MOLECULAR STUDIES OF BAB--LONG DURATION ANESTHETIC

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A promising new approach for the treatment of chronic pain is the use of sustained release methodologies that directly deliver anesthetics to the dorsal roots resulting in long-term regional anesthesia. This usually involves dissolving anesthetics in suspensions that are injected into our epidural space. The slow leeching of the anesthetics from the suspension provides a constant source of anesthetic to the sensory nerve fibers resulting in the prolong relief of pain. In 1987 Shulman/37 reported that the epidural administration of n-butyl-p-aminobenzoate (BAB), an ester derivative of benzoic acid, produce long lasting analgesia in terminally ill cancer patients that can last up to several months. Clinically, few deleterious side effects have been identified with BAB treatment. Surprisingly, the pain relief produced by BAB is not associated with any demonstratable loss in motor function. This suggests that BAB acts by selectively targeting nociceptive neurons of the dorsal root ganglion (DRG). Although BAB shows great promise as a long-lasting anesthetic for the treatment of chronic pain, the effects of BAB at the cellular level are not known. Preliminary studies indicate that BAB selectively inhibits voltage-gated Na channels. At least five different components of Na current contribute to the action potentials of DRG neurons. This heterogeneity has significantly hampered more detailed studies of BAB action. In an attempt to eliminate some of this ambiguity, we plan to further study the effects of BAB on cloned Na channels expressed in cultured cells and recorded by patch clamp techniques. Our experiments will focus on the peripheral nerve (PN1, PN3) and brain (RBI, rBIIA) Na channels that are known to be expressed in the DRG. We plan to use site- directed mutagenesis to characterize the BAB binding sites of these neuronal Na channels. In addition we plan to correlate our studies of cloned channels with data from native neurons by using antisense oligodeoxynucleotides to selectively suppress the expression of native DRG Na channels. Our proposed studies will provide a better understanding of the molecular mechanism of BAB action and its effects on the nociceptive neurons of the DRG.