The aim of this study was to explore whether substance P could modulate the response mediated by ATP receptor. Experiments were carried out on rat dorsal root ganglion (DRG) neurons isolated acutely with enzymatic and mechanical treatment. The ATP-activated inward currents were recorded using the whole-cell patch-clamp technique. The majority of the neurons examined (82/85, 96.5%) were sensitive to ATP (1-1000 microM). Application of substance P (0.01-100 microM) also caused an inward current. Several differences between these two kinds of currents were observed. 0.01, 0.1 and 1 microM substance P increased the ATP (10 microM)-activated current to 113.7 +/- 3.1%, (n = 8); 127.2 +/- 6.7%, (n = 12) and 154.7 +/- 14.4% (n = 6) (means +/- S.E.M.), respectively. This potentiating effect can be blocked by spantide, an NK1 receptor antagonist, and intracellular application of H7 (which is a potent inhibitor of PKC) could also block this kind of potentiation of SP on ATP-activated current. Since the substance P receptor and ATP receptor can coexist in rat DRG neurons and activation of substance P receptor can modulate the response mediated by ATP receptor, it suggests that they may cooperate with each other in activating peripheral nociceptive endings of sensory neurons, especially during tissue damage and/or inflammation.