DYNORPHIN A-INDUCED RAT SPINAL-CORD INJURY - EVIDENCE FOR EXCITATORY AMINO-ACID INVOLVEMENT IN A PHARMACOLOGICAL MODEL OF ISCHEMIC SPINAL-CORD INJURY

Dynorphin A reduced lumbosacral blood flow, elevated cerebrospinal flu id lactic acid concentrations and caused flaccid hindlimb paralysis an d striking neuropathological changes after its injection into the spin al subarachnoid space in rats. Coadministration of the vasodilator hyd ralazine substantially eliminated the paralytic, anaerobic metabolic a nd neuropathological responses to dynorphin A. In contrast, in concent rations up to 1 mM, dynorphin A did not alter the viability of culture d rat spinal cord neurons. Thus, it appears that this peptide lacks di rect neurotoxic effects and that neuronal injuries in vivo result prim arily from ischemia associated with dynorphin A-induced blood flow red uctions. NMDA receptor antagonists significantly improved recovery fro m dynorphin A-induced hindlimb paralysis, and substantially eliminated neuropathological changes without attenuating the acute blood flow re ductions or lactic acid elevations. Additionally, glutamate and aspart ate concentrations were increased significantly in spinal cord cerebro spinal fluid samples removed during the time that peptide-induced spin al cord blood flow reductions were observed. In contrast, neither amin o acid concentration was elevated in media removed after 1-hr exposure of spinal cord neuronal cell cultures to 100 mu M concentrations of d ynorphin A. These results indicate that the paralysis and spinal cord injuries produced in rats after spinal subarachnoid injection of dynor phin A result predominantly from spinal cord ischemia, and further ide ntify excitatory amino acids and N-methyl-D-aspartate receptor mechani sms as important mediators in this injury model.