{"key":"313_CR23","doi-asserted-by":"publisher","first-page":"3413","DOI":"10.1073\/pnas.0409713102","volume":"102","author":"F Fornai","year":"2005","unstructured":"Fornai F, Schl\u00fcter OM, Lenzi P, Gesi M, Ruffoli R, Ferrucci M, Lazzeri G, Busceti CL, Pontarelli F, Battaglia G, Pellegrini A, Nicoletti F, Ruggieri S, Paparelli A, S\u00fcdhof TC (2005) Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and alpha synuclein. Proc Natl Acad Sci U.S.A. 102:3413\u20133418. https:\/\/doi.org\/10.1073\/pnas.0409713102","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"313_CR24","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/s0149-7634(00)00028-2","volume":"24","author":"M Gesi","year":"2000","unstructured":"Gesi M, Soldani P, Giorgi FS, Santinami A, Bonaccorsi I, Fornai F (2000) The role of the locus coeruleus in the development of Parkinson\u2019s disease. Neurosci Biobehav Rev 24:655\u2013668. https:\/\/doi.org\/10.1016\/s0149-7634(00)00028-2","journal-title":"Neurosci Biobehav Rev"},{"key":"313_CR25","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1111\/j.1471-4159.2009.06072.x","volume":"109","author":"C Gibrat","year":"2009","unstructured":"Gibrat C, Saint-Pierre M, Bousquet M, Levesque D, Rouillard C, Cicchetti F (2009) Differences between subacute and chronic MPTP mice models: Investigation of dopaminergic neuronal degeneration and alpha-synuclein inclusions. J Neurochem 109:1469\u20131482. https:\/\/doi.org\/10.1111\/j.1471-4159.2009.06072.x","journal-title":"J Neurochem"},{"key":"313_CR26","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1136\/jnnp.2008.158659","volume":"80","author":"J Gierthmuhlen","year":"2009","unstructured":"Gierthmuhlen J, Lienau F, Maag R, Hagenah JM, Deuschl G, Fritzer E, Klein C, Baron R, Helmchen C (2009) Somatosensory processing in a German family with PINK1 mutations: Its potential role in Parkinson disease. J Neurol Neurosurg Psychiatry 80:571\u2013574. https:\/\/doi.org\/10.1136\/jnnp.2008.158659","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"313_CR27","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1046\/j.1365-2818.1999.00457.x","volume":"193","author":"HJ Gundersen","year":"1999","unstructured":"Gundersen HJ, Jensen EB, Ki\u00eau K, Nielsen J (1999) The efficiency of systematic sampling in stereology reconsidered. J Microsc 193:199\u2013211. https:\/\/doi.org\/10.1046\/j.1365-2818.1999.00457.x","journal-title":"J Microsc"},{"key":"313_CR28","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.neuroscience.2018.12.009","volume":"398","author":"M Gutierrez-Mecinas","year":"2019","unstructured":"Gutierrez-Mecinas M, Davis O, Polg\u00e1r E, Shahzad M, Navarro-Batista K, Furuta T, Watanabe M, Hughes DI, Todd AJ (2019) Expression of calretinin among different neurochemical classes of interneuron in the superficial dorsal horn of the mouse spinal cord. Neurosci 398:171\u2013181. https:\/\/doi.org\/10.1016\/j.neuroscience.2018.12.009","journal-title":"Neurosci"},{"key":"313_CR29","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1007\/s00429-018-1629-x","volume":"223","author":"M Gutierrez-Mecinas","year":"2018","unstructured":"Gutierrez-Mecinas M, Polg\u00e1r E, Bell AM, Herau M, Todd AJ (2018) Substance P-expressing excitatory interneurons in the mouse superficial dorsal horn provide a propriospinal input to the lateral spinal nucleus. Brain Struct Funct 223:2377\u20132392. https:\/\/doi.org\/10.1007\/s00429-018-1629-x","journal-title":"Brain Struct Funct"},{"key":"313_CR30","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1038\/s41593-018-0141-1","volume":"21","author":"M Haring","year":"2018","unstructured":"Haring M, Zeisel A, Hochgerner H, Rinwa P, Jakobsson JET, Lonnerberg P, La Manno G, Sharma N, Borgius L, Kiehn O, Lagerstrom MC, Linnarsson S, Ernfors P (2018) Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types. Nat Neurosci 21:869\u2013880","journal-title":"Nat Neurosci"},{"key":"313_CR31","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/nprot.2006.342","volume":"2","author":"V Jackson-Lewis","year":"2007","unstructured":"Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson\u2019s disease. Nat Protoc 2:141\u201351. https:\/\/doi.org\/10.1038\/nprot.2006.342","journal-title":"Nat Protoc"},{"key":"313_CR32","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/s1046-2023(02)00235-9","volume":"28","author":"MA King","year":"2002","unstructured":"King MA, Scotty N, Klein RL, Meyer EM (2002) Particle detection, number estimation, and feature measurement in gene transfer studies: Optical fractionator stereology integrated with digital image processing and analysis. Methods 28:293\u2013299. https:\/\/doi.org\/10.1016\/s1046-2023(02)00235-9","journal-title":"Methods"},{"key":"313_CR33","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/S0304-3959(96)03188-0","volume":"68","author":"E Kosek","year":"1996","unstructured":"Kosek E, Ekholm J, Hansson P (1996) Sensory dysfunction in fibromyalgia patients with implications for pathogenic mechanisms. Pain 68:375\u2013383. https:\/\/doi.org\/10.1016\/S0304-3959(96)03188-0","journal-title":"Pain"},{"key":"313_CR34","doi-asserted-by":"publisher","first-page":"e3058","DOI":"10.1097\/MD.0000000000003058","volume":"95","author":"CH Lin","year":"2016","unstructured":"Lin CH, Chao CC, Wu SW, Hsieh PC, Feng FP, Lin YH, Chen YM, Wu RM, Hsieh ST (2016) Pathophysiology of small-fiber sensory system in Parkinson\u2019s disease: Skin innervation and contact heat evoked potential. Medicine (Baltim.) 95:e3058. https:\/\/doi.org\/10.1097\/MD.0000000000003058","journal-title":"Medicine (Baltim.)"},{"key":"313_CR35","doi-asserted-by":"publisher","first-page":"2293","DOI":"10.1038\/s41467-018-04422-2","volume":"9","author":"MHR Ludtmann","year":"2018","unstructured":"Ludtmann MHR, Angelova PR, Horrocks MH, Choi ML, Rodrigues M, Baev AY, Berezhnov AV, Yao Z, Little D, Banushi B, Al-Menhali AS, Ranasinghe RT, Whiten DR, Yapom R, Dolt KS, Devine MJ, Gissen P, Kunath T, Jaganjac M, Pavlov EV, Klenerman D, Abramov AY, Gandhi S (2018) \u03b1-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson\u2019s disease. Nat Commun 9:2293. https:\/\/doi.org\/10.1038\/s41467-018-04422-2","journal-title":"Nat Commun"},{"key":"313_CR36","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/311464a0","volume":"311","author":"SP Markey","year":"1984","unstructured":"Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nat 311:464\u2013467. https:\/\/doi.org\/10.1038\/311464a0","journal-title":"Nat"},{"key":"313_CR37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.abb.2018.04.018","volume":"651","author":"JH Mart\u00ednez","year":"2018","unstructured":"Mart\u00ednez JH, Fuentes F, Vanasco V, Alvarez S, Alaimo A, Cassina A, Coluccio Leskow F, Velazquez F (2018) Alpha-synuclein mitochondrial interaction leads to irreversible translocation and complex I impairment. Arch Biochem Biophys 651:1\u201312. https:\/\/doi.org\/10.1016\/j.abb.2018.04.018","journal-title":"Arch Biochem Biophys"},{"key":"313_CR38","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1093\/brain\/85.2.331","volume":"85","author":"R Melzack","year":"1962","unstructured":"Melzack R, Wall PD (1962) On the nature of cutaneous sensory mechanisms. Brain 85:331\u2013356. https:\/\/doi.org\/10.1093\/brain\/85.2.331","journal-title":"Brain"},{"key":"313_CR39","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1126\/science.150.3699.971","volume":"150","author":"R Melzack","year":"1965","unstructured":"Melzack R, Wall PD (1965) Pain mechanisms: A new theory. Science 150:971\u2013979. https:\/\/doi.org\/10.1126\/science.150.3699.971","journal-title":"Science"},{"key":"313_CR40","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1111\/j.1526-4637.2010.00866.x","volume":"11","author":"R Nandhagopal","year":"2010","unstructured":"Nandhagopal R, Troiano AR, Mak E, Schulzer M, Bushnell MC, Stoessl AJ (2010) Response to heat pain stimulation in idiopathic Parkinson\u2019s disease. Pain Med 11:834\u2013840. https:\/\/doi.org\/10.1111\/j.1526-4637.2010.00866.x","journal-title":"Pain Med"},{"key":"313_CR41","first-page":"203","volume":"151","author":"G Natale","year":"2013","unstructured":"Natale G, Biagioni F, Vivacqua G, D\u2019Este L, Fumagalli L, Fornai F (2013) The neurobiology of dysautonomia in Parkinson\u2019s disease. Arch Ital Biol 151:203\u201318","journal-title":"Arch Ital Biol"},{"key":"313_CR42","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1093\/brain\/awn102","volume":"131","author":"M Nolano","year":"2008","unstructured":"Nolano M, Provitera V, Estraneo A, Selim MM, Caporaso G, Stancanelli A, Saltalamacchia AM, Lanzillo B, Santoro L (2008) Sensory deficit in Parkinson\u2019s disease: Evidence of a cutaneous denervation. Brain 131:1903\u20131911. https:\/\/doi.org\/10.1093\/brain\/awn102","journal-title":"Brain"},{"key":"313_CR43","doi-asserted-by":"publisher","unstructured":"Park J, Lim CS, Seo H, Park CA, Zhuo M, Kaang BK, Lee K (2015) Pain perception in acute model mice of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mol Pain 11:28. https:\/\/doi.org\/10.1186\/s12990-015-0026-1","DOI":"10.1186\/s12990-015-0026-1"},{"key":"313_CR44","volume-title":"The mouse brain in stereotaxic coordinates","author":"G Paxinos","year":"2004","unstructured":"Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego","edition":"2"},{"key":"313_CR45","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.neuron.2015.07.029","volume":"87","author":"C Peirs","year":"2015","unstructured":"Peirs C, Williams SP, Zhao X, Walsh CE, Gedeon JY, Cagle NE, Goldring AC, Hioki H, Liu Z, Marell PS, Seal RP (2015) Dorsal horn circuits for persistent mechanical pain. Neuron 87:797\u2013812","journal-title":"Neuron"},{"key":"313_CR46","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/s0306-4522(01)00295-0","volume":"106","author":"E Petroske","year":"2001","unstructured":"Petroske E, Meredith GE, Callen S, Totterdell S, Lau YS (2001) Mouse model of Parkinsonism: A comparison between subacute MPTP and chronic MPTP\/probenecid treatment. Neurosci 106:589\u2013601. https:\/\/doi.org\/10.1016\/s0306-4522(01)00295-0","journal-title":"Neurosci"},{"key":"313_CR47","doi-asserted-by":"publisher","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease Nat Rev Dis Primers 3:17013. https:\/\/doi.org\/10.1038\/nrdp.2017.13","journal-title":"Parkinson disease Nat Rev Dis Primers"},{"key":"313_CR48","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/0165-0173(94)90010-8","volume":"19","author":"K Ren","year":"1994","unstructured":"Ren K, Ruda MA (1994) A comparative study of the calcium-binding proteins calbindin-D28K, calretinin, calmodulin and parvalbumin in the rat spinal cord. Brain Res Brain Res Rev 19:163\u2013179","journal-title":"Brain Res Brain Res Rev"},{"key":"313_CR49","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1002\/cne.902090205","volume":"209","author":"A Ribeiro-da-Silva","year":"1982","unstructured":"Ribeiro-da-Silva A, Coimbra A (1982) Two types of synaptic glomeruli and their distribution in laminae I-III of the rat spinal cord. J Comp Neurol 209:176\u2013186. https:\/\/doi.org\/10.1002\/cne.902090205","journal-title":"J Comp Neurol"},{"key":"313_CR50","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1523\/JNEUROSCI.11-04-01068.1991","volume":"11","author":"A Ribeiro-da-Silva","year":"1991","unstructured":"Ribeiro-da-Silva A, Pioro EP, Cuello AC (1991) Substance P- and enkephalin-like immunoreactivities are colocalized in certain neurons of the substantia gelatinosa of the rat spinal cord: An ultrastructural double-labeling study. J Neurosci 11:1068\u20131080. https:\/\/doi.org\/10.1523\/JNEUROSCI.11-04-01068.1991","journal-title":"J Neurosci"},{"key":"313_CR51","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1196\/annals.1432.002","volume":"1139","author":"S Samantaray","year":"2008","unstructured":"Samantaray S, Butler JT, Ray SK, Banik NL (2008) Extranigral neurodegeneration in Parkinson\u2019s disease. Ann N Y Acad Sci 1139:331\u2013336. https:\/\/doi.org\/10.1196\/annals.1432.002","journal-title":"Ann N Y Acad Sci"},{"key":"313_CR52","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1111\/j.1471-4159.2007.05091.x","volume":"104","author":"S Samantaray","year":"2008","unstructured":"Samantaray S, Knaryan VH, Butler JT, Ray SK, Banik NL (2008) Spinal cord degeneration in C57BL\/6N mice following induction of experimental parkinsonism with MPTP. J Neurochem 104:1309\u20131320. https:\/\/doi.org\/10.1111\/j.1471-4159.2007.05091.x","journal-title":"J Neurochem"},{"key":"313_CR53","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/j.neuroscience.2007.01.056","volume":"146","author":"S Samantaray","year":"2007","unstructured":"Samantaray S, Knaryan VH, Guyton MK, Matzelle DD, Ray SK, Banik NL (2007) The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneurons degeneration in spinal cord of Lewis rats. Neurosci 146:741\u2013755. https:\/\/doi.org\/10.1016\/j.neuroscience.2007.01.056","journal-title":"Neurosci"},{"key":"313_CR54","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1007\/s12035-015-9255-6256","volume":"52","author":"S Samantaray","year":"2015","unstructured":"Samantaray S, Knaryan VH, Shields DC, Cox AA, Haque A, Banik NL (2015) Inhibition of calpain activation protects MPTP-induced nigral and spinal cord neurodegeneration, reduces inflammation, and improves gait dynamics in mice. Mol Neurobiol 52:1054\u201366. https:\/\/doi.org\/10.1007\/s12035-015-9255-6256","journal-title":"Mol Neurobiol"},{"key":"313_CR55","doi-asserted-by":"publisher","first-page":"2216","DOI":"10.1016\/j.celrep.2018.02.003","volume":"22","author":"A Sathyamurthy","year":"2018","unstructured":"Sathyamurthy A, Johnson KR, Matson KJE, Dobrott CI, Li L, Ryba AR, Bergman TB, Kelly MC, Kelley MW, Levine AJ (2018) Massively parallel single nucleus transcriptional profiling defines spinal cord neurons and their activity during behavior. Cell Rep 22:2216\u20132225","journal-title":"Cell Rep"},{"key":"313_CR56","doi-asserted-by":"publisher","unstructured":"Schapira AHV, Chaudhuri KR, Jenner P (2017). Non-motor features of Parkinson disease. Nat Rev Neurosci 18:435-450. https:\/\/doi.org\/10.1038\/nrn.2017.62. Epub 2017 Jun 8. Erratum in: Nat Rev Neurosci 18:509.","DOI":"10.1038\/nrn.2017.62"},{"key":"313_CR57","doi-asserted-by":"publisher","first-page":"e49190","DOI":"10.7554\/eLife.49190","volume":"8","author":"KM Smith","year":"2019","unstructured":"Smith KM, Browne TJ, Davis OC, Coyle A, Boyle KA, Watanabe M, Dickinson SA, Iredale JA, Gradwell MA, Jobling P, Callister RJ, Dayas CV, Hughes DI, Graham BA (2019) Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn. Elife 8:e49190. https:\/\/doi.org\/10.7554\/eLife.49190","journal-title":"Elife"},{"key":"313_CR58","doi-asserted-by":"publisher","first-page":"9799","DOI":"10.1523\/JNEUROSCI.1787-16.2017","volume":"37","author":"DJ Surmeier","year":"2017","unstructured":"Surmeier DJ, Obeso JA, Halliday GM (2017) Parkinson\u2019s disease is not simply a prion disorder. J Neurosci 37:9799\u20139807. https:\/\/doi.org\/10.1523\/JNEUROSCI.1787-16.2017","journal-title":"J Neurosci"},{"key":"313_CR59","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1001\/archneur.63.12.1724","volume":"63","author":"J Tong","year":"2006","unstructured":"Tong J, Hornykiewicz O, Kish SJ (2006) Inverse relationship between brain noradrenaline level and dopamine loss in Parkinson disease: A possible neuroprotective role for noradrenaline. Arch Neurol 63:1724\u20131728. https:\/\/doi.org\/10.1001\/archneur.63.12.1724","journal-title":"Arch Neurol"},{"key":"313_CR60","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1097\/j.pain.0000000000001287","volume":"159","author":"N Uceyler","year":"2018","unstructured":"Uceyler N, Vollert J, Broll B, Riediger N, Langjahr M, Saffer N, Schubert AL, Siedler G, Sommer C (2018) Sensory profiles and skin innervation of patients with painful and painless neuropathies. Pain 159:1867\u20131876. https:\/\/doi.org\/10.1097\/j.pain.0000000000001287","journal-title":"Pain"},{"key":"313_CR61","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1007\/s12640-019-00121-y","volume":"37","author":"G Vivacqua","year":"2020","unstructured":"Vivacqua G, Biagioni F, Busceti CL, Ferrucci M, Madonna M, Ryskalin L, Yu S, D\u2019Este L, Fornai F (2020) Motor neurons pathology after chronic exposure to MPTP in mice. Neurotox Res 37:298\u2013313. https:\/\/doi.org\/10.1007\/s12640-019-00121-y","journal-title":"Neurotox Res"},{"key":"313_CR62","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.jchemneu.2012.04.003","volume":"44","author":"G Vivacqua","year":"2012","unstructured":"Vivacqua G, Biagioni F, Yu S, Casini A, Bucci D, D\u2019Este L, Fornai F (2012) Loss of spinal motor neurons and alteration of alpha-synuclein immunostaining in MPTP induced Parkinsonism in mice. J Chem Neuroanat 44:76\u201385. https:\/\/doi.org\/10.1016\/j.jchemneu.2012.04.003","journal-title":"J Chem Neuroanat"},{"key":"313_CR63","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.jchemneu.2010.12.003","volume":"41","author":"G Vivacqua","year":"2011","unstructured":"Vivacqua G, Casini A, Vaccaro R, Fornai F, Yu S, D\u2019Este L (2011) Different Sub-cellular localization of alpha-synuclein in the C57BL\/6J mouse\u2019s central nervous system by two novel monoclonal antibodies. J Chem Neuroanat 41:97\u2013110. https:\/\/doi.org\/10.1016\/j.jchemneu.2010.12.003","journal-title":"J Chem Neuroanat"},{"key":"313_CR64","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.jchemneu.2011.03.001","volume":"42","author":"G Vivacqua","year":"2011","unstructured":"Vivacqua G, Casini A, Vaccaro R, Parisi Salvi E, Pasquali L, Fornai F, Yu S, D\u2019Este L (2011) Spinal cord and parkinsonism: Neuromorphological evidences in humans and experimental studies. J Chem Neuroanat 42:327\u2013340. https:\/\/doi.org\/10.1016\/j.jchemneu.2011.03.001","journal-title":"J Chem Neuroanat"},{"key":"313_CR65","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1016\/j.neuroscience.2008.12.001","volume":"158","author":"G Vivacqua","year":"2009","unstructured":"Vivacqua G, Yin JJ, Casini A, Li X, Li YH, D\u2019Este L, Chan P, Renda TG, Yu S (2009) Immunolocalization of alpha-synuclein in the rat spinal cord by two novel monoclonal antibodies. Neurosci 158:1478\u20131487. https:\/\/doi.org\/10.1016\/j.neuroscience.2008.12.001","journal-title":"Neurosci"},{"key":"313_CR66","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1002\/ar.1092310411","volume":"231","author":"MJ West","year":"1991","unstructured":"West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482\u2013497. https:\/\/doi.org\/10.1002\/ar.1092310411","journal-title":"Anat Rec"},{"key":"313_CR67","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.pain.2010.08.008","volume":"151","author":"T Yasaka","year":"2010","unstructured":"Yasaka T, Tiong SYX, Hughes DI, Riddell JS, Todd AJ (2010) Populations of inhibitory and excitatory interneurons in lamina II of the adult rat spinal dorsal horn revealed by a combined electrophysiological and anatomical approach. Pain 151:475\u2013488. https:\/\/doi.org\/10.1016\/j.pain.2010.08.008","journal-title":"Pain"},{"key":"313_CR68","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1038\/sc.2016.74","volume":"54","author":"TS Yeh","year":"2016","unstructured":"Yeh TS, Huang YP, Wang HI, Pan SL (2016) Spinal cord injury and Parkinson\u2019s disease: A population-based, propensity score-matched, longitudinal follow-up study. Spinal Cord 54:1215\u20131219. https:\/\/doi.org\/10.1038\/sc.2016.74","journal-title":"Spinal Cord"},{"key":"313_CR69","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1001\/archneur.60.3.337","volume":"60","author":"C Zarow","year":"2003","unstructured":"Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337\u2013341. https:\/\/doi.org\/10.1001\/archneur.60.3.337","journal-title":"Arch Neurol"},{"key":"313_CR70","doi-asserted-by":"publisher","first-page":"3803","DOI":"10.1007\/s00429-016-1191-3","volume":"221","author":"MD Zhang","year":"2016","unstructured":"Zhang MD, Barde S, Szodorai E, Josephson A, Mitsios N, Watanabe M, Attems J, Lubec G, Kov\u00e1cs GG, Uhl\u00e9n M, Mulder J, Harkany T, H\u00f6kfelt T (2016) Comparative anatomical distribution of neuronal calcium-binding protein (NECAB) 1 and -2 in rodent and human spinal cord. Brain Struct Funct 221:3803\u20133823. https:\/\/doi.org\/10.1007\/s00429-016-1191-3","journal-title":"Brain Struct Funct"}],"container-title":["Neurotoxicity Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s12640-020-00313-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s12640-020-00313-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s12640-020-00313-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T17:24:24Z","timestamp":1615051464000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s12640-020-00313-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,18]]},"references-count":70,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["313"],"URL":"https:\/\/doi.org\/10.1007\/s12640-020-00313-x","relation":{},"ISSN":["1029-8428","1476-3524"],"issn-type":[{"value":"1029-8428","type":"print"},{"value":"1476-3524","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,18]]},"assertion":[{"value":"5 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}