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The irritancy of initial application of capsaicin and related substances limits their therapeutic potential as novel analgesics. The purpose of the present study was to determine whether the irritant properties of the potent, capsaicin-like compound resiniferatoxin (RTX) would be attenuated by pretreatment with a local anesthetic and to determine whether the local anesthetic had significant effects on RTX-induced desensitization of sensory afferents. A model of visceral nociception in which irritants are instilled directly into the bladder (intravesical, i.ves.) of awake, freely moving rats was used. The nociceptive response, abdominal licking (grooming) was scored for 15 min; locomotor activity was scored concurrently. Tetracaine (0.125–1.0%) attenuated the increases in abdominal licking produced by RTX (3.0 nmol) in a dose- and time-dependent manner. At high doses, tetracaine also suppressed locomotor activity. Thirty minutes and 24 h later, the same dose of RTX was administered again to assess development of desensitization of bladder sensory afferents. Rats that had been pretreated with saline showed decreases in licking behavior from the first to subsequent injections of RTX, indicating the development of desensitization. Tetracaine-pretreated rats showed equivalent or significantly greater decreases in licking behavior, suggesting that local anesthetic pretreatment either did not alter or enhanced development of desensitization to RTX. In a second experiment, tetracaine (0.25 or 0.5%) produced similar effects against a high dose of RTX (3.0 nmol), but did not consistently alter excitatory or desensitizing effects of a low dose of RTX (0.1 nmol). Similar results were obtained when rats were retested under the same conditions 2 and 4 weeks later. This study demonstrates that pretreatment with a local anesthetic can attenuate the irritancy of initial treatment with RTX without disrupting development of desensitization of sensory afferents. Furthermore, the effects of both drugs are not diminished with repeated application.