In animals, the recovery of motoneuron excitability in the months following a complete spinal cord injury is mediated, in part, by increases in constitutive serotonin (5HT2) and noradrenaline (α1) receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents (CaPICs) without the ligands serotonin and noradrenaline below the injury. Here, we sought evidence for a similar role of constitutive monoamine receptor activity in the development of spasticity in human spinal cord injury. In chronically injured participants with partially preserved sensory and motor function, the serotonin reuptake inhibitor, citalopram, facilitated long-lasting reflex responses (spasms) previously shown to be mediated by CaPICs, suggesting that in incomplete spinal cord injury, functional descending sources of monoamines are present to activate monoamine receptors below the lesion. However, in participants with motor or motor/sensory complete injuries the inverse agonist cyproheptadine, which blocks both ligand and constitutive 5HT2/α1 receptor activity, decreased long-lasting reflexes whereas the neutral antagonist chlorpromazine, which only blocks ligand activation of these receptors, had no effect. When tested in non-injured control participants having functional descending sources of monoamines, chlorpromazine was effective in reducing CaPIC-mediated motor unit activity. Based on these combined results it appears that in severe spinal cord injury, facilitation of persistent inward currents and muscle spasms are mainly mediated by the activation of constitutive 5HT2 and α1 receptor activity. Drugs that more selectively block these constitutively-active monoamine receptors may provide better oral control of spasticity, especially in motor complete spinal cord injury where reducing motoneuron excitability is the primary goal.
- inverse agonist
- Copyright © 2012, Journal of Neurophysiology