Previous studies demonstrated that acute irritation of the lower urinary tract (LUT) induces the expression of the immediate early gene, c-fos, in lumbo-sacral spinal cord neurons "J. Neurosci. 12 (1992) 4878" "Am. J. Physiol. 265 (1993) 326" "Somatosens. Mot. Res. 15 (1998) 5". This effect was mediated in part by activation of capsaicin-sensitive bladder afferents "Am. J. Physiol. 265 (1993) 326". Here we investigate the role of preprotachykinin gene products (neurokinin A and substance P) in the response to bladder irritation in urethane-anesthetized mice. Acute irritation of the LUT (intravesical acetic acid) induced smaller numbers of Fos-positive neurons in the spinal cord of mice with a mutated preprotachykinin gene than in wild type mice. Increased Fos expression following LUT irritation or a sham operation in wild type mice was also significantly reduced by pretreatment with the NK2 antagonist, MEN 11420, but Fos expression in mutant mice was not altered by the antagonist. During cystometrograms, a significantly higher percentage (83%) of mutant mice exhibited urinary retention and overflow incontinence as compared to wild type controls. These findings suggest an involvement of tachykinins and NK2 receptors in the response to chemical irritation of the LUT in mice and also suggest that tachykinins contribute to the regulation of normal reflex bladder activity.