PD19-10 P38 MITOGEN-ACTIVATED PROTEIN KINASE INHIBITOR REDUCES HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY

Abstract

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology I1 Apr 2018PD19-10 P38 MITOGEN-ACTIVATED PROTEIN KINASE INHIBITOR REDUCES HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY Takahisa Suzuki, Takahiro Shimizu, Nobutaka Shimizu, Jianshu Ni, Shinsuke Mizoguchi, Eiichiro Takaoka, Hideaki Miyake, Anthony J Kanai, and Naoki Yoshimura Takahisa SuzukiTakahisa Suzuki More articles by this author , Takahiro ShimizuTakahiro Shimizu More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Jianshu NiJianshu Ni More articles by this author , Shinsuke MizoguchiShinsuke Mizoguchi More articles by this author , Eiichiro TakaokaEiichiro Takaoka More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , Anthony J KanaiAnthony J Kanai More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1000AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nerve growth factor (NGF) has been implicated as an important mediator to induce C-fiber bladder afferent hyperexcitability, which contributes to the emergence of neurogenic detrusor overactivity following spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined whether p38 MAPK inhibition using SB203580 (p38 MAPK inhibitor) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fiber bladder afferent neurons in the mouse SCI model. METHODS The spinal cord was transected at the Th8/9 level in 8-9 weeks old female C57BL/6 mice. Two weeks later, SB203580 (1 mg/ml) was injected intrathecally using an osmotic pump at infusion rate of 0.51 µl/hr for 2 weeks. Instead of SB203580, artificial cerebrospinal fluid was injected in separate groups of spinal intact (SI) and SCI mice as controls. Bladder afferent neurons were labeled with axonal transport of Fast Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Dissociated L6 and S1 dorsal root ganglion neurons were prepared 4 weeks after SCI. Whole cell patch clamp recordings were performed in FB-labeled bladder afferent neurons, and the data were compared among control SI, SCI and SCI treated with p38 MAPK inhibitor mice. After recording action potentials (AP) or voltage-gated K+ (Kv) currents, the sensitivity of each neuron to capsaicin was evaluated. RESULTS In capsaicin-sensitive bladder afferent neurons, the threshold for eliciting AP was significantly reduced in control SCI compared to SI mice. Also, SCI increased the number of AP during 800 ms membrane depolarization. These SCI induced hyperexcitability was reversed by p38 MAPK inhibitor. Densities of slow decaying KA and sustained KDR currents evoked by depolarization to 0 mV were significantly reduced after SCI. The treatment with a p38 MAPK inhibitor reversed the SCI-induced reduction in the KA current density, but not in the KDR. CONCLUSIONS In SCI mice, p38 MAPK signaling pathways play an important role in hyperexcitability of capsaicin sensitive C-fiber bladder afferent neurons due to KA current reduction. Thus, p38 MAPK-targeting therapies could be effective for treatment of afferent hyperexcitability in SCI. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e399-e400 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Takahisa Suzuki More articles by this author Takahiro Shimizu More articles by this author Nobutaka Shimizu More articles by this author Jianshu Ni More articles by this author Shinsuke Mizoguchi More articles by this author Eiichiro Takaoka More articles by this author Hideaki Miyake More articles by this author Anthony J Kanai More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...