scholarly journals Effects of Baclofen on Spinal Reflexes and Persistent Inward Currents in Motoneurons of Chronic Spinal Rats With Spasticity

2004 ◽  
Vol 92 (5) ◽  
pp. 2694-2703 ◽  
Author(s):  
Y. Li ◽  
X. Li ◽  
P. J. Harvey ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Ventral Root ◽  
Spinal Reflexes ◽  
Monosynaptic Reflex ◽  
Persistent Inward Currents ◽  
Inward Currents ◽  
Muscle Spasms ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats ◽  
Higher Doses

In the months after spinal cord injury, motoneurons develop large voltage-dependent persistent inward currents (PICs) that cause sustained reflexes and associated muscle spasms. These muscle spasms are triggered by any excitatory postsynaptic potential (EPSP) that is long enough to activate the PICs, which take >100 ms to activate. The PICs are composed of a persistent sodium current (Na PIC) and a persistent calcium current (Ca PIC). Considering that Ca PICs have been shown in other neurons to be inhibited by baclofen, we tested whether part of the antispastic action of baclofen was to reduce the motoneuron PICs as opposed to EPSPs. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (with sacral spinal transection 2 mo previously) was studied in vitro. Ventral root reflexes were recorded in response to dorsal root stimulation. Intracellular recordings were made from motoneurons, and slow voltage ramps were used to measure PICs. Chronic spinal rats exhibited large monosynaptic and long-lasting polysynaptic ventral root reflexes, and motoneurons had associated large EPSPs and PICs. Baclofen inhibited these reflexes at very low doses with a 50% inhibition (EC50) of the mono- and polysynaptic reflexes at 0.26 ± 0.07and 0.25 ± 0.09 (SD) μM, respectively. Baclofen inhibited the monosynaptic reflex in acute spinal rats at even lower doses (EC50 = 0.18 ± 0.02 μM). In chronic (and acute) spinal rats, all reflexes and EPSPs were eliminated with 1 μM baclofen with little change in motoneuron properties (PICs, input resistance, etc), suggesting that baclofen's antispastic action is presynaptic to the motoneuron. Unexpectedly, in chronic spinal rats higher doses of baclofen (20–30 μM) significantly increased the total motoneuron PIC by 31.6 ± 12.4%. However, the Ca PIC component (measured in TTX to block the Na PIC) was significantly reduced by baclofen. Thus baclofen increased the Na PIC and decreased the Ca PIC with a net increase in total PIC. By contrast, when a PIC was induced by 5-HT (10–30 μM) in motoneurons of acute spinal rats, baclofen (20–30 μM) significantly decreased the PIC by 38.8 ± 25.8%, primarily due to a reduction in the Ca PIC (measured in TTX), which dominated the total PIC in these acute spinal neurons. In summary, baclofen does not exert its antispastic action postsynaptically at clinically achievable doses (<1 μM), and at higher doses (10–30 μM), baclofen unexpectedly increases motoneuron excitability (Na PIC) in chronic spinal rats.

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.

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.

Spastic Long-Lasting Reflexes of the Chronic Spinal Rat Studied In Vitro

2004 ◽  
Vol 91 (5) ◽  
pp. 2236-2246 ◽  
Author(s):  
Y. Li ◽  
P. J. Harvey ◽  
X. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Adrenergic Receptor ◽  
Dorsal Root ◽  
Low Threshold ◽  
Muscle Spasms ◽  
Ventral Roots ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats ◽  
Adrenergic Receptor Agonist

Over the months following sacral spinal cord transection in adult rats, a pronounced spasticity syndrome emerges in the affected tail musculature, where long-lasting muscle spasms can be evoked by low-threshold afferent stimulation (termed long-lasting reflex). To develop an in vitro preparation to examine the neuronal mechanisms underlying spasticity, we removed the whole sacrocaudal spinal cord of these spastic chronic spinal rats (>1 mo after S2 sacral spinal transection) and maintained it in artificial cerebral spinal fluid in a recording chamber. The ventral roots were mounted on monopolar recording electrodes in grease, and the reflex responses to dorsal root stimulation were recorded and compared with the reflexes seen in the awake chronic spinal rat. When the dorsal roots were stimulated with a single pulse, a long-lasting reflex occurred in the ventral roots, with identical characteristics to the long-lasting reflex in the awake spastic rat tail. The reflex response was low threshold ( T), short latency, long duration (∼2 s), and enhanced by repeated stimulation. Brief high-frequency stimulation trains (0.5 s, 100 Hz, 1.5 × T) evoked even longer duration responses (5–10 s), with repeated bursts of activity that were similar to the repeated muscle spasms evoked in awake rats with stimulation trains or manual skin stimulation. Stimulation of a given dorsal root evoked long-lasting reflexes in both the ipsilateral and contralateral ventral roots. Long-lasting reflexes did not occur in the sacrocaudal spinal cord of acute spinal rats (S2 transection), which is similar to the areflexia seen in awake acute spinal rats. However, long-lasting reflexes could be made to occur in the acute spinal rat by altering K+ (7 mM) or Mg2+ (0 mM) concentrations, or by application of high doses of the neuromodulators norepinephrine (NE, >20 μM) or serotonin (5-HT, >20 μM). In chronic spinal rats, much lower doses of these neuromodulators (0.1 μM) enhanced the long-lasting reflexes, suggesting a denervation supersensitivity to 5-HT and NE following injury. Higher doses of NE or 5-HT produced a paradoxical inhibition of the long-lasting reflexes. The high dose inhibition by NE was mimicked by the α2-adrenergic receptor agonist clonidine but not the α1-adrenergic receptor agonist methoxamine. In summary, the sacral spinal in vitro preparation offers a new approach to the study of spinal cord injury and analysis of antispastic drugs.

The Effects of Substance P and Baclofen on Motoneurones of Isolated Spinal Cord of the Newborn Rat

1980 ◽  
Vol 89 (1) ◽  
pp. 201-214
Author(s):  
MASANORI OTSUKA ◽  
MITSUHIKO YANAGISAWA
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Ventral Root ◽  
Spinal Reflexes ◽  
Monosynaptic Reflex ◽  
Artificial Cerebrospinal Fluid ◽  
Site Of Action ◽  
Spinal Neurones ◽  
Depolarizing Agents ◽  
Root Stimulation

The effects of substance P (SP) and baclofen were studied in the isolated spinal cord of newborn rats. Potential changes generated in motoneurones were recorded extracellularly from the ventral root (L3-L5). When SP (8 × 10−5M) was introduced into the bath, the depolarization of motoneurones began with a delay of 1·1 s. A large part of this delay can be explained as a time needed for SP to reach the site of action on spinal neurones. When the preparation was perfused with artificial cerebrospinal fluid (CSF) containing low Ca (0·1 mM) and high Mg (1·6-3·5 mM), the spinal reflexes induced by dorsal root stimulation and recorded from the corresponding ventral root were completely abolished. The depolarizing action of SP (10−7M) on the motoneurones was potentiated in the low-Ca medium, suggesting that SP acts directly on the motoneurones. Baclofen at 10−6M depressed the monosynaptic reflex by about 75%. The SP-induced depolarization of motoneurones was greatly depressed by baclofen in both normal and 0·1 mM-Ca mediums. The effects of baclofen (10−6M) on the responses to various depolarizing agents were compared with that on the response to SP in artificial CSF containing 0·1 mM-Ca and 1·6-2 mM-Mg. The SP response was reduced by about 80%, whereas the responses to acetylcholine and glycine were not appreciably affected, and those to L-glutamate, GABA and noradrenaline were depressed by 10–22% by baclofen. These results suggest that baclofen blocks transmission at certain primary afferent synapses by antagonizing the action of SP that is released as a transmitter.

Motoneuron properties during motor inhibition produced by microinjection of carbachol into the pontine reticular formation of the decerebrate cat

1987 ◽  
Vol 57 (4) ◽  
pp. 1118-1129 ◽  
Author(s):  
F. R. Morales ◽  
J. K. Engelhardt ◽  
P. J. Soja ◽  
A. E. Pereda ◽  
M. H. Chase
Keyword(s):  
Spinal Cord ◽  
Motor Activity ◽  
Reticular Formation ◽  
Input Resistance ◽  
Ventral Root ◽  
Monosynaptic Reflex ◽  
Pontine Reticular Formation ◽  
Active Sleep ◽  
Decerebrate Cat ◽  
Inhibitory Postsynaptic Potentials

It is well established that cholinergic agonists, when injected into the pontine reticular formation in cats, produce a generalized suppression of motor activity (1, 3, 6, 14, 18, 27, 33, 50). The responsible neuronal mechanisms were explored by measuring ventral root activity, the amplitude of the Ia-monosynaptic reflex, and the basic electrophysiological properties of hindlimb motoneurons before and after carbachol was microinjected into the pontine reticular formation of decerebrate cats. Intrapontine microinjections of carbachol (0.25-1.0 microliter, 16 mg/ml) resulted in the tonic suppression of ventral root activity and a decrease in the amplitude of the Ia-monosynaptic reflex. An analysis of intracellular records from lumbar motoneurons during the suppression of motor activity induced by carbachol revealed a considerable decrease in input resistance and membrane time constant as well as a reduction in motoneuron excitability, as evidenced by a nearly twofold increase in rheobase. Discrete inhibitory postsynaptic potentials were also observed following carbachol administration. The changes in motoneuron properties (rheobase, input resistance, and membrane time constant), as well as the development of discrete inhibitory postsynaptic potentials, indicate that spinal cord motoneurons were postsynaptically inhibited following the pontine administration of carbachol. In addition, the inhibitory processes that arose after carbachol administration in the decerebrate cat were remarkably similar to those that are present during active sleep in the chronic cat. These findings suggest that the microinjection of carbachol into the pontine reticular formation activates the same brain stem-spinal cord system that is responsible for the postsynaptic inhibition of alpha-motoneurons that occurs during active sleep.

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 Comparison of the Effects on Spinal Reflexes of Acetylsalicylate and Metamizol in Spinalized and Normal Rats

2005 ◽  
Vol 48 (3-4) ◽  
pp. 149-152
Author(s):  
Osman Genç ◽  
Sebahat Turgut ◽  
Günfer Turgut ◽  
Selim Kortunay
Keyword(s):  
Spinal Cord ◽  
Arachidonic Acid ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Ventral Root ◽  
Spinal Reflexes ◽  
Reflex Response ◽  
Antiinflammatory Drugs ◽  
Lumbosacral Region ◽  
Adult Rats ◽  
Stimulation Of

The effects of nonsteroidal antiinflammatory drugs, acetylsalicylate and metamizol, on spinal monosynaptic reflexes were investigated in spinalized and normal rats. Adult rats (n=36) weighing 150–200 g were anesthetized with ketamine and artificially ventilated. Half of rats were spinalized at C1 level. A laminectomy was performed in the lumbosacral region. Following electrical stimulation of the sciatic nerve by single pulses, reflex potentials were recorded from the ipsilateral L5 ventral root. Acetylsalicylate was administered orally (100 mg/kg for both spinalized and normal rats). Metamizol was administered intramuscularly (15 mg/kg for both spinalized and normal rats). These drug administrations significantly decreased the amplitude of reflex response in all groups (p<0.05). These data verify that observed inhibition by acetylsalicylicate and metamizol may be at the level of spinal cord. Also we suggested that the cyclooxygenase products of arachidonic acid may play an important role in regulating the reflex potential.

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.

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