Levels of substance P-like immunoreactivity (SP-LI) of the rat urinary bladder were unaffected up to 1 h from exposure to capsaicin (1 microM) in vitro. A longer (3-6 h) exposure to capsaicin decreased SP-LI by about 40-60% as compared to 10-20% of controls. An analysis of the time course of bladder SP-LI changes following s.c. capsaicin (50 mg/kg) or extrinsic bladder denervation (pelvic ganglionectomy) indicated that at 3 h from capsaicin administration bladder SP-LI was reduced at an extent similar to that observed following in vitro exposure to the drug. These findings provide evidence that the early phase of tissue depletion of sensory neuropeptides following systemic capsaicin desensitization may involve a peripheral site of action.