The long term goal of this research is to increase our understanding of the mechanisms underlying recovery and alteration of function following spinal cord injury. Damage to descending pathways in the human spinal cord has been found to result in an exaggerated painful response to noxious and non-noxious stimuli, developing over a period of several weeks following injury. The Principal Investigator hypothesizes that this is due to denervation supersensivity to substance P and/or other tachykinins occurring in spinal cord nociceptive neurons. To test this hypothesis, the Principal Investigator will perform the following studies in normal animals and in animals with dorsolateral funiculus (DLF) lesions at survival times of 1 to 30 days: 1. The response properties of lumbar spinal cord neurons to noxious and non-noxious stimuli and to glutamate pulses will be tested in the presence of graded levels of applied substance P, with and without concurrent application of serotonin. 2. Similar experiments will be performed using ligands that are specific for NK1, NK2, and NK3 tachykinin receptors, in place of substance P. 3. A substance P antagonist will be applied chronically to the lumbar spinal cord of intact animals. These animals will be tested to determine if this procedure can mimic the effects of DFL lesions. 4. The electrical properties of spinal cord neurons in normal and lesioned animals will be measured to determine if changes in these properties can account for increased responsiveness to tachykinins, independent of changes in tachykinin receptors. 5. Receptor binding autoradiography will be used to measure the levels of tachykinin and serotonin receptors in the spinal cord grey matter of normal and lesioned animals. The first four studies will involve extracellular and intracellular electrophysiological recording, and iontophoretic and pressure application of drugs in cats. The last study will involve quantitative analysis of receptor binding autoradiography in rats and cats. These studies relate not only to the specific question of the basis for chronic pain after spinal cord injury, but also to the more general question of the role of denervation supersensivity following central and peripheral nervous system injury. These results may ultimately lead to new drug therapies for the treatment of intractable pain after spinal cord injury.
