scholarly journals Reduction of spinal sensory transmission by facilitation of 5-HT1B/D receptors in noninjured and spinal cord-injured humans

2013 ◽  
Vol 109 (6) ◽  
pp. 1485-1493 ◽  
Author(s):  
Jessica M. D'Amico ◽  
Yaqing Li ◽  
David J. Bennett ◽  
Monica A. Gorassini
Keyword(s):  
Spinal Cord ◽  
H Reflex ◽  
Controlled Study ◽  
Double Blind ◽  
Afferent Pathways ◽  
Persistent Inward Currents ◽  
Sensory Transmission ◽  
Cord Injury ◽  
Inward Currents ◽  
Spinal Cord Injured

Activation of receptors by serotonin (5-HT1) and norepinephrine (α2) on primary afferent terminals and excitatory interneurons reduces transmission in spinal sensory pathways. Loss or reduction of descending sources of serotonin and norepinephrine after spinal cord injury (SCI) and the subsequent reduction of 5-HT1/α2 receptor activity contributes, in part, to the emergence of excessive motoneuron activation from sensory afferent pathways and the uncontrolled triggering of persistent inward currents that depolarize motoneurons during muscle spasms. We tested in a double-blind, placebo-controlled study whether facilitating 5-HT1B/D receptors with the agonist zolmitriptan reduces the sensory activation of motoneurons during an H-reflex in both noninjured control and spinal cord-injured participants. In both groups zolmitriptan, but not placebo, reduced the size of the maximum soleus H-reflex with a peak decrease to 59% (noninjured) and 62% (SCI) of predrug values. In SCI participants we also examined the effects of zolmitriptan on the cutaneomuscular reflex evoked in tibialis anterior from stimulation to the medial arch of the foot. Zolmitriptan, but not placebo, reduced the long-latency, polysynaptic component of the cutaneomuscular reflex (first 200 ms of reflex) by ∼50%. This ultimately reduced the triggering of the long-lasting component of the reflex (500 ms poststimulation to end of reflex) known to be mediated by persistent inward currents in the motoneuron. These results demonstrate that facilitation of 5-HT1B/D receptors reduces sensory transmission in both monosynaptic and polysynaptic reflex pathways to ultimately reduce long-lasting reflexes (spasms) after SCI.

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 Persistent beneficial impact of H-reflex conditioning in spinal cord-injured rats

2014 ◽  
Vol 112 (10) ◽  
pp. 2374-2381 ◽  
Author(s):  
Yi Chen ◽  
Lu Chen ◽  
Yu Wang ◽  
Jonathan R. Wolpaw ◽  
Xiang Yang Chen
Keyword(s):  
Spinal Cord ◽  
H Reflex ◽  
Spinal Reflex ◽  
Spinal Cord Regeneration ◽  
Lateral Column ◽  
Beneficial Effects ◽  
Cord Injury ◽  
Beneficial Impact ◽  
The Right ◽  
Spinal Cord Injured

Operant conditioning of a spinal cord reflex can improve locomotion in rats and humans with incomplete spinal cord injury. This study examined the persistence of its beneficial effects. In rats in which a right lateral column contusion injury had produced asymmetric locomotion, up-conditioning of the right soleus H-reflex eliminated the asymmetry while down-conditioning had no effect. After the 50-day conditioning period ended, the H-reflex was monitored for 100 [±9 (SD)] (range 79–108) more days and locomotion was then reevaluated. After conditioning ended in up-conditioned rats, the H-reflex continued to increase, and locomotion continued to improve. In down-conditioned rats, the H-reflex decrease gradually disappeared after conditioning ended, and locomotion at the end of data collection remained as impaired as it had been before and immediately after down-conditioning. The persistence (and further progression) of H-reflex increase but not H-reflex decrease in these spinal cord-injured rats is consistent with the fact that up-conditioning improved their locomotion while down-conditioning did not. That is, even after up-conditioning ended, the up-conditioned H-reflex pathway remained adaptive because it improved locomotion. The persistence and further enhancement of the locomotor improvement indicates that spinal reflex conditioning protocols might supplement current therapies and enhance neurorehabilitation. They may be especially useful when significant spinal cord regeneration becomes possible and precise methods for retraining the regenerated spinal cord are needed.

scholarly journals Alendronate Prevents Bone Loss in Patients with Acute Spinal Cord Injury: A Randomized, Double-Blind, Placebo-Controlled Study

2007 ◽  
Vol 92 (4) ◽  
pp. 1385-1390 ◽  
Author(s):  
N. L. Gilchrist ◽  
C. M. Frampton ◽  
R. H. Acland ◽  
M. G. Nicholls ◽  
R. L. March ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Bone Loss ◽  
Acute Spinal Cord Injury ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Cord Injury

scholarly journals Serotonin Facilitates a Persistent Calcium Current in Motoneurons of Rats With and Without Chronic Spinal Cord Injury

2007 ◽  
Vol 97 (2) ◽  
pp. 1236-1246 ◽  
Author(s):  
X. Li ◽  
K. Murray ◽  
P. J. Harvey ◽  
E. W. Ballou ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Calcium Currents ◽  
High Dose ◽  
Chronic Injury ◽  
Persistent Inward Currents ◽  
Cord Injury ◽  
Inward Currents ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats

In the months after spinal cord transection, motoneurons in the rat spinal cord develop large persistent inward currents (PICs) that are responsible for muscle spasticity. These PICs are mediated by low-threshold TTX-sensitive sodium currents (Na PIC) and L-type calcium currents (Ca PIC). Recently, the Na PIC was shown to become supersensitive to serotonin (5-HT) after chronic injury. In the present paper, a similar change in the sensitivity of the Ca PIC to 5-HT was investigated after injury. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (S2 level transection 2 mo previously) was studied in vitro. Intracellular recordings were made from motoneurons and slow voltages ramps were applied to measure PICs. TTX was used to block the Na PIC. For motoneurons of chronic spinal rats, a low dose of 5-HT (1 μM) significantly lowered the threshold of the Ca PIC from −56.7 ± 6.0 to −63.1 ± 7.1 mV and increased the amplitude of the Ca PIC from 2.4 ± 1.0 to 3.0 ± 0.73 nA. Higher doses of 5-HT acted similarly. For motoneurons of acute spinal rats, low doses of 5-HT had no significant effects, whereas a high dose (about 30 μM) significantly lowered the threshold of the L-Ca PIC from −58.5 ± 14.8 to −62.5 ± 3.6 mV and increased the amplitude of the Ca PIC from 0.69 ± 1.05 to 1.27 ± 1.1 nA. Thus Ca PICs in motoneurons are about 30-fold supersensitive to 5-HT in chronic spinal rats. The 5-HT–induced facilitation of the Ca PIC was blocked by nimodipine, not by the Ih current blocker Cs+ (3 mM) or the SK current blocker apamin (0.15 μM), and it lasted for hours after the removal of 5-HT from the nCSF, even increasing initially after removing 5-HT. The effects of 5-HT make motoneurons more excitable and ultimately lead to larger, more easily activated plateaus and self-sustained firing. The supersensitivity to 5-HT suggests the small amounts of endogenous 5-HT below the injury in a chronic spinal rat may act on supersensitive receptors to produce large Ca PICs and ultimately enable muscle spasms.

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