Treatment With Botulinum Neurotoxin of Gastrointestinal Smooth Muscles and Sphincters Spasms Giuseppe Brisinda, MD, 1 Anna Rita Bentivoglio, MD, 2 Giorgio Maria, MD, 1 and Alberto Albanese, MD 2,3 * 1 Istituto di Clinica Chirurgica, Universita ` Cattolica del Sacro Cuore, Roma, Italy 2 Istituto di Neurologia, Universita ` Cattolica del Sacro Cuore, Roma, Italy 3 Istituto Nazionale Neurologico Carlo Besta, Milano, Italy Abstract: Local injections of botulinum neurotoxin are now considered an efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin provides benefit in diseases of the gastrointesti- nal tract. Botulinum neurotoxin inhibits contraction of gas- trointestinal smooth muscles and sphincters; it has also been shown that the neurotoxin blocks cholinergic nerve endings in the autonomic nervous system, but it does not block nonadrenergic responses mediated by nitric oxide. This as- pect has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles, such as the anal sphincters to treat anal fissure and outlet- type constipation, or the lower esophageal sphincter to treat esophageal achalasia. Knowledge of the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understanding many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review pre- sents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system. © 2004 Move- ment Disorder Society Key words: anus; physiopathology; autonomic nervous sys- tem diseases; botulinum toxin; therapeutic use; enteric nervous system; esophageal achalasia; esophageal diseases; exocytosis; fissure-in-ano; gastric emptying; gastrointestinal motility; membrane fusion; membrane proteins; neuromuscular agents; spasm After the discovery that botulinum neurotoxins (BoNT) inhibit neuromuscular transmission, the range of clinical applications has grown to encompass sev- eral neurological and non-neurological conditions. Over the years, the number of primary clinical publi- cations has grown exponentially and continues to in- crease every year. One of the most recent discoveries is the observation that injections of BoNT ameliorate diseases of the gastrointestinal tract (GIT). BoNT is not only potent in blocking skeletal neuromuscular transmission but also in blocking cholinergic nerve endings in the autonomic nervous system. 1 The capa- bility of BoNT to inhibit contraction of GIT smooth muscles, first based on in vitro and later on in vivo observations, has been shown to be due to inhibition of acetyl choline (ACh) release rather than affecting con- tractions mediated by nitric oxide (NO). 2 This finding has further promoted the interest to use BoNT as a treatment for overactive smooth muscles and sphinc- ters, such as the lower esophageal sphincter (LES), to treat achalasia, or for the anal sphincters, to treat anal fissure and outlet-type constipation. Information on the anatomical and functional orga- nization of GIT innervation is a prerequisite to under- standing many features of BoNT action on the GIT and the effects of injections placed into specific sphincters. This review presents current data on the use of BoNT to treat GIT diseases and summarizes recent knowledge on the pathogenesis of GIT disor- ders due to a dysfunction of the enteric nervous system (ENS). *Correspondence to: Dr. Alberto Albanese, Istituto Neurologico Carlo Besta, Via Caloria 11, 20133 Milano, Italy. E-mail: alberto.albanese@rm.unicatt.it DOI 10.1002/mds.20070 Published online in Wiley InterScience (www.interscience.wiley. com). Movement Disorders Vol. 19, Suppl. 8, 2004, pp. S146 –S156 © 2004 Movement Disorder Society S146