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

2013 ◽  
Vol 109 (6) ◽  
pp. 1473-1484 ◽  
Author(s):  
Jessica M. D'Amico ◽  
Katherine C. Murray ◽  
Yaqing Li ◽  
K. Ming Chan ◽  
Mark G. Finlay ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Receptor Activity ◽  
Persistent Inward Currents ◽  
Human Spinal Cord ◽  
Cord Injury ◽  
Inward Currents ◽  
Monoamine Receptors ◽  
Muscle Spasms ◽  
Complete 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.

scholarly journals Spinal Cord Injury Causes Plasticity in a Subpopulation of Lamina I GABAergic Interneurons

2008 ◽  
Vol 100 (1) ◽  
pp. 212-223 ◽  
Author(s):  
Kimberly J. Dougherty ◽  
Shawn Hochman
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Membrane Properties ◽  
Gabaergic Interneurons ◽  
Persistent Inward Currents ◽  
Lamina I ◽  
Cord Injury ◽  
Single Spike ◽  
Inward Currents ◽  
In Cells

Dysfunction of the spinal GABAergic system has been implicated in pain syndromes following spinal cord injury (SCI). Since lamina I is involved in nociceptive and thermal signaling, we characterized the effects of chronic SCI on the cellular properties of its GABAergic neurons fluorescently identified in spinal slices from GAD67-GFP transgenic mice. Whole cell recordings were obtained from the lumbar cord of 13- to 17-day-old mice, including those having had a thoracic segment (T8-11) removed 6–9 days prior to experiments. Following chronic SCI, the distribution, incidence, and firing classes of GFP+ cells remained similar to controls, and there were minimal changes in membrane properties in cells that responded to current injection with a single spike. In contrast, cells displaying tonic/initial burst firing had more depolarized membrane potentials, increased steady-state outward currents, and increased spike heights. Moreover, higher firing frequencies and spontaneous plateau potentials were much more prevalent after chronic SCI, and these changes occurred predominantly in cells displaying a tonic firing pattern. Persistent inward currents (PICs) were observed in a similar fraction of cells from spinal transects and may have contributed to these plateaus. Persistent Na+ and L-type Ca2+ channels likely contributed to the currents as both were identified pharmacologically. In conclusion, chronic SCI induces a plastic response in a subpopulation of lamina I GABAergic interneurons. Alterations are directed toward amplifying neuronal responsiveness. How these changes alter spinal sensory integration and whether they contribute to sensory dysfunction remains to be elucidated.

scholarly journals Role of Endogenous Release of Norepinephrine in Muscle Spasms After Chronic Spinal Cord Injury

2007 ◽  
Vol 97 (5) ◽  
pp. 3166-3180 ◽  
Author(s):  
Michelle M. Rank ◽  
Xiaole Li ◽  
David J. Bennett ◽  
Monica A. Gorassini
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Persistent Inward Currents ◽  
Reflex Responses ◽  
Cord Injury ◽  
Inward Currents ◽  
Presynaptic Release ◽  
Endogenous Release

The recovery of persistent inward currents (PICs) and motoneuron excitability after chronic spinal cord transection is mediated, in part, by the development of supersensitivity to residual serotonin (5HT) below the lesion. The purpose of this paper is to investigate if, like 5HT, endogenous sources of norepinephrine (NE) facilitate motoneuron PICs after chronic spinal transection. Cutaneous-evoked reflex responses in tail muscles of awake chronic spinal rats were measured after increasing presynaptic release of NE by administration of amphetamine. An increase in long-lasting reflexes, known to be mediated by the calcium component of the PIC (CaPIC), was observed even at low doses (0.1–0.2 mg/kg) of amphetamine. These findings were repeated in a reduced S2 in vitro preparation, demonstrating that the increased long-lasting reflexes by amphetamine were neural. Under intracellular voltage clamp, amphetamine application led to a large facilitation of the motoneuron CaPIC. This indicates that the increases in long-lasting reflexes induced by amphetamine in the awake animal were, in part, due to actions directly on the motoneuron. Reflex responses in acutely spinal animals were facilitated by amphetamine similar to chronic animals but only at doses that were ten times greater than that required in chronic animals (0.2 mg/kg chronic vs. 2.0 mg/kg acute), pointing to a development of supersensitivity to endogenous NE in chronic animals. In summary, the increases in long-lasting reflexes and associated motoneuron CaPICs by amphetamine are likely due to an increased release of endogenous NE, which motoneurons become supersensitive to in the chronic stages of spinal cord injury.

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

2011 ◽  
Vol 105 (1) ◽  
pp. 410-422 ◽  
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.

Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human chronic spinal cord injury

2011 ◽  
Vol 105 (6) ◽  
pp. 2781-2790 ◽  
Author(s):  
Renée D. Theiss ◽  
T. George Hornby ◽  
W. Zev Rymer ◽  
Brian D. Schmit
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neuronal Excitability ◽  
Spinal Neurons ◽  
Chronic Spinal Cord Injury ◽  
Persistent Inward Currents ◽  
Reflex Responses ◽  
Withdrawal Reflex ◽  
Cord Injury ◽  
Inward Currents

The objectives of this study were to probe the contribution of spinal neuron persistent sodium conductances to reflex hyperexcitability in human chronic spinal cord injury. The intrinsic excitability of spinal neurons provides a novel target for medical intervention. Studies in animal models have shown that persistent inward currents, such as persistent sodium currents, profoundly influence neuronal excitability, and recovery of persistent inward currents in spinal neurons of animals with spinal cord injury routinely coincides with the appearance of spastic reflexes. Pharmacologically, this neuronal excitability can be decreased by agents that reduce persistent inward currents, such as the selective persistent sodium current inhibitor riluzole. We were able to recruit seven subjects with chronic incomplete spinal cord injury who were not concurrently taking antispasticity medications into the study. Reflex responses (flexion withdrawal and H-reflexes) and volitional strength (isometric maximum voluntary contractions) were tested at the ankle before and after placebo-controlled, double-blinded oral administration of riluzole (50 mg). Riluzole significantly decreased the peak ankle dorsiflexion torque component of the flexion withdrawal reflex. Peak maximum voluntary torque in both dorsiflexion and plantarflexion directions was not significantly changed. Average dorsiflexion torque sustained during the 5-s isometric maximum voluntary contraction, however, increased significantly. There was no effect, however, on the monosynaptic plantar and dorsiflexor H-reflex responses. Overall, these results demonstrate a contribution of persistent sodium conductances to polysynaptic reflex excitability in human chronic spinal cord injury without a significant role in maximum strength production. These results suggest that intrinsic spinal cellular excitability could be a target for managing chronic spinal cord injury hyperreflexia impairments without causing a significant loss in volitional strength.

scholarly journals Modulation of inhibitory strength and kinetics facilitates regulation of persistent inward currents and motoneuron excitability following spinal cord injury

2011 ◽  
Vol 106 (5) ◽  
pp. 2167-2179 ◽  
Author(s):  
Sharmila Venugopal ◽  
Thomas M. Hamm ◽  
Sharon M. Crook ◽  
Ranu Jung
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Treatment Strategies ◽  
Reversal Potential ◽  
Current Frequency ◽  
Persistent Inward Currents ◽  
Motoneuron Excitability ◽  
Cord Injury ◽  
Inward Currents ◽  
The Impact

Spasticity is commonly observed after chronic spinal cord injury (SCI) and many other central nervous system disorders (e.g., multiple sclerosis, stroke). SCI-induced spasticity has been associated with motoneuron hyperexcitability partly due to enhanced activation of intrinsic persistent inward currents (PICs). Disrupted spinal inhibitory mechanisms also have been implicated. Altered inhibition can result from complex changes in the strength, kinetics, and reversal potential ( ECl−) of γ-aminobutyric acid A (GABAA) and glycine receptor currents. Development of optimal therapeutic strategies requires an understanding of the impact of these interacting factors on motoneuron excitability. We employed computational methods to study the effects of conductance, kinetics, and ECl− of a dendritic inhibition on PIC activation and motoneuron discharge. A two-compartment motoneuron with enhanced PICs characteristic of SCI and receiving recurrent inhibition from Renshaw cells was utilized in these simulations. This dendritic inhibition regulated PIC onset and offset and exerted its strongest effects at motoneuron recruitment and in the secondary range of the current-frequency relationship during PIC activation. Increasing inhibitory conductance compensated for moderate depolarizing shifts in ECl− by limiting PIC activation and self-sustained firing. Furthermore, GABAA currents exerted greater control on PIC activation than glycinergic currents, an effect attributable to their slower kinetics. These results suggest that modulation of the strength and kinetics of GABAA currents could provide treatment strategies for uncontrollable spasms.

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