Prostaglandins, metabolites of arachidonic acid, released during tissue injury and inflammation sensitize primary afferent nociceptors. While it has been suggested that this effect on nociceptors is mediated mainly via the cAMP second messenger system, recent evidence suggests that nitric oxide (NO) is also involved in peripheral pain mechanisms. To test the hypothesis that NO contributes to the sensitization of nociceptors to mechanical stimuli induced by hyperalgesic prostaglandins, we compared von Frey hair mechanical threshold as well as the response evoked by 10-s sustained threshold mechanical stimulation before and after injection of prostaglandin E2 (PGE2) alone, and NOS inhibitor NG-methyl-L-arginine (L-NMA) or its inactive stereoisomer NG-methyl-D-arginine (D-NMA) plus PGE2, adjacent to the receptive field of C-fiber nociceptors. The reduction of mechanical threshold and increase in number of action potentials to sustained mechanical stimulation induced by intradermal application of PGE2 was blocked by L-NMA, but not D-NMA. It is suggested that NO contributes to nociceptor sensitization induced by hyperalgesic prostaglandins.