|Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2003: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
In 2001, we investigated primary location and character of the neurotoxic lesions caused by tetracaine, lidocaine, bupivacaine, mepibacaine, prilocaine, procaine, dibucaine, levobupivacaine, ropivacaine. We found that these lesions commonly commence from posterior root just entrance into the spinal cord, extending to posterior white matter due to axonal degeneration. Thus, histopathogical character was virtually identical. However, grade of neurotoxicity was quite different. In our result, bupivacaine, lidocaine, tetracaine has higher neurotoxicity in order, while ropivacaine, levobupivacaine, procaine have less neurotoxicity in order. In 2002 and 2003, to determine mechanisms of neurotoxicity of lidocaine, the lidocaine-induced impairment of axonal transport in cultured mouse dorsal root ganglion neurons was investigated. Lidocaine inhibited axonal transport in a dose-dependent manner. Higher concentrations (50-100 mM) of lidocaine caused membrane rupture and cell death. Ca2+-free solution and the Ca2+calmodulin Kinase II (CAM Kinase II) inhibitor KN-62 reduced the inhibition of axonal transport but not membrane rupture. Lysophosphatidic acid, a bioactive phospholipid, blocked both the inhibition of axonal transport and membrane rupture. Thus, lidocaine at tower concentration(<10 mM) may form pores in the membrane, resulting in Ca2+ influx and activation of CAM Kinase II to inhibit axonal transport. Neurotoxic effect of higher concentrations of lidocaine seems to be a direct disruption of cell membrane. Lysophosphatidic acid may be useful to prevent neurotoxicity of lidocaine even at higher concentrations.