Plasticity of nociception: recent advances in function-oriented structural pain research.

Traditional concept holds that the pain unit consists of three neurons. The first of these, the primary nociceptive neuron, starts with the nociceptors and terminates in the dorsal spinal cord. The second one, called spinothalamic neuron, crosses over in front of the central canal and connects the dorsal horn with the thalamus. The third one, called thalamo-cortical neuron, terminates in the "pain centres" of the cerebral cortex. While this simplistic scheme is useful for didactic purposes, the actual situation is more complex. First, in the periphery it is only nociception that occurs, while pain is restricted to the levels of thalamus and the cortex. Second, pain results from interactions of excitation and inhibition, from divergence and convergence and from attention and distraction, in a diffuse and plastic system, characteristic for all levels of organization. This study describes the major cytochemical markers of primary nociceptive neurons followed by the presentation of recent data on the functional anatomy of nociception and pain, with special focus on the intrinsic antinociceptive system and the role of nitrogen oxide, opiate receptors, nociceptin and nocistatin. In addition to the classic intrinsic antinociceptive centres such as the periaqueductal gray matter and the raphe nuclei, roles of several recently discovered members of the antinociceptive system are discussed, such as the pretectal nucleus, the reticular formation, the nucleus accumbens, the nucleus tractus solitarii, the amygdala and the reticular thalamic nucleus, this latter being a coincidence detector and a centre for attention and distraction. The localisation of cortical centres involved in the generation of pain are presented based on the results of studies using imaging techniques, and the structural basis of corticospinal modulation is also outlined. Seven levels of nociception and pain are highlighted where pharmacological intervention may be successful, 1. the peripheral nociceptor, 2. the spinal ganglion, 3. the multisynaptic system of the dorsal horn, 4. the modulatory system of the brain stem, 5. the antinociceptive system, 6. the multisynaptic system of the thalamus, and 7. the cortical evaluating and localisation system that is also responsible for descending (inhibiting) control. The many levels of nociception and pain opens new ways both for pharmacological research and the general practitioner aiming to alleviate pain.