The administration of epidural doses of the local anesthetic NESACAINE-CE (2-chloroprocaine) was the common factor in recent reports of long-lasting neurological deficits following regional anesthesia. Subsequent reviews of the clinical literature as well as numerous experimental studies have failed to discriminate if nerve injury should be attributed to some or all local anesthetics, the NESACAINE antioxidant, or the inadvertent administration of large epidural doses into the spinal cord subarachnoid space. It is not possible to explain these inconsistencies in the absence of information about the mechanisms of the observed injury. Using a rat sciatic nerve model, the applicant has demonstrated that local anesthetic-induced peripheral nerve injury is mediated by an initial increase in permeability of the perineurial sheath, followed by decreased nerve blood flow, dilution of normally hypertonic endoneurial fluid, increased endoneurial fluid pressure, injury of Schwann cells, and nerve fiber injury. In spinal cord the possible interactions between altered permeability of barrier systems, injury-induced fluid accumulation, and changes in interstitial fluid chemistry have not been considered previously for any model of central nervous system toxicity; therefore, it is important that studies in the sciatic nerve be extended to test the hypothesis that spinal cord toxicity following local anesthetic administration is mediated by changes in the interstitial environment affecting both structure and function. Specifically, neurological injury might be secondary to alterations in protective barrier systems and a compromise of nutritive blood flow. Commercial local anesthetic preparations will first be tested using quantitative measures of electrophysiological function in order to determine the relative toxicity of the epidural and subarachnoid routes of administration. Nerve conduction velocity and refractory periods will be determined for both dorsal roots and microfilaments. Using this model of functional deficit, the toxicity of local anesthetics, drug vehicles, and injection volume will be tested. Subsequent experiments will provide functional and structural evidence for corresponding changes in nerve fibers, the dura mater barrier, spinal cord blood flow, and interstitial fluid. These experiments will quantify changes in barrier permeability (penetration of horseradish peroxidase), blood flow (measured with a diffusible tracer), endoneurial fluid electrolytes (visualized with energy dispersive x-ray spectrometry), and fluid pressure.
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