Previous work has demonstrated that pain facilitation can occur following injection of subcutaneous irritants, such as formalin. Such studies have focused on apparent pain facilitation induced at the site of irritant injection. Changes in processing of incoming pain information have typically been assumed to result from activation of neurocircuitry intrinsic to the spinal cord. The present series of studies have examined hyperalgesia exhibited at a site distant from the site of irritant injection and have begun to define the neurocircuitry and neuropharmacology underlying this pain enhancement. This work demonstrates that s.c. formalin injected into the dorsum of one hindpaw in rats produces prolonged hyperalgesia as measured by the tailflick test. Hyperalgesia is not mediated solely by circuitry intrinsic to the spinal cord, but rather involves activation of centrifugal pathways originating within the brain and descending to the spinal cord via pathway(s) outside of the dorsolateral funiculus. At the level of the spinal cord, this hyperalgesic state is mediated by an NMDA-nitric oxide cascade, since hyperalgesia can be abolished by administration of either an NMDA antagonist (APV) or a nitric oxide synthesis inhibitor (L-NAME).