Stimulation of the periaqueductal gray matter (PAG) is known to modulate nociception at the spinal level. Several studies have suggested that nociception may also be modulated via ascending projections from the PAG. To study this hypothesis, the descending pathway was selectively disrupted immediately caudal to the PAG in 28 rats. Twenty-eight additional rats served as non-lesioned controls. All animals were chronically implanted with a stimulating electrode in the PAG, and antinociception was assessed using tests involving spinally and supraspinally mediated responses (tail-flick and hot-plate tests, respectively). Significantly fewer lesioned than non-lesioned rats showed stimulation-produced analgesia (SPA) in the tail-flick test (4 of 28 vs 14 of 28, respectively). In contrast, no significant difference in the incidence of SPA occurred between lesioned and non-lesioned rats in the hot-plate test. These findings demonstrate that nociception can be modulated at the supraspinal, as well as spinal, level.