Constitutively Active 5HT2/α1 Receptors Facilitate Muscle Spasms

45 46 In animals, the recovery of motoneuron excitability in the months following a complete spinal cord 47 injury is mediated, in part, by increases in constitutive serotonin (5HT2) and noradrenaline (α1) 48 receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents 49 (CaPICs) without the ligands serotonin and noradrenaline below the injury. Here, we sought 50 evidence for a similar role of constitutive monoamine receptor activity in the development of 51 spasticity in human spinal cord injury. In chronically injured participants with partially preserved 52 sensory and motor function, the serotonin reuptake inhibitor, citalopram, facilitated long-lasting 53 reflex responses (spasms) previously shown to be mediated by CaPICs, suggesting that in incomplete 54 spinal cord injury, functional descending sources of monoamines are present to activate monoamine 55 receptors below the lesion. However, in participants with motor or motor/sensory complete injuries 56 the inverse agonist cyproheptadine, which blocks both ligand and constitutive 5HT2/α1 receptor 57 activity, decreased long-lasting reflexes whereas the neutral antagonist chlorpromazine, which only 58 blocks ligand activation of these receptors, had no effect. When tested in non-injured control 59 participants having functional descending sources of monoamines, chlorpromazine was effective in 60 reducing CaPIC-mediated motor unit activity. Based on these combined results it appears that in 61 severe spinal cord injury, facilitation of persistent inward currents and muscle spasms are mainly 62 mediated by the activation of constitutive 5HT2 and α1 receptor activity. Drugs that more selectively 63 block these constitutively-active monoamine receptors may provide better oral control of spasticity, 64 especially in motor complete spinal cord injury where reducing motoneuron excitability is the 65 primary goal. 66 67