Vasoneuroactive substances were applied through intradermal microdialysis membranes and characterized as itch- or pain-inducing in psychophysical experiments. Histamine always provoked itching and rarely pain, capsaicin always pain but never itching. Prostaglandin E[2] (PGE[2]) led preferentially to moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more often than itching. Subsequently the same substances were used in microneurography experiments to characterize the sensitivity profile of human cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMi[H][i][s][-]), and 24 mechanoinsensitive, histamine-positive (CMi[H][i][s][+]) units were compared. CMi[H][i][s][+] units were most responsive to histamine and to PGE[2] and less to serotonin, ACh, bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMi[H][i][s] units showed significantly weaker responses to histamine, PGE[2], and acetylcholine. Capsaicin and bradykinin responses were not significantly different in the two classes of mechano-insensitive units. We conclude that CMi[H][i][s][+]units are "selective," but not "specific" for pruritogenic substances and that the pruritic potency of a mediator increases with its ability to activate CMi[H][i][s][+] units but decreases with activation of CMH and CMi[H][i][s] units.