For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Neurology Vol 1 July 2002 http://neurology.thelancet.com 167 Review Intravesical vanilloid therapy Vanilloid sensitivity is a functional signature of a subset of unmyelinated fibres innervating the urinary bladder. The role that these nerves have in the physiological control of storage and voiding is unclear. However, after the bladder has been disconnected by spinal injury from the pontine micturition centre, vanilloid-sensitive fibres assume a central role in the reflex emptying of the bladder that occurs at low volumes. Intravesical vanilloid (capsaicin or resiniferatoxin) administration is beneficial in this disorder by “desensitising” these nerves. Resiniferatoxin is superior to capsaicin in terms of its tolerability profile. Investigators are moving rapidly to identify the mechanisms by which desensitisation to vanilloids occurs. Vanilloids induce lasting, but fully reversible, changes in gene expression, including downregulation of the vanilloid receptor subtype 1. It is hoped that application of gene chip technologies will address the global profile of vanilloid- induced changes in gene expression and their relative contribution to desensitisation. Drugs that target signalling mechanisms that bring about these changes in gene expression have obvious therapeutic potential. Lancet Neurology 2002; 1: 167–72 A subset of primary sensory neurons is distinguished by their sensitivity to capsaicin (figure 1), the pungent principle in hot pepper. 1,2 These neurons are unique in that their initial excitation by capsaicin is followed by a lasting refractory state, traditionally referred to as desensitisation. 1 This characteristic provides capsaicin with a clear therapeutic potential in disease states, such as neuropathic pain, pruritus, and other disorders, particularly disorders of the urinary bladder in which abnormal afferent sensory information conveyed by capsaicin-sensitive nerves is a major factor in the aetiology. 3 The use of capsaicin to relieve pain and itching has been reviewed extensively 3–5 and will not be dealt with here. As is common for natural products, clinical trials with capsaicin began many years before the discovery of its receptor and the subcellular mechanisms of action downstream to receptor activation. Since the molecular cloning in 1997 of cDNA encoding a functional capsaicin receptor, termed vanilloid-receptor subtype 1 (VR1), 6 there has been a steady flow of bewildering new discoveries causing us to rethink what is known about vanilloid receptor ligands and their therapeutic potential. This review focuses on the implications for intravesical vanilloid therapy of newly acquired knowledge of the molecular pharmacology of VR1. Attempts to develop novel vanilloid drugs will be AS is at the Department of Pathology and Immunology, Washington University School of Medicine, St Louis, USA. CJF is at the Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, UK Correspondence: Arpad Szallasi, Division of Clinical Pathology, Department of Pathology and Immunology, Washington University School of Medicine, 1 Barnes Plaza, St Louis, MO 63110, USA. Tel +1 314 836 5467; fax +1 314 362 8950; email aszallasi@path.wustl.edu. After a decade of intravesical vanilloid therapy: still more questions than answers Arpad Szallasi and Clare J Fowler O Anandamide Capsaicin Resiniferatoxin OH OH H OCH 3 OCH 3 OH O O N H N H OH O O O O Figure 1. Vanilloid structures: capsaicin, the irritant principle in hot pepper; resiniferatoxin, isolated from the medicinal plant Euphorbia resinifera; and anandamide, originally identified as an endogenous activator (“endocannabinoid”) of cannabinoid CB 1 receptors. The vanillyl moiety, after which the vanilloid receptor VR1 was named, is highlighted in red. Anandamide lacks the vanillyl group but shows limited structural similarity to capsaicin in the amide linkage (highlighted in blue).