Abstract We provide evidence supporting the idea that the relationship between tissue damage, or the threat of tissue damage, and the response to such stimuli is variant and dependent on neuronal networks by which attentional, emotional and cognitive components of pain experience activate endogenous descending modulatory systems. Most previous studies have focused on responses to transient noxious stimuli with little information on the influence of descending modulation on behavioral responses to persistent pain and hyperalgesia after tissue or nerve injury. Utilizing correlative behavioral and neuronal studies we have demonstrated that (1) behavioral context modulates neuronal activity in nociceptive and non-noniceptive somatosensory pathways, supporting the hypothesis that responses in these pathways are not immutable; (2) descending modulation influences behavior and neuronal activity at spinal cord levels after inflammation and persistent pain; and (3) there are descending facilitatory as well as inhibitory influences on behavior and spinal cord neuronal activity that may impact on persistent pain particularly of deep muscle and visceral origin. Cortical as well as subcortical pathways are available by which dorsal horn activity can be modulated by attentional, motivational and cognitive factors. It appears that the same neuronal mechanisms in the forebrain and brain stem are available for behavioral modulation in a learned task involving the threat of tissue damage (transient noxious stimuli) as are available in the development and amplification of persistent pain produced by inflammation. These parallel brain mechanisms emphasize the saliency of pain experience as an important learned behavior for the survival of the organism, similar to sequential goal-directed behaviors in an operant task.