Keywords
How to Cite
Abstract
Botulinum neurotoxins (BoNT) are toxins produced by bacteria of the genus Clostridium botulinum and are considered as the most potent toxins nowadays. Firstly, known as a food poison, later explored as a biological weapon and currently considered a great therapeutic resource. Seven different BoNT serotypes (A-G) have already been identified. Among them, serotypes A and B are used in clinics, and serotype A is the most used for the highest efficacy and safety. BoNT is widely known and used in aesthetics, through intramuscular injections to attenuate dynamic wrinkles. Additionally, it has been used as therapy in the treatment of strabismus, blepharospasm, cervical dystonia, hyperhidrosis, sialorrhea, hemifacial spasm, and many other clinical conditions in areas such as urology, neurology, ophthalmology, gastroenterology and more recently evaluated in psychiatry. BoNTs are also being studied for a new therapeutic horizon: the treatment of pain. In some painful syndromes that can be treated with BoNT, the mechanism of action is related to the inhibition of muscle contraction through inhibition of acetylcholine release at the neuromuscular junction. This effect involves a selective toxin action on SNARE family proteins (soluble N-ethylmaleimide sensitive factor attachment protein receptor), which mediate the acetylcholine exocytosis process. Moreover, it shows analgesic effect in some clinical conditions that are not related to excessive muscle contraction, such as in the treatment of migraine. Therefore, it has been suggested that BoNT is capable of producing analgesia independent of muscle contraction inhibition. This evidence has stimulated the study of BoNT in other painful conditions, such as trigeminal neuralgia. One of the advantages of BoNT clinical application is its safety. Major adverse effects are application-related and include pain, erythema, pruritus, edema, bruising, hematoma, paraesthesia, and ptosis. In this review BoNT will be analyzed in the historical, pharmacological, biochemical and clinical aspects, but the focus will be on the investigation of the analgesic effect of BoNT that occurs regardless of its muscle relaxant effect.
References
ARCHANA, M. Toxin yet not toxic: botulinum toxin in dentistry. The Saudi Dental Journal, v. 28, 63–69, 2016.
ATTAL, N.et al. Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial. The Lancet Neurology, 15(6), 555–565. doi:10.1016/s1474-4422(16)00017-x
BALI, J.; THAKUR, R.. Poison as cure: a clinical review of botulinum toxin as an invaluable drug. J. Venom. Anim. Toxins incl. Trop. Dis, Botucatu , v. 11, n. 4, p. 412-421, Dec. 2005 . Available from <http://www.scielo.br/scielo.php?script=sci_arttext&pi91992005000400003&lng=en&nrm=iso>. access on 21 Nov. 2019. http://dx.doi.org/10.1590/S1678-91992005000400003.
BOTOX®: Toxina botulínica A. ALLERGAN. Bula de medicamento.
CARDOSO, F. Toxina botulínica tipo B no manejo de distonia não responsiva à toxina botulínica tipo A. Arq Neuropsiquiatr., v.61: 607-610. 2003.
CHUANG, Y.-C.; YOSHIMURA, N.; HUANG, C.-C.; WU, M.; CHIANG, P.-H.; CHANCELLOR, M.B. Intraprostatic botulinum toxin a injection inhibits cyclooxygenase-2 expression and suppresses prostatic pain on capsaicin induced prostatitis model in rat. J. Urol., 180, 742–748. 2008.
CHUANG, Y.-C.; YOSHIMURA, N.; HUANG, C.-C.; WU, M.; CHIANG, P.-H.; CHANCELLOR, M.B. Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats. Eur. Urol., v.56, 159–166. 2009.
CUI, M.; KHANIJOU, S.; RUBINO, J.; AOKI, K.R. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain, 107, 125–133. 2004
DODICK, D.W. et al. OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double-Blind, Randomized, Placebo-Controlled Phases of the PREEMPT Clinical Program. Headach J. Head Face Pain, 50, 921–936. 2010
DRESSLER D, BENECKE R. Pharmacology of therapeutic botulinum toxin preparations. Disabil Rehabill; 29:1761–1768. 2007.
DURHAM, PL; CADY, R .; CADY, R. Regulação da secreção de peptídeos relacionados ao gene da calcitonina das células nervosas trigêmeos pela toxina botulínica tipo A: implicações para a terapia da enxaqueca. Dor de cabeça; v.44 , 35-42; discussão 42-43. 2004.
FAVRE-GUILMARD, C.; CHABRIER, P.-E.; KALINICHEV, M. Bilateral analgesic effects of abobotulinumtoxinA (Dysport®) following unilateral administration in the rat. Eur. J. Pain; v.21, 927–937. 2017
He, Y., Elias, C.L., Huang, Y.C., Gao, X., Leung, Y.M., Kang, Y., Xie, H., Chaddock, J.A., Tsushima, R.G., Gaisano, H.Y. 2008 Botulinum neurotoxin A and neurotoxin E cleavage products of synaptosome-associated protein of 25 kd exhibit distinct actions on pancreatic islet beta-cell Kv2. 1 channel gating. Pancreas 36, 10-17.
Ji, J., Salapatek, A.M., Lau, H., Wang, G., Gaisano, H.Y., Diamant, N.E. 2002 SNAP-25, a SNARE protein, inhibits two types of K channels in esophageal smooth muscle. Gastroenterology 122, 994-1006.
KUKREJA, Roshan. SINGH, Bal. The botulinum toxin as a therapeutic agent: molecular and pharmacological insights. 2015
KUMAR, Raj. Therapeutic use of botulinum toxin in pain treatment. 2018. Neuronal Signaling (2018) 2 NS20180058 https://doi.org/10.1042/NS20180058
MARQUES. Joana Raquel Santos. A Toxina Botulínica: O seu uso clínico. Dissertação de mestrado. Repositório Institucional da Universidade Fernando Pessoa. 2014 acessado: http://hdl.handle.net/10284/4851
Matak I, Bölcskei K, Bach-Rojecky L, Helyes Z. Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins (Basel). 2019 Aug 5;11(8):459. doi: 10.3390/toxins11080459. PMID: 31387301; PMCID: PMC6723487.
Waskitho A, Yamamoto Y, Raman S, Kano F, Yan H, Raju R, Afroz S, Morita T, Ikutame D, Okura K, Oshima M, Yamamoto A, Baba O, Matsuka Y. Peripherally Administered Botulinum Toxin Type A Localizes Bilaterally in Trigeminal Ganglia of Animal Model. Toxins (Basel). 2021 Oct 5;13(10):704. doi: 10.3390/toxins13100704. PMID: 34678997; PMCID: PMC8541196.
Morenilla-Palao, C.; Planells-Cases, R.; García-Sanz, N.; Ferrer-Montiel, A. Regulated Exocytosis Contributes to Protein Kinase C Potentiation of Vanilloid Receptor Activity. J. Biol. Chem. 2004, 279, 25665–25672.
Go EJ, Ji J, Kim YH, Berta T, Park CK. Transient Receptor Potential Channels and Botulinum Neurotoxins in Chronic Pain. Front Mol Neurosci. 2021 Oct 29;14:772719. doi: 10.3389/fnmol.2021.772719. PMID: 34776867; PMCID: PMC8586451.
NEY, John; JOSEPH, Kevin. Neurologic uses of botulinum neurotoxin type A. Neuropsychiatr Dis Treat. 2007 Dec; 3(6): 785–798. doi: 10.2147/ndt.s1612 2007
Pirazzini M, Rossetto O, Eleopra R, Montecucco C. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. Pharmacol Rev. 2017 Apr;69(2):200-235. doi: 10.1124/pr.116.012658. PMID: 28356439; PMCID: PMC5394922.
Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 2008; 64:274-283.
Rosales RL, Arimura K, Takenaga S, Osame M. Extrafusal and intrafusal muscle effects in experimental botulinum toxin-Ainjection. Muscle Nerve 1996;19:488-496.
ROSSETTO, Ornella. PIRAZZINI, Marco. MONTECUCCO, Cesare. Botulinumneurotoxins: genetic, structuralandmechanistic insights. Nature Reviews Microbiology volume12, pages535–549 2014)
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)
SILBERSTEIN et al. Botulinum toxin type a in the prophylactic treatment of chonic Tension-type headache: A multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia, 2006 Jul;26(7):790-800 https://www.ncbi.nlm.nih.gov/pubmed/16776693
SILVA, Joana Filipe Nogueira. A aplicação da Toxina Botulínica e suas complicações: Revisão Bibliográfica, Dissertação de Candidatura ao grau de. Mestre em Medicina Legal submetida ao Instituto de Ciências Biomédicas de Abel Salazar da Universidade do Porto.2011.
Simpson L. The life history of a botulinum toxin molecule. Toxicon. 2013 Jun;68:40-59. doi: 10.1016/j.toxicon.2013.02.014. Epub 2013 Mar 18. PMID: 23518040.
Tehran DA, Pirazzini M. Novel Botulinum Neurotoxins: Exploring Underneath the Iceberg Tip. Toxins (Basel). 2018;10(5):190. Published 2018 May 10. doi:10.3390/toxins10050190
Ting PT, Freiman A. The story of Clostridium botulinum: from food poisoning to Botox. Clin Med (Lond). 2004 May-Jun;4(3):258-61. doi: 10.7861/clinmedicine.4-3-258. PMID: 15244362; PMCID: PMC4953590.
Unno E, Sakata R, Issy A. Estudo comparativo entre toxina botulínica e bupivacaína para infiltração de pontos-gatilho em síndrome miofascial crônica. Rev Bras Anestesiol. 2005;55(2):250-5. http://dx.doi.org/10.1590/S0034-70942005000200011
Zamponi GW. Regulation of presynaptic calcium channels by synaptic proteins. J Pharmacol Sci. 2003 Jun;92(2):79-83. doi: 10.1254/jphs.92.79. PMID: 12832834.