The focus of this project will be the cellular and molecular mechanism mediating opiate-induced deafness and vestibular dysfunction. Profound bilateral deafness requiring cochlear implantation secondary to chronic high dose use of acetaminophen/hydrocodone has been reported by our Neurotology Clinic. Heroin and propoxyphene have also been associated with profound deafness and vestibular dysfunction. These experiments will test the hypotheses that: 1) There is a differential expression of opioid receptor mRNA in the rat and human auditory and vestibular periphery. 2) There is conservation of mRNA opioid receptor expression between rodent and human. 3) There is a higher degree of opioid receptor expression in the auditory than vestibular periphery. 4) NMDA and opioid receptors colocalize within the inner cochlear and type I vestibular hair cell. 5) Activation of opioid receptors in the inner ear will induce similar changes in cellular signaling pathways as activation in the central nervous system. 6) Chronic opiates induce opioid receptor mediated supersensitivity state, characterized by increased activation of adenylate cyclase, cAMP-response element binding protein (CREB), mitogen- activated kinase (MAP kinase), and Akt (a serine/threonine protein kinase). In order to accomplish these objectives, inner ear tissues will be used for reverse-transcription-polymerase chain reaction (RT-PCR), in situ hybridization, immunohistochernistry, morphological studies, and biochemical assays in both in vitro and in vivo models of acute and chronic opiate use. Information gained during the five year period will also provide basic science data relevant to the normal function of opioid signaling in the audiovestibular periphery. The mentored clinical scientist development award (MCSDA) is critical for the principal investigator to master the molecular and cellular biological techniques needed to establish herself as an academic neurotologist as it allows protected and mentored time.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DC005187-05
Application #
7079281
Study Section
Communication Disorders Review Committee (CDRC)
Program Officer
Sklare, Dan
Project Start
2002-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$185,256
Indirect Cost
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Nguyen, Kimanh D; Mowlds, Donald; Lopez, Ivan A et al. (2014) Mu-opioid receptor (MOR) expression in the human spiral ganglia. Brain Res 1590:10-9
Calzada, Audrey P; Balaker, Ashley E; Ishiyama, Gail et al. (2012) Temporal bone histopathology and immunoglobulin deposition in Sjogren's syndrome. Otol Neurotol 33:258-66
Miller, Mia E; Makary, Chadi; Lopez, Ivan A et al. (2010) Endolymphatic hydrops in otologic syphilis: a temporal bone study. Otol Neurotol 31:681-6
Ishiyama, Gail; Lopez, Ivan A; Beltran-Parrazal, Luis et al. (2010) Immunohistochemical localization and mRNA expression of aquaporins in the macula utriculi of patients with Meniere's disease and acoustic neuroma. Cell Tissue Res 340:407-19
Ishiyama, Akira; Mowry, Sarah E; Lopez, Ivan A et al. (2009) Immunohistochemical distribution of basement membrane proteins in the human inner ear from older subjects. Hear Res 254:1-14
Ishiyama, Gail (2009) Imbalance and vertigo: the aging human vestibular periphery. Semin Neurol 29:491-9
Ishiyama, Gail; Tokita, Joshua; Lopez, Ivan et al. (2007) Unbiased stereological estimation of the spiral ligament and stria vascularis volumes in aging and Meniere's disease using archival human temporal bones. J Assoc Res Otolaryngol 8:8-17
Ishiyama, Gail; Lopez, Ivan; Baloh, Robert W et al. (2007) Histopathology of the vestibular end organs after intratympanic gentamicin failure for Meniere's disease. Acta Otolaryngol 127:34-40
Kho, Soochuen T; Lopez, Ivan A; Evans, Christopher et al. (2006) Immunolocalization of orphanin FQ in rat cochlea. Brain Res 1113:146-52
Ishiyama, Gail; Lopez, Ivan A; Ishiyama, Akira (2006) Aquaporins and Meniere's disease. Curr Opin Otolaryngol Head Neck Surg 14:332-6

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