Multiple separate and distinct supraspinally organized descending inhibitory systems have been identified which are capable of powerfully modulating spinal nociceptive transmission. Until recently, brainstem sites known to be involved in the centrifugal modulation of spinal nociceptive transmission were few in number, being limited to midline structures in the midbrain and medulla (e.g., periaqueductal gray and nucleus raphe magnus). However, with continued investigation, that number has increased and brainstem sites previously thought to be primarily involved in cardiovascular function and autonomic regulation (e.g., nucleus tractus solitarius; locus coeruleus/subcoeruleus (LC/SC); A5 cell group; lateral reticular nucleus) also have been demonstrated to play a role in the modulation of spinal nociceptive transmission. Spinal monoamines (norepinephrine (NE) and serotonin) have been shown to mediate stimulation-produced descending inhibition of nociceptive transmission from these brainstem sites. The majority of NE-containing fibers and terminations in the spinal cord arise from supraspinal sources; thus, the LC/SC, the parabrachial nuclei, the Kölliker-Fuse nucleus and the A5 cell group have all been suggested as possible sources of the spinal noradrenergic (NA) innervation involved in the centrifugal modulation of spinal nociceptive transmission. Several lines of evidence suggest that the LC/SC plays a significant role in a functionally important descending inhibitory NA system. Focal electrical stimulation in the LC produces an antinociception and increases significantly the spinal content of NA metabolites. The inhibition of the nociceptive tail-flick withdrawal reflex produced by electrical stimulation in the LC/SC has been demonstrated to be mediated by postsynaptic alpha 2-adrenoceptors in the lumbar spinal cord. Similarly, electrical or chemical stimulation given in the LC/SC inhibits noxious-evoked dorsal horn neuronal activity. Thus, results reported in electrophysiological experiments confirm those reported in functional studies and the NA coeruleospinal system appears to play a significant role in spinal nociceptive processing.