Peripheral neural blockade with local anesthetics is commonly used as a method of effective postoperative analgesia, however, the value of blockade is decreased by its non-selective nature. In this project, we will examine the mechanisms of neural blockade induced by vanilloid agonists with the aim of using these mechanisms in the search for an agent with selective, long-lasting, and spontaneously reversible local analgesic action. The main hypothesis of this project is that a single local application of a vanilloid agonist to a peripheral nerve can abolish pain behavior and hyperalgesia for the whole period of postincisional inflammation. We will also examine the cellular mechanisms of vanilloid-induced neural blockade. The following three Specific Aims are proposed: to determine, (1) if resiniferatoxin (RTX) applied locally to a peripheral nerve, provides a long-lasting suppression of the responses to noxious stimuli; in addition, it will be determined if this effect is mediated by vanilloid receptors and has a sufficient safety in relation to irreversible neural blockade and to disruption of other functions; (2) if selective neural blockade by RTX prevents and reverses pain behavior and hyperalgesia in carrageenan-induced inflammation and incisional injury; and (3) if the inactivation phase of the local effect of RTX on nerves is primarily dependent on abolition of voltage-gated, tetrodotoxin-resistant (TTX-R) sodium currents. To study the specific aims of the project the effects of RTX will be examined in rats by behavioral methods; and whole cell voltage-clamp technique will be used to identify a mechanism for impulse failure induced by RTX.
