Role of Glutamatergic System in SCI-induced Spasticity in the Axial

Spasticity, exaggerated stretch reflexes and abnormal muscle tone, poses a major detrimental impact on the quality of life in a significant number of patients with spinal cord injury (SCI). Spasticity of the midline (axial) musculature can significantly hinder performing transfers and lead to development of pressure sores. Currently, significant gaps exist in our knowledge of the pathophysiology involved in spasticity development following SCI, especially regarding the axial musculature. Recent observations in our laboratory, using a sacral spinal (S2)transection spasticity model, suggest an increase in glutamatergic input to sacrocaudal (sacral (S) and coccygeal (Co" motoneurons arising ITompresumptive spinal segmental sources. The goals of this proposal are: I) to determine the effects ofS, transection on the number and distribution of glutarnatergic inputs, arising ITomprimary afferents or intraspinal sources, on more caudal motoneurons, 2) to correlate these changes with the development of spasticity within the tail musculature, which are the caudal counterparts to the trunk (axial) musculature, and 3) to examine the therapeutic efficacy of riluzole and gabapentin, which selectively interfere with gIutamatergic transmission, in decreasing the development of spasticity within the tail musculature. Anirnals with S2spinal transection will be tested behaviorally using our established system. At each of four well defined, progressive stages of spasticity, temporal changes in gIutamatergic inputs to sacrocaudal motoneurons, arising ITomprimary afferents or intraspinal sources, will be assessed using antibodies specific for these neuron subtypes and confocal microscopy. Changes in number and distribution of immunoreactive connections to motoneuron soma and dendrites will be correlated with changes in spasticity in the tail musculature. In a separate group of animals, a welh:stablished method of dorsal rhizotomy, of the S,-C04 spinal roots, will determine the direct contribution of primary afferents to the total glutamate input to sacrocaudal motoneurons in normal versus SCI-spastic animals. A final group of animals, demonstrating advanced spasticity within the tail, will receive therapeutic doses of either riluzole or gabapentin and behaviorally tested. Results ITomthese experiments will further define the role of the gIutamatergic system in the development of spasticity and assess the efficacy of two clinically available drugs, which inhibit the glutamatergic system, in the management of SCI-induce spasticity in the axial musculature.