This study was conducted to determine whether adenosine 5'-triphosphate (ATP) contributes to nociceptor activity induced by ureter distension. Multifibre recordings of ureter afferents were made using the guinea pig ureter preparation perfused in vitro. Distension of the ureter resulted in an initial rapid and later maintained increase in afferent nerve discharge. Intraluminal application of ATP (10-1000 microM, 0.1 ml/min for 3 min) or alpha,beta-meATP (10-1000 microM) mimicked these increases in afferent activity. The afferent responses consisted of fast and slow components. Both agonists caused a sensitisation of the afferents to ureter distensions. TNP-ATP (30 microm), a P2X3 receptor antagonist, and the non-specific P2 antagonist, PPADS (100 microm), blocked the rapid and reduced the slower response to ATP. The remaining responses were blocked by the selective A1 receptor antagonist, DPCPX. TNP-ATP and PPADS reduced distension-induced afferent activity. The selective ecto-ATPase inhibitor, ARL-67156 (100, 200 microM) and suramin (100, 200 microM), an ecto-nucleotidase inhibitor as well as a P2 receptor antagonist, produced an increase in baseline and distension-induced discharge. These results indicate that the ureter epithelium may tonically (at rest) as well as phasically (on distension) release ATP, which stimulates afferent terminals by interacting with multiple P2 and P1 receptors.