PAIN MEDICINE Anesthesiology 2010; 112:1452– 63 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins Pungent General Anesthetics Activate Transient Receptor Potential-A1 to Produce Hyperalgesia and Neurogenic Bronchoconstriction Helge Eilers, M.D.,* Fiore Cattaruzza, Ph.D.,† Romina Nassini, Ph.D.,§ Serena Materazzi, Ph.D.,§ Eunice Andre, Ph.D., Catherine Chu, B.A.,# Graeme S. Cottrell, Ph.D.,† Mark Schumacher, Ph.D., M.D.,* Pierangelo Geppetti, M.D.,** Nigel W. Bunnett, Ph.D.†† ABSTRACT Background: Volatile anesthetics such as isoflurane and halo- thane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anes- thesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of pe- ripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways. Methods: To test the hypothesis that irritant inhaled anesthet- ics activate the excitatory ion-channel transient receptor poten- tial (TRP)-A1 and thereby contribute to hyperalgesia and irri- tant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our func- tional experiments, we used models of isolated guinea pig bron- chi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice. Results: Irritant inhaled anesthetics activate TRPA1 ex- pressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonir- ritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction. Conclusions: General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting. A NNUALLY, there are approximately 21 million general anesthesia cases in the United States, 1 most of which in- volve administration of volatile anesthetics for maintenance of anesthesia. Although general anesthetics have different effect * Associate Professor, # Assistant Researcher, Department of An- esthesia, † Assistant Researcher, Department of Surgery, †† Profes- sor, Departments of Surgery and Physiology, University of Califor- nia, San Francisco, San Francisco, California. § Assistant Researcher, Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.  Assistant Researcher, Center of Excel- lence for the Study of Inflammation, University of Ferrara, Ferrara, Italy. ** Professor, Center of Excellence for the Study of Inflamma- tion, University of Ferrara, and Department of Preclinical and Clin- ical Pharmacology, University of Florence. Received from Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California. Sub- mitted for publication October 13, 2009. Accepted for publication January 19, 2010. Supported by Hellman Family Foundation Fellow- ship, San Francisco, California (to Dr. Eilers), and by DK57840, DK39957, DK43207, DK46285, National Institute of Diabetes and Di- gestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (to Dr. Bunnett). Presented in part at the Annual Meeting of the American Society of Anesthesiologists, San Francisco, California, October 13, 2007, and at the Annual Meetings of the International Anesthesia Research Society, San Francisco, California, March 19, 2008, and International Association for the Study of Pain, World Congress on Pain, Glasgow, United Kingdom, August 20, 2008. Address correspondence to Dr. Eilers: Department of Anesthesia and Perioperative Care, University of California, San Francisco, 513 Parnassus Avenue, Room S-436, Box 0427, San Francisco, California 94143-0427. eilersh@anesthesia.ucsf.edu. This article may be ac- cessed for personal use at no charge through the Journal Web site, www.anesthesiology.org.  This article is featured in “This Month in Anesthesiology.” Please see this issue of ANESTHESIOLOGY, page 9A.  This article is accompanied by an Editorial View. Please see: Gallos G, Flood P: Wasabi and a volatile anesthetic. ANESTHESIOLOGY 2010; 112:1309 –10. What We Already Know about This Topic ❖ Volatile anesthetics produce irritant airway effects and can, in low concentrations, increase pain perception ❖ Transient receptor potential (TRP) channels are found in sensory neurons and airway cells and could be activated by volatile agents to cause these effects What This Article Tells Us That Is New ❖ Using cells in cultures, bronchial rings in vitro, and behavior tests in rats, general anesthetics activate TRPA1 channels and cause hypersensitivity and bronchial constriction 1452 Anesthesiology, V 112 • No 6 • June 2010 Downloaded from anesthesiology.pubs.asahq.org by guest on 06/10/2020