The long term objective of this research is to understand the mechanisms underlying the unmasking of latent motor pathways which restore function to muscle paralyzed by spinal cord injury. The present proposal will perform pharmacological manipulations of the respiratory system to demonstrate that the output of the respiratory centers can be enhanced by drugs in order to restore function to a hemidiaphragm paralyzed by ipsilateral cervical spinal cord hemisection. The functional restitution is mediated by methylxanthine-induced activation of a latent motor respiratory pathway. The immediate goals are twofold. First, the principal investigator will focus on the specific pharmacological mechanisms of the methylxanthines on activating the latent motor pathways, and second, he will determine if methylxanthines can be used to achieve long term functional restitution of the diaphragm after cervical spinal cord injury.
Three specific aims will address the following hypotheses: 1. that activation of the latent crossed phrenic pathway by methylxanthines is mediated by central neuronal adenosine receptor antagonism, 2. that of the four cloned receptor subtypes, antagonism of the A1 receptor primarily mediates hemidiaphragmatic functional recovery in rats subjected to a C2 spinal cord hemisection, and 3. that oral administration of theophylline in C2 spinal hemisected rats will not only induce, but also will chronically maintain function in the previously paralyzed ipsilateral hemidiaphragm.
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