Nociceptive input into the central nervous system is not simply passively received but rather is subject to modulation through spinal cord neuroplasticity and descending influences from supraspinal sites activated by a variety of environmental signals, including the acute or persistent nociceptive input itself and behavioral and emotional stimuli. The significant role of NMDA receptors and production of NO. in central sensitization, hyperalgesia, and chronic pain has been demonstrated in numerous models of peripheral injury. It has been shown that persistent nociceptive input is also subject to centrifugal descending modulation through activation of both prominent facilitatory and masked inhibitory influences from supraspinal sites (e.g., RVM) likely involving a spino-bulbar-spinal loop. These descending modulatory influences from the RVM appear to contribute selectively to hyperalgesia observed in uninjured tissue, distant from the site of insult (secondary hyperalgesia), and involve mechanisms similar to those found in the spinal cord (i.e., NMDA receptors and production of NO.). The significant role that modulatory influences in the central nervous system have in the development and maintenance of chronic pain and hyperalgesia clearly supports continued investigation into the physiologic mechanisms contributing to these events.