Impaired platelet prostacyclin receptor activity: a monozygotic twin study discordant for spinal cord injury

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.

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Locomotion After Spinal Cord Injury Depends on Constitutive Activity in Serotonin Receptors

Journal of Neurophysiology ◽

10.1152/jn.00499.2010 ◽

2010 ◽

Vol 104 (6) ◽

pp. 2975-2984 ◽

Cited By ~ 51

Author(s):

K. Fouad ◽

M. M. Rank ◽

R. Vavrek ◽

K. C. Murray ◽

L. Sanelli ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Positive Control ◽

Receptor Activity ◽

Constitutive Activity ◽

Weight Support ◽

Injury Model ◽

Cord Injury ◽

It Application ◽

Locomotor Ability

Following spinal cord injury (SCI) neurons caudal to the injury are capable of rhythmic locomotor-related activity that can form the basis for substantial functional recovery of stepping despite the loss of crucial brain stem-derived neuromodulators like serotonin (5-HT). Here we investigated the contribution of constitutive 5-HT2 receptor activity (activity in the absence of 5-HT) to locomotion after SCI. We used a staggered hemisection injury model in rats to study this because these rats showed a robust recovery of locomotor function and yet a loss of most descending axons. Immunolabeling for 5-HT showed little remaining 5-HT below the injury, and locomotor ability was not correlated with the amount of residual 5-HT. Furthermore, blocking 5-HT2 receptors with an intrathecal (IT) application of the neutral antagonist SB242084 did not affect locomotion (locomotor score and kinematics were unaffected), further indicating that residual 5-HT below the injury did not contribute to generation of locomotion. As a positive control, we found that the same application of SB242084 completely antagonized the muscle activity induced by exogenous application of the 5-HT2 receptor agonists alpha-methyl-5-HT (IT). In contrast, blocking constitutive 5-HT2 receptor activity with the potent inverse agonist SB206553 (IT) severely impaired stepping as assessed with kinematic recordings, eliminating most hindlimb weight support and overall reducing the locomotor score in both hind legs. However, even in the most severely impaired animals, rhythmic sweeping movements of the hindlimb feet were still visible during forelimb locomotion, suggesting that SB206553 did not completely eliminate locomotor drive to the motoneurons or motoneuron excitability. The same application of SB206553 had no affect on stepping in normal rats. Thus while normal rats can compensate for loss of 5-HT2 receptor activity, after severe spinal cord injury rats require constitutive activity in these 5-HT2 receptors to produce locomotion.

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Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

Journal of Neurophysiology ◽

10.1152/jn.00775.2010 ◽

2011 ◽

Vol 105 (1) ◽

pp. 410-422 ◽

Cited By ~ 40

Author(s):

M. M. Rank ◽

K. C. Murray ◽

M. J. Stephens ◽

J. D'Amico ◽

M. A. Gorassini ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Adrenergic Receptors ◽

Receptor Activity ◽

Chronic Spinal Cord Injury ◽

Motoneuron Excitability ◽

Cord Injury ◽

Muscle Spasms

The brain stem provides most of the noradrenaline (NA) present in the spinal cord, which functions to both increase spinal motoneuron excitability and inhibit sensory afferent transmission to motoneurons (excitatory postsynaptic potentials; EPSPs). NA increases motoneuron excitability by facilitating calcium-mediated persistent inward currents (Ca PICs) that are crucial for sustained motoneuron firing. Spinal cord transection eliminates most NA and accordingly causes an immediate loss of PICs and emergence of exaggerated EPSPs. However, with time PICs recover, and thus the exaggerated EPSPs can then readily trigger these PICs, which in turn produce muscle spasms. Here we examined the contribution of adrenergic receptors to spasms in chronic spinal rats. Selective activation of the α1A adrenergic receptor with the agonists methoxamine or A61603 facilitated Ca PIC and spasm activity, recorded both in vivo and in vitro. In contrast, the α2 receptor agonists clonidine and UK14303 did not facilitate Ca PICs, but did decrease the EPSPs that trigger spasms. Moreover, in the absence of agonists, spasms recorded in vivo were inhibited by the α1 receptor antagonists WB4010, prazosin, and REC15/2739, and increased by the α2 receptor antagonist RX821001, suggesting that both adrenergic receptors were endogenously active. In contrast, spasm activity recorded in the isolated in vitro cord was inhibited only by the α1 antagonists that block constitutive receptor activity (activity in the absence of NA; inverse agonists, WB4010 and prazosin) and not by the neutral antagonist REC15/2739, which only blocks conventional NA-mediated receptor activity. RX821001 had no effect in vitro even though it is an α2 receptor inverse agonist. Our results suggest that after chronic spinal cord injury Ca PICs and spasms are facilitated, in part, by constitutive activity in α1 adrenergic receptors. Additionally, peripherally derived NA (or similar ligand) activates both α1 and α2 adrenergic receptors, controlling PICs and EPSPs, respectively.

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