BASIC AND CLINICAL RESEARCHES ON THE DYSFUNCTION OF COCHLEAR EFFERENT SIGNAL TRANSDUCTION AS A MECHANISM OF TINNITUS

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In the clinical studies, the effects of sound stimulation and lidocaine on the otoacoustic emissions which reflect the function of cochlear efferent system, were investigated. The ipsi- and contra-lateral sound stimulations reduced the otoacoustic emissions, suggesting that the cochlear efferent nerve stimulation may inhibit the cochlear outer hair cell motility. Lidocaine is well known to be capable of releasing tinnitus. We introduced an intravenous continuous lidocaine infusion therapy, and showed that this therapy might be useful for tinnitus management. However, the effects of lidocaine on the otoacoustic emissions varied in each tinnitus patients. Therefore, we basically investigated the effects of lidocaine on the cochlear efferent signal transduction. At first, we studied the signal transduction mechanisms in the cochlear efferent system including the outer hair cells. The IP3 second messenger system in the outer hair cells regulated by the efferent nerves via muscarinic receptors. Acethylcholine stimulates PLC via G-protein, which results in the release of IP3 and diacylglycerol. The efferent nerve stimulates the release of IP3 with mobilizes intracellular calcium in the outer hair cells. These second messengers are postulated to modulate the active motile property of the outer hair cells. We also showed the heterogeneity of PLC and PKC isozymes in the cochlear sensory epithelia. Lidocaine induced the release of inositol phosphates (IPs) in the dose-dependent manner. This effect of lidocaine was independent of the cholinergic receptor nor G-protein mediated releases of IPs, indicating that lidocaine may directly activate PLC.In addition, lidocainc increased intracellular Ca^<2+> concentration of OHCs and shortened OHCs. From these results, we hypothesized that lidocaine stimulates the IP3 second messenger system of OHCs, which results in the suppression of tinnitus. Further study will be conducted on the mechanisms of tinnitus.