Subplantar injection of 0.10 micrograms of serotonin in the rat resulted in a brief period (0-20 min) of increased pain sensitivity to an applied force (hyperalgesia) which preceded a longer period (40-120 min) of decreased pain sensitivity (hypoalgesia). The magnitude of each of these changes and the duration of the hypoalgesia were dose-dependent. The development of hyperalgesia was selectively and dose dependently reduced by inhibitors of arachidonate cyclooxygenase. The hypoalgesia was selectively and dose dependently reduced by the serotonin antagonist methysergide. Selective inhibition of the hyperalgesia by aspirin and of the hypoalgesia by methysergide revealed that components of both hyperalgesia and hypoalgesia were present in the 10-120 min interval. These findings, the level of serotonin reported to be released in rat dermal tissue, and selective drug inhibition studies suggest that some irritant-induced changes in algesia measured in the rat hindlimb result from release of dermal stores of serotonin. Selective inhibition of the hypoalgesic component of the hindlimb irritant trypsin by the antiserotonin agent methysergide supports this hypothesis. The principal conclusion derived from these studies is that the algesic response to the subplantar injection of a single agent can be the resultant of independent, temporally overlapping hyperalgesic and hypoalgesic components each of different intensity and pharmacological sensitivity.