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Severe neurologic sequelae have been reported with the use of lidocaine after spinal anesthesia. This is considered a consequence of the high concentrations reached in the cerebrospinal fluid. We have previously shown that lidocaine increases the phosphorylation of focal adhesion kinase (FAK, a nonreceptor tyrosine kinase playing a role in neuronal plasticity and cell death). Here, we compared the effects of lidocaine and bupivacaine on FAK phosphorylation and cleaved caspase 3 expression in rat hippocampal slices. Slices were treated with increasing concentrations of lidocaine (4.3 nM to 4.3 mM) or bupivacaine (3.4 nM to 3.4 mM) in the presence or absence of the specific inhibitor of the FAK tyrosine kinase PP2 (10 μM). Caspase 3 expression and FAK phosphorylation were examined by immunoblotting. Lidocaine induced a concentration-related increase in FAK phosphorylation while the bupivacaine effect was biphasic. The maximal effect observed with millimolar lidocaine concentrations was significantly more than with clinically equipotent bupivacaine concentrations (4.3 × 10−3 M lidocaine: 168% ± 20%, mean value ± sd; 10−3 M bupivacaine: 145% ± 19% P < 0.001). The expression of cleaved caspase 3 was increased by lidocaine, but not bupivacaine, at millimolar concentrations and was blocked by PP2. Our results indicate that millimolar concentrations of lidocaine, but not bupivacaine, increase cleaved caspase 3 expression. The role of FAK phosphorylation in this effect remains to be clarified.