Tissue injury is associated with sensitization of nociceptors and subsequent changes in the excitability of central ( Hardy et al.(1) investigated two types of experimentally produced cutaneous hyperalgesia, primary and secondary. Primary hyperalgesia occurs at the site of injury; secondary hyperalgesia is associated with the injury, but occurs in ''undamaged tissues adjacent to and at some distance from the site of an injury.'' They proposed a ''new formulation'' to explain the spread of hyperalgesia away from the site of injury, namely that a central (spinal) excitatory state, and not a peripheral mechanism as advanced by Lewis (2), was responsible for secondary hyperalgesia. Subsequent intensive study of the altered sensations that arise from and adjacent to injured tissues has supported this ''formulation'' and it is now widely accepted that mechanisms of primary and secondary hyperalgesia are, respectively, peripheral and central (e.g., see refs. 3, 4).The increase in excitability of spinal neurons after peripheral injury, termed central sensitization, has been extensively studied by Woolf and colleagues (see ref. 5 for overview). They documented that the enhanced reflex excitability after peripheral tissue damage did not require ongoing peripheral input, and that spinal dorsal horn neuron receptive fields expanded, responsiveness to suprathreshold stimuli increased, response thresholds decreased, and sensitivity to novel stimuli was acquired after peripheral injury. The focus of investigation has remained the spinal cord, and many investigators have since documented the importance of the spinal N-methyl-Daspartate (NMDA) receptor to the induction and maintenance of central sensitization (see ref. 6 for recent overview). A growing body of evidence, however, reveals a significant contribution of descending influences from supraspinal sites in the development and maintenance of central sensitization͞ secondary hyperalgesia. We review here and discuss evidence that peripheral tissue injury engages spinobulbospinal circuitry that may be important to the development and maintenance of central sensitization and secondary hyperalgesia.Descending Facilitation. Although the potency of descending inhibitory influences has long been appreciated, the study and characterization of descending facilitatory influences have been more recent developments. Interestingly, inhibitory and facilitatory influences can be produced at many of the same sites in the brainstem, particularly in the rostral ventromedial medulla (RVM). Generally, low intensities of electrical stimulation or low concentrations of chemical (e.g., glutamate, neurotensin) facilitate spinal nociception, whereas greater intensities of stimulation or concentrations of chemical at the same sites typically inhibit spinal nociception (7-10). These dual influences appear to involve anatomically distinct independent spinal pathways and are mediated by different lumbar spinal receptors. For example, high-intensity electrical stimulation or high-dose glutamate...