Grant: Operating Grant

A prerequisite for normal movement is that motoneurons in the spinal cord are sufficiently excitable to be able to produce sustained muscle contractions in response to command signals from the brain. Motoneuron excitability is facilitated by monoamines like norepinephrine and serotonin that come from the brainstem. Spinal cord injury causes loss of brainstem monoamine innervation, which leads to dramatically decreased motoneuron excitability and muscle weakness. Yet in the weeks after injury, motoneurons undergo a remarkable recovery, becoming very excitable. While this aids in the recovery of residual motor function, it also leads to the development of debilitating muscle spasms because the motoneurons are not under normal descending inhibitory control. We recently found that this recovery of motoneuron excitability and development of spasms involves monoamine receptors that somehow become activated despite the loss of most monoamines. We hypothesize that this occurs because the monoamine receptors become constitutively active - spontaneously entering their active state without the binding of monoamines. We will test this hypothesis with a new class of drugs that selectively block constitutively active receptors, which may prove useful as novel antispastic medications. These studies are possible because of our unique in vitro rat spinal cord preparation, which for the first time allows study of chronic injury and spasticity with comprehensive pharmacological methods (spasticity in a dish). In summary, the proposed experiments evaluate a novel mechanism of spinal cord plasticity, involving constitutive receptor activity, that will have broad ranging implications to normal and pathological control of movement. Considering that we have recently shown that muscle spasms are caused by a similar cellular pathology in rats and humans, the proposed experiments will directly translate to understanding and treating spasticity in humans with spinal cord injury.