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

在临床研究中，观察了声刺激和利多卡因对反映耳蜗传出系统功能的耳声发射的影响。同侧和对侧声刺激均使耳声发射减少，提示耳蜗神经传出神经刺激可能抑制耳蜗外毛细胞的运动。众所周知，利多卡因能够缓解耳鸣。我们介绍了一种静脉持续利多卡因输注疗法，并表明这种疗法可能对耳鸣的治疗有用。然而，利多卡因对每个耳鸣患者的耳声发射的影响是不同的。因此，我们主要研究利多卡因对耳蜗传出信号转导的影响。首先，我们研究了包括外毛细胞在内的耳蜗神经传出系统的信号转导机制。外毛细胞中的IP3第二信使系统受传出神经通过M受体调节。乙酰胆碱通过G蛋白刺激PLC，导致IP3和二酰甘油的释放。传出神经通过动员外毛细胞内钙离子来刺激IP3的释放。这些第二信使被认为是调节外毛细胞的主动运动特性。我们还发现耳蜗感觉上皮中PLC和PKC同工酶的异质性。利多卡因以剂量依赖的方式诱导肌醇磷酸酶(IP)释放。利多卡因的这种作用不依赖于胆碱能受体或G蛋白介导的IP释放，提示利多卡因可直接激活PLC。此外，利多卡因还可增加内皮细胞和缩短的内皮细胞内钙离子浓度。根据这些结果，我们假设利多卡因刺激毛细胞的IP3第二信使系统，从而导致耳鸣的抑制。对耳鸣的机制将进行进一步的研究。

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.