Constitutively active 5-HT₂/α₁ receptors facilitate muscle spasms after human spinal cord injury

Abstract

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 (5-HT2) and norepinephrine (α1) receptor activity, which facilitates the reactivation of calcium-mediated persistent inward currents (CaPICs) without the ligands serotonin and norepinephrine below the injury. In this study 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 5-HT2/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 noninjured control participants having functional descending sources of monoamines, chlorpromazine was effective in reducing CaPIC-mediated motor unit activity. On the basis of these combined results, it appears that in severe spinal cord injury, facilitation of persistent inward currents and muscle spasms is mainly mediated by the activation of constitutive 5-HT2 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.

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

“…In line with this, ∆ F‐D measurements in humans have been shown to be sensitive to monoamines, especially serotonin (D'Amico et al . ). In ALS, the brainstem serotoninergic neurones are affected (Dupuis et al .…”

“…Monoaminergic centres in the brainstem are known to activate the sodium and calcium channels inducing PICs . In line with this, F-D measurements in humans have been shown to be sensitive to monoamines, especially serotonin (D'Amico et al 2013). In ALS, the brainstem serotoninergic neurones are affected (Dupuis et al 2010;Dentel et al 2013), which may have repercussion on activation of PICs and the neuromodulation of motoneuron discharge.…”

Recovery of neuronal and network excitability after spinal cord injury and implications for spasticity

“…To examine if constitutive activity in 5-HT 2 and NAα 1 receptors mediates the recovery of motoneuron PICs in chronic injury, the effects of two types of antagonists, an inverse agonist and a neutral antagonist, on PIC-mediated LLR (spasms) has been examined, first in completely transected rats (Murray et al, 2010) and then in humans with SCI (D'Amico et al, 2013b). An inverse agonist stabilizes the receptor in its inactive resting state (R), preventing it from entering into its active state (R * ).…”

Effect of fluoxetine on disease progression in a mouse model of ALS

“…Cyproheptadine is a 5-HT 2 receptor antagonist that has been shown to decrease motoneuron excitability (Barbeau and Rossignol 1990;D'Amico et al 2013;Murray et al 2010;Thompson and Hornby 2013;Yamazaki et al 1992). Cyproheptadine therefore either 1) does not decrease motoneuron excitability in neonatal mice, 2) was not at a concentration high enough to produce an effect, or 3) decreased excitability but did not affect disease progression.…”