botulinum toxin type A; central sensitization; lemniscal system; migraine; pain; peripheral sensitization; trigemino-cervical complex; Botulinum Toxins, Type A; Humans; Nociception; Pain; Sense Organs; Botulinum Toxins, Type A/therapeutic use; Botulinum Toxins, Type A/pharmacology; Migraine Disorders/drug therapy; Migraine Disorders; Toxicology; Health, Toxicology and Mutagenesis
Abstract :
[en] (1) Background: OnabotulinumtoxinA (BoNT-A) is a commonly used prophylactic treatment for chronic migraine (CM). Although randomized placebo studies have shown its clinical efficacy, the mechanisms by which it exerts its therapeutic effect are still incompletely understood and debated. (2) Methods: We studied in 15 CM patients the cephalic and extracephalic nociceptive and lemniscal sensory systems using electrophysiological techniques before and 1 and 3 months after one session of pericranial BoNT-A injections according to the PREEMPT protocol. We recorded the nociceptive blink reflex (nBR), the trigemino-cervical reflex (nTCR), the pain-related cortical evoked potential (PREP), and the upper limb somatosensory evoked potential (SSEP). (3) Results: Three months after a single session of prophylactic therapy with BoNT-A in CM patients, we found (a) an increase in the homolateral and contralateral nBR AUC, (b) an enhancement of the contralateral nBR AUC habituation slope and the nTCR habituation slope, (c) a decrease in PREP N-P 1st and 2nd amplitude block, and (d) no effect on SSEPs. (4) Conclusions: Our study provides electrophysiological evidence for the ability of a single session of BoNT-A injections to exert a neuromodulatory effect at the level of trigeminal system through a reduction in input from meningeal and other trigeminovascular nociceptors. Moreover, by reducing activity in cortical pain processing areas, BoNT-A restores normal functioning of the descending pain modulation systems.
Disciplines :
Neurology
Author, co-author :
Sebastianelli, Gabriele ; Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino-ICOT, 04100 Latina, Italy
Casillo, Francesco; Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino-ICOT, 04100 Latina, Italy
Di Renzo, Antonio; IRCCS-Fondazione Bietti, 00198 Rome, Italy
Abagnale, Chiara; Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino-ICOT, 04100 Latina, Italy
Cioffi, Ettore ; Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino-ICOT, 04100 Latina, Italy
This research received external funding from Allergan Ireland (now Abbvie, Legacy Grant ID: IIT-EAME-NEU-0417).The contribution of the G.B. Bietti Foundation in this paper was supported by the Italian Ministry of Health and Fondazione Roma.
D’amico D. Usai S. Grazzi L. Rigamonti A. Solari A. Leone M. Bussone G. Quality of life and disability in primary chronic daily headaches Neurol. Sci. 2003 24 (Suppl. 2) S97 S100 10.1007/s100720300052
Blumenfeld A.M. Varon S.F. Wilcox T.K. Buse D.C. Kawata A.K. Manack A. Goadsby P. Lipton R.B. Disability, HRQoL and resource use among chronic and episodic migraineurs: Results from the International Burden of Migraine Study (IBMS) Cephalalgia 2010 31 301 315 10.1177/0333102410381145
Buse D.C. Manack A.N. Fanning K.M. Serrano D. Reed M.L. Turkel C.C. Lipton R.B. Chronic Migraine Prevalence, Disability, and Sociodemographic Factors: Results From the American Migraine Prevalence and Prevention Study Headache 2012 52 1456 1470 10.1111/j.1526-4610.2012.02223.x
Munakata J. Hazard E. Serrano D. Klingman D. Rupnow M.F. Tierce J. Reed M. Lipton R.B. Economic Burden of Transformed Migraine: Results From the American Migraine Prevalence and Prevention (AMPP) Study Headache 2009 49 498 508 10.1111/j.1526-4610.2009.01369.x
Berra E. Sances G. De Icco R. Avenali M. Berlangieri M. De Paoli I. Bolla M. Allena M. Ghiotto N. Guaschino E. et al. Cost of Chronic and Episodic Migraine: A pilot study from a tertiary headache centre in northern Italy J. Headache Pain 2015 16 1 8 10.1186/s10194-015-0532-6
Linde M. Gustavsson A. Stovner L.J. Steiner T.J. Barré J. Katsarava Z. Lainez J.M. Lampl C. Lantéri-Minet M. Rastenyte D. et al. The cost of headache disorders in Europe: The Eurolight project Eur. J. Neurol. 2011 19 703 711 10.1111/j.1468-1331.2011.03612.x
Straube A. Pfaffenrath V. Ladwig K.-H. Meisinger C. Hoffmann W. Fendrich K. Vennemann M. Berger K. Prevalence of chronic migraine and medication overuse headache in Germany—The German DMKG headache study Cephalalgia 2009 30 207 213 10.1111/j.1468-2982.2009.01906.x
Scher A.I. Stewart W.F. Liberman J. Lipton R.B. Prevalence of Frequent Headache in a Population Sample Headache 1998 38 497 506 10.1046/j.1526-4610.1998.3807497.x
Katsarava Z. Schneeweiss S. Kurth T. Kroener U. Fritsche G. Eikermann A. Diener H.-C. Limmroth V. Incidence and predictors for chronicity of headache in patients with episodic migraine Neurology 2004 62 788 790 10.1212/01.WNL.0000113747.18760.D2
Scher I.A. Stewart F.W. Ricci A.J. Lipton B.R. Factors associated with the onset and remission of chronic daily headache in a population-based study Pain 2003 106 81 89 10.1016/S0304-3959(03)00293-8
May A. Schulte A.M.L.H. Chronic migraine: Risk factors, mechanisms and treatment Nat. Rev. Neurol. 2016 12 455 464 10.1038/nrneurol.2016.93
Jabbari B. Botulinum neurotoxins in the treatment of refractory pain Nat. Clin. Pract. Neurol. 2008 4 676 685 10.1038/ncpneuro0948
Aurora S.K. Winner P. Freeman M.C. Spierings E.L. Heiring J.O. DeGryse R.E. Turkel C.C. OnabotulinumtoxinA for treatment of chronic migraine: Pooled analyses of the 56-Week PREEMPT clinical program Headache 2011 51 1358 1373 10.1111/j.1526-4610.2011.01990.x
Aoki K. Review of a Proposed Mechanism for the Antinociceptive Action of Botulinum Toxin Type A Neurotoxicology 2005 26 785 793 10.1016/j.neuro.2005.01.017
Cui M. Khanijou S. Rubino J. Aoki K.R. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain Pain 2004 107 125 133 10.1016/j.pain.2003.10.008
Durham P.L. Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: Implications for migraine therapy Headache 2004 44 35 42 10.1111/j.1526-4610.2004.04007.x
Purkiss J. Welch M. Doward S. Foster K. Capsaicin-stimulated release of substance P from cultured dorsal root ganglion neurons: Involvement of two distinct mechanisms Biochem. Pharmacol. 2000 59 1403 1406 10.1016/S0006-2952(00)00260-4
Welch M.J. Purkiss J.R. Foster K.A. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins Toxicon 1999 38 245 258 10.1016/S0041-0101(99)00153-1
Ferrandiz-Huertas C. Mathivanan S. Wolf C.J. Devesa I. Ferrer-Montiel A. Trafficking of ThermoTRP Channels Membranes 2014 4 525 564 10.3390/membranes4030525
Apostolidis A. Popat R. Yiangou Y. Cockayne D. Ford A. Davis J. Dasgupta P. Fowler C. Anand P. Decreased sensory receptors p2x 3 and trpv1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity J. Urol. 2005 174 977 983 10.1097/01.ju.0000169481.42259.54
McMahon H.T. Foran P. Dolly J.O. Verhage M. Wiegant V.M. Nicholls D.G. Tetanus toxin and botulinum toxins type A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and met-enkephalin release from synaptosomes. Clues to the locus of action J. Biol. Chem. 1992 267 21338 21343 10.1016/S0021-9258(19)36614-1 1356988
Becker W.J. Botulinum Toxin in the Treatment of Headache Toxins 2020 12 803 10.3390/toxins12120803
Kępczyńska K. Domitrz I. Botulinum Toxin—A Current Place in the Treatment of Chronic Migraine and Other Primary Headaches Toxins 2022 14 619 10.3390/toxins14090619 36136557
Shimizu T. Shibata M. Toriumi H. Iwashita T. Funakubo M. Sato H. Kuroi T. Ebine T. Koizumi K. Suzuki N. Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A Neurobiol. Dis. 2012 48 367 378 10.1016/j.nbd.2012.07.010
Edvinsson J. Warfvinge K. Edvinsson L. Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: An organ culture study J. Headache Pain 2015 16 555 10.1186/s10194-015-0555-z 26245187
Diener H.C. Dodick D.W. Aurora S.K. Turkel C.C. DeGryse R.E. Lipton R.B. Brin M.F. OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial Cephalalgia 2010 30 804 814 10.1177/0333102410364677
Casillo F. Sebastianelli G. Di Renzo A. Cioffi E. Parisi V. Di Lorenzo C. Serrao M. Coppola G. The monoclonal CGRP-receptor blocking antibody erenumab has different effects on brainstem and cortical sensory-evoked responses Cephalalgia 2022 10.1177/03331024221103811
Serrao M. Coppola G. Di Lorenzo C. Di Fabio R. Padua L. Sandrini G. Pierelli F. Nociceptive trigeminocervical reflexes in healthy subjects Clin. Neurophysiol. 2010 121 1563 1568 10.1016/j.clinph.2010.03.031
e Tommaso M. Santostasi R. Devitofrancesco V. Franco G. Vecchio E. Delussi M. Livrea P. Katzarava Z. A comparative study of cortical responses evoked by transcutaneous electrical vs CO2 laser stimulation Clin. Neurophysiol. 2011 122 2482 2487 10.1016/j.clinph.2011.05.006
Pellizzari R. Rossetto O. Schiavo G. Montecucco C. Tetanus and botulinum neurotoxins: Mechanism of action and therapeutic uses Philos. Trans. R. Soc. B Biol. Sci. 1999 354 259 268 10.1098/rstb.1999.0377
Joussain C. Le Coz O. Pichugin A. Marconi P. Lim F. Sicurella M. Aranda Muñoz A. Botulinum Neurotoxin Light Chains Expressed by Defective Herpes Simplex Virus Type-1 Vectors Cleave SNARE Proteins and Inhibit CGRP Release in Rat Sensory Neurons Toxins 2019 11 123 10.3390/toxins11020123 30791373
Cernuda-Morollón E. Ramón C. Martínez-Camblor P. Serrano-Pertierra E. Larrosa D. Pascual J. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine Pain 2015 156 820 824 10.1097/j.pain.0000000000000119
da Silva L.B. Karshenas A. Bach F.W. Rasmussen S. Arendt-Nielsen L. Gazerani P. Blockade of Glutamate Release by Botulinum Neurotoxin Type A in Humans: A Dermal Microdialysis Study Pain Res. Manag. 2014 19 126 132 10.1155/2014/410415
Burstein R. Blumenfeld A.M. Silberstein S.D. Adams A.M. Brin M.F. Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review Headache 2020 60 1259 1272 10.1111/head.13849 32602955
Gfrerer L. Xu W. Austen W. Ashina S. Melo-Carrillo A. Longhi M.S. Adams A.M. Houle T. Brin M.F. Burstein R. OnabotulinumtoxinA alters inflammatory gene expression and immune cells in chronic headache patients Brain 2021 145 2436 2449 10.1093/brain/awab461
Burstein R. Zhang X. Levy D. Aoki K.R. Brin M.F. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: Therapeutic implications for migraine and other pains Cephalalgia 2014 34 853 869 10.1177/0333102414527648
Kosaras B. Jakubowski M. Kainz V. Burstein R. Sensory innervation of the calvarial bones of the mouse J. Comp. Neurol. 2009 515 331 348 10.1002/cne.22049
Noseda R. Melo-Carrillo A. Nir R.-R. Strassman A.M. Burstein R. Non-Trigeminal Nociceptive Innervation of the Posterior Dura: Implications to Occipital Headache J. Neurosci. 2019 39 1867 1880 10.1523/JNEUROSCI.2153-18.2018 30622169
Kaube H. Katsarava Z. Käufer T. Diener H.-C. Ellrich J. A new method to increase nociception specificity of the human blink reflex Clin. Neurophysiol. 2000 111 413 416 10.1016/S1388-2457(99)00295-3
De Marinis M. Pujia A. Colaizzo E. Accornero N. The blink reflex in “chronic migraine” Clin. Neurophysiol. 2007 118 457 463 10.1016/j.clinph.2006.10.011
Sohn J.-H. Kim C.-H. Choi H.-C. Differences in central facilitation between episodic and chronic migraineurs in nociceptive-specific trigeminal pathways J. Headache Pain 2016 17 35 10.1186/s10194-016-0637-6
De Tommaso M. Brighina F. Delussi M. Effects of Botulinum Toxin A on Allodynia in Chronic Migraine: An Observational Open-Label Two-Year Study Eur. Neurol. 2019 81 37 46 10.1159/000499764 31013496
Sava S.L. De Pasqua V. Magis D. Schoenen J. Effects of Visual Cortex Activation on the Nociceptive Blink Reflex in Healthy Subjects PLoS ONE 2014 9 e100198 10.1371/journal.pone.0100198 24936654
Di Clemente L. Coppola G. Magis D. Fumal A. De Pasqua V. Di Piero V. Schoenen J. Interictal habituation deficit of the nociceptive blink reflex: An endophenotypic marker for presymptomatic migraine? Brain 2007 130 765 770 10.1093/brain/awl351 17251239
Ellrich J. Brain Stem Reflexes: Probing Human Trigeminal Nociception Physiology 2000 15 94 97 10.1152/physiologyonline.2000.15.2.94
Esteban A. A neurophysiological approach to brainstem reflexes. Blink reflex Neurophysiol. Clin. 1999 29 7 38 10.1016/S0987-7053(99)80039-2
Valls-Sole J. Assessment of excitability in brainstem circuits mediating the blink reflex and the startle reaction Clin. Neurophysiol. 2012 123 13 20 10.1016/j.clinph.2011.04.029
Calabresi P. Cupini L.M. Medication-overuse headache: Similarities with drug addiction Trends Pharmacol. Sci. 2005 26 62 68 10.1016/j.tips.2004.12.008 15681022
de Tommaso M. Delussi M. Ricci K. Montemurno A. Carbone I. Vecchio E. Effects of OnabotulintoxinA on Habituation of Laser Evoked Responses in Chronic Migraine Toxins 2016 8 163 10.3390/toxins8060163
Drinovac V. Bach-Rojecky L. Matak I. Lacković Z. Involvement of μ-opioid receptors in antinociceptive action of botulinum toxin type A Neuropharmacology 2013 70 331 337 10.1016/j.neuropharm.2013.02.011
Drinovac V. Bach-Rojecky L. Lacković Z. Association of antinociceptive action of botulinum toxin type A with GABA-A receptor J. Neural Transm. 2014 121 665 669 10.1007/s00702-013-1150-6
Matak I. Riederer P. Lacković Z. Botulinum toxin’s axonal transport from periphery to the spinal cord Neurochem. Int. 2012 61 236 239 10.1016/j.neuint.2012.05.001 22580329
Matak I. Bach-Rojecky L. Filipović B. Lacković Z. Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A Neuroscience 2011 186 201 207 10.1016/j.neuroscience.2011.04.026
Matak I. Lacković Z. Botulinum toxin A, brain and pain Prog. Neurobiol. 2014 119–120 39 59 10.1016/j.pneurobio.2014.06.001 24915026
Lawrence G.W. Ovsepian S.V. Wang J. Aoki K.R. Dolly J.O. Extravesicular intraneuronal migration of internalized botulinum neurotoxins without detectable inhibition of distal neurotransmission Biochem. J. 2011 441 443 452 10.1042/BJ20111117
Cai B.B. Francis J. Brin M.F. Broide R.S. Botulinum neurotoxin type A-cleaved SNAP25 is confined to primary motor neurons and localized on the plasma membrane following intramuscular toxin injection Neuroscience 2017 352 155 169 10.1016/j.neuroscience.2017.03.049
Weise D. Weise C.M. Naumann M. Central Effects of Botulinum Neurotoxin—Evidence from Human Studies Toxins 2019 11 21 10.3390/toxins11010021 30621330
Matak I. Bölcskei K. Bach-Rojecky L. Helyes Z. Mechanisms of Botulinum Toxin Type A Action on Pain Toxins 2019 11 459 10.3390/toxins11080459
Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition Cephalalgia 2018 38 1 211 10.1177/0333102417738202
Giffin J.N. Katsarava Z. Pfundstein A. Ellrich J. Kaube H. The effect of multiple stimuli on the modulation of the ‘nociceptive’ blink reflex Pain 2004 108 124 128 10.1016/j.pain.2003.12.014
Coppola G. Di Clemente L. Fumal A. Magis D. De Pasqua V. Pierelli F. Schoenen J. Inhibition of the Nociceptive R2 Blink Reflex after Supraorbital or Index Finger Stimulation is Normal in Migraine Without Aura Between Attacks Cephalalgia 2007 27 803 808 10.1111/j.1468-2982.2007.01323.x
Ayzenberg I. Obermann M. Nyhuis P. Gastpar M. Limmroth V. Diener H.C. Kaube H. Katsarava Z. Central Sensitization of The Trigeminal and Somatic Nociceptive Systems in Medication Overuse Headache Mainly Involves Cerebral Supraspinal Structures Cephalalgia 2006 26 1106 1114 10.1111/j.1468-2982.2006.01183.x 16919061
Coppola G. Currà A. Di Lorenzo C. Parisi V. Gorini M. Sava S.L. Schoenen J. Pierelli F. Abnormal cortical responses to somatosensory stimulation in medication-overuse headache BMC Neurol. 2010 10 126 10.1186/1471-2377-10-126
Di Clemente L. Coppola G. Magis D. Gérardy P.-Y. Fumal A. De Pasqua V. Di Piero V. Schoenen J. Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: Evidence from a study of nociceptive blink reflexes and visual evoked potentials Pain 2009 144 156 161 10.1016/j.pain.2009.04.018 19457613
Dunn O.J. Multiple Comparisons Using Rank Sums Technometrics 1964 6 241 252 10.1080/00401706.1964.10490181
