Cell damage excites nociceptors through release of cytosolic ATP.

The release of cytosol from damaged cells has been proposed to be a chemical trigger for nociception. K(+), H(+), adenosine triphosphate (ATP), and glutamate are algogenic agents within cytosol that might contribute to such an effect. To examine which, if any, compounds in cytosol activate ion channels on nociceptors, we recorded currents in dissociated nociceptors when nearby skin cells were damaged. Skin cell damage caused action potential firing and inward currents in nociceptors. Extracts of fibroblast cytosol did the same. Virtually all response to extract and cell killing was eliminated by enzymatic degradation of ATP or desensitization or blockade of P2X receptors, ion channels that are activated by extracellular ATP. Thus, if cytosol provides a rapid nociceptive signal from damaged tissue, then ATP is a critical messenger and P2X receptors are its sensor.