MP1-03 HERPES SIMPLEX VIRUS (HSV) VECTOR-MEDIATED GENE DELIVERY OF PROTEIN PHOSPHATASE 1α REDUCES BLADDER OVERACTIVITY AND NOCICEPTION IN RATS

Abstract

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research I1 Apr 2014MP1-03 HERPES SIMPLEX VIRUS (HSV) VECTOR-MEDIATED GENE DELIVERY OF PROTEIN PHOSPHATASE 1α REDUCES BLADDER OVERACTIVITY AND NOCICEPTION IN RATS Tsuyoshi Majima, Naoki Kawamorita, Hiroki Okada, Yasuhito Funahashi, Momokazu Gotoh, William Goins, Joseph Glorioso, Justus Cohen, Bonnie Hall, Asaff Harel, and Naoki Yoshimura Tsuyoshi MajimaTsuyoshi Majima More articles by this author , Naoki KawamoritaNaoki Kawamorita More articles by this author , Hiroki OkadaHiroki Okada More articles by this author , Yasuhito FunahashiYasuhito Funahashi More articles by this author , Momokazu GotohMomokazu Gotoh More articles by this author , William GoinsWilliam Goins More articles by this author , Joseph GloriosoJoseph Glorioso More articles by this author , Justus CohenJustus Cohen More articles by this author , Bonnie HallBonnie Hall More articles by this author , Asaff HarelAsaff Harel More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.101AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Increased afferent excitability has been proposed as an important pathophysiological basis of overactive bladder (OAB) and hypersensitive bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). It has also been reported that transient receptor potential vanilloid-1 (TRPV1) receptors predominantly expressed in C-fiber afferent pathways greatly contribute to afferent sensitization in these disease conditions. We recently found Protein Phosphatase 1α (PP1α) as a modulator of TRPV1 receptor activity using an HSV vector cDNA library screen method to identify genes that inhibit TRPV1 activation, and showed that HSV vector-mediated PP1α expression led to the reduction in capsaicin-induced thermal hyperalgesia. Therefore, this led us to investigate the effect of HSV vectors-mediated gene delivery of PP1α on TRPV1-mediated bladder overactivity and pain-related behavior in rats. METHODS Replication-deficient HSV vectors encoding PP1α or green fluorescent protein (GFP) as control were injected into the bladder wall of adult female Sprague-Dawley rats. Cystometry (CMG) under urethane anesthesia was performed 1 week after viral injection to evaluate bladder overactivity induced by resiniferatoxin (RTX, a TRPV1 agonist). RTX-induced nociceptive behavior such as licking (lower abdominal licking) and freezing (motionless head-turning) was observed 2 weeks after viral injection. Using immunohistochemistry, GFP expression in L6/S1 DRG and the bladder as well as c-Fos positive cells in the L6 spinal cord dorsal horn were evaluated. RESULTS GFP expression was seen in L6/S1 DRG sections. In CMG, the PP1α group showed a significantly (p<0.05) smaller reduction (46.5±1.7%) in intercontraction intervals after RTX infusion than the GFP group (65.7±3.8%). The number of RTX-induced freezing behavior, which is correlated with bladder pain sensation, was significantly (p<0.001) decreased in PP1α vs. GFP groups. The number of c-Fos positive cells in the L6 spinal dorsal horn was significantly (p<0.01) smaller in PP1α vs. GFP rats (24±4 vs. 59±6 cells per section). CONCLUSIONS These results indicate that HSV vectors injected into the bladder wall are transported to lumbosacral DRGs that contain bladder afferent neurons, and that PP1α gene delivery in the bladder is effective in suppressing TRPV1-mediated bladder overactivity and pain behavior. Thus, HSV-mediated PP1α gene therapy could be effective for the treatment of OAB and/or hypersensitive bladder disorders such as IC/BPS. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e1-e2 Peer Review Report Advertisement Copyright & Permissions© 2014MetricsAuthor Information Tsuyoshi Majima More articles by this author Naoki Kawamorita More articles by this author Hiroki Okada More articles by this author Yasuhito Funahashi More articles by this author Momokazu Gotoh More articles by this author William Goins More articles by this author Joseph Glorioso More articles by this author Justus Cohen More articles by this author Bonnie Hall More articles by this author Asaff Harel More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...