Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans.

1. Nitric oxide (NO) evokes pain on intracutaneous application, apparently by exciting cutaneous nociceptors. To look for similarities in the responsiveness and sensitivity of other nociceptive systems to NO we determined pain intensity-concentration relations for NO applied to paravascular tissue and veins in humans. 2. NO solutions (0.4-2.0 mM) were either injected paravascularly or perfused through a vascularly isolated hand vein segment. The subjects rated pain continuously with the help of an electronically controlled visual analog scale, which made it possible to determine both the time course (latency, duration) and the intensity of NO-evoked pain. 3. Regardless of where it was applied, at concentrations above 0.7 mM NO always evoked pain of similar time course and concentration dependence. Pain increased proportionally to the concentration of applied NO, reaching subjects' tolerance maximum at four to five times the threshold concentration. 4. Pain intensity-NO concentration relations were congruent, indicating that the respective nociceptive systems are equally sensitive to NO. 5. Our observations are consistent with the hypothesis that NO is a chemical link in peripheral nociception.