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.
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