title: Targeting afferent hyperexcitability for therapy of the painful bladder syndrome.
abstract: The involvement of C-fiber afferent pathways in urinary frequency and pain associated with painful bladder syndrome raises the possibility of multiple targets for the treatment of this disease. Using an in vivo measurement of bladder activity as well as whole-cell patch clamp recording techniques to examine the properties of bladder afferent neurons in animal models of chronic cystitis, we have documented that tetrodotoxin-resistant sodium channels encoded by the Na(v) 1.8 (PN3/SNS) gene and nitric oxide acting via a cyclic guanosine monophosphate (cGMP)-dependent mechanism are important in modulating bladder pain responses. Thus, suppression of C-fiber afferent nerve activity by blocking specific sodium channels, elevating nitric oxide levels, or activating cGMP-dependent pathways might represent novel strategies for the treatment of symptoms in patients with painful bladder syndrome. Another treatment strategy is suppression of release or activity of proinflammatory agents that can cause normally unexcitable C-fiber afferents to become hyperactive or hyperexcitable. This approach to management of bladder pain was tested in patients with painful bladder syndrome by examining the effectiveness of the antiallergic agent suplatast tosilate (IPD-1151T), which suppresses urinary frequency in a rat model of cystitis. IPD-1151T is an immunoregulator that suppresses cytokine production in T-helper 2 cells and inhibits immunoglobulin E antibody formation and antigen-induced histamine release from mast cells. Preliminary data from an open-label clinical trial showed that 16 of 23 (70%) patients responded to treatment with IPD-1151T (300 mg/day orally for 12 months). The finding that expression of platelet-derived endothelial cell growth factor, which can activate mast cells, was lower in the bladder of responders than nonresponders indicates that bladder levels of platelet-derived endothelial cell growth factor may be a useful marker for this disease.
authors: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. nyos@pitt.edu
authors: Naoki
authors: N
authors: Yoshimura
authors: Satoshi
authors: S
authors: Seki
authors: Michael B
authors: MB
authors: Chancellor
authors: William C
authors: WC
authors: de Groat
authors: Tomohiro
authors: T
authors: Ueda
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects* / Q000502:physiology; D018926:Anti-Allergic Agents / Q000627:therapeutic use*; D001190:Arylsulfonates / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D009412:Nerve Fibers / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D026941:Sodium Channel Blockers; D013452:Sulfonium Compounds / Q000627:therapeutic use*; D013577:Syndrome; D001743:Urinary Bladder / Q000294:innervation; D001745:Urinary Bladder Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D014555:Urination Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D018926:Anti-Allergic Agents; D001190:Arylsulfonates; D020319:Oligodeoxyribonucleotides, Antisense; D026941:Sodium Channel Blockers; D013452:Sulfonium Compounds; D009569:Nitric Oxide; C073028:suplatast tosilate; D006152:Cyclic GMP