Autonomic,sensory, and motor dysfunction following intrathecal administration of three substance P antagonists*

Summary Antagonists of the putative peptide neurotransmitter substance P have been found to produce pronounced cardiovascular effects when administered into the spinal subarachnoid space. These previous studies have not, however, provided any direct evidence that these effects result from interaction with substance P receptors. The present study was designed to characterize the modification of cardiovascular function resulting from administration of these compounds, and evaluate their effects on the integrity of spinal cord function. Intrathecal administration of two substance P antagonists produced a depressor response accompanied by a reduction of hindquarter vascular resistance. Following administration of a substance P antagonist, the integrated cardiovascular responses to electrical stimulation of the renal afferent nerves and ventrolateral medulla were markedly attenuated. Intrathecal administration to conscious rats of three substance P antagonists led to a variety of sensory and motor dysfunctions, including loss of spontaneous motor function, responsiveness to mechanical and thermal stimuli, and bladder function. No such effects were produced by administration of substance P, luteinizing hormone releasing hormone (LHRH), or LHRH antagonist. These effects from administration of a substance P antagonist were associated with a dose-dependent necrosis of spinal cord tissue. The necrosis may be secondary to ischemia since pretreatment with the vasodilator adenosine significantly delayed or blocked the sensory and motor dysfunctions. This conclusion was supported by the demonstration that cerebrovascular smooth muscle (pial vessels) was constricted by a SP antagonist. Taken together, these data suggest that substance P antagonists appear to non-specifically block transmission in the spinal cord, by mechanisms which may involve reduction of blood flow to the spinal cord.Supported by grants HL-14388, GM07069, and a gift from the Searle Family Trust Fund