Evidence for a Dynorphin-Mediated Inner Ear Immune Response/Inflammatory Response/ Glutamate-Induced Neural Excitotoxicity: An Updated Analysis.

Manuscript Re-Submission/Revision: Accepted Pending Revisions (in progress). TL Sahley, DJ Anderson, MD Hammonds, K Chandu, FE Musiek (2018). Evidence for a Dynorphin-Mediated Inner Ear Immune/Inflammatory Response and Glutamate-Induced Neural Excitotoxicity: An Updated Analysis. (originally 65 pages-374 citations); submitted: The Journal of Neurophysiology The Revised Manuscript (above) is now Completed-It is presently undergoing careful editing by the co-authors. It has 61 pages of text; plus added pages with 374 citations. Evidence for a Dynorphin-Mediated Inner Ear Immune Response/Inflammatory Response/ Glutamate-Induced Neural Excitotoxicity: An Updated Analysis Tony L. Sahley, Ph.D.a*; David J. Anderson, Ph.D.b; Michael D. Hammonds, Ph.D.c; Karthik Chandub and Frank E. Musiek, Ph.D.d a School of Health Sciences and Department of Biological, Geological and Environmental Sciences, 116 Center for Innovation in Medical Professions, Cleveland State University, Cleveland OH, USA. b Department of Chemistry, Cleveland State University, Cleveland OH, USA. c School of Health Sciences, 118 Center for Innovation in Medical Professions, Cleveland State University, Cleveland OH, USA. d Department of Speech, Language & Hearing Sciences, University of Arizona, Tucson AZ, USA. Abstract Acoustic overstimulation (AOS) is defined as the stressful over-exposure to high intensity sounds. AOS is a precipitating factor that leads to a glutamate (GLU)-induced Type-I auditory neural excitotoxicity and an activation of an immune/inflammatory/oxidative stress response within the inner ear, often resulting in cochlear hearing loss. The dendrites of the Type-I auditory neural neurons that innervate the inner hair cells (IHCs) and respond to the IHC release of the excitatory neurotransmitter GLU are themselves directly innervated by the dynorphin (DYN)-bearing axon terminals of the descending brainstem lateral olivocochlear (LOC) system. DYNs are known to increase GLU availability, potentiate GLU excitotoxicity, and induce superoxide production. DYNs also increase the production of pro-inflammatory cytokines and chemokines by modulating immune/inflammatory signal transduction pathways. Evidence is provided supporting the possibility that the GLU-mediated Type-I auditory neural dendritic swelling, inflammation, excitotoxicity and cochlear hearing loss that follows AOS may be part of a brainstem activated, DYN-mediated cascade of inflammatory events subsequent to a LOC release of DYNs into the cochlea. In support of this DYN-mediated cascade of events are established investigations linking DYNs to the immune/inflammatory/excitotoxic response in other neural systems. Key Words: Dynorphins; Glutamate; Excitotoxicity; Inflammation; NMDA receptors; Lateral olivocochlear system; Locus coeruleus; Cytokines; Chemokines; Oxidative Stress;