Control of pain perception, essential for organism surviving and recovery from disease, is exerted by higher brain centers integrating nociception with emotional and cognitive information and modulating the brainstem-spinal feedback loops that regulate spinal nociceptive transmission. Development of chronic pain deregulates the forebrain-brainstem-spinal pain control system, which leads to neuroplasticity and disruption of a balanced brain-spinal communication. Targets for impeding pain chronification are being developed using the manipulation of the cross talk between brain and dorsal horn, at both sites of the loop.