Chronic Spinal Cord Transection Research Articles

Effects of a High-Fat Diet on Tissue Mass, Bone, and Glucose Tolerance after Chronic Complete Spinal Cord Transection in Male Mice.

Spinal cord injury (SCI) is associated with obesity and is a risk factor for type 2 diabetes mellitus (T2DM). Immobilization, muscle atrophy, obesity, and loss of sympathetic innervation to the liver are believed to contribute to risks of these abnormalities. Systematic study of the mechanisms underlying SCI-induced metabolic disorders has been limited by a lack of animal models of insulin resistance following SCI. Therefore, the effects of a high-fat diet (HFD), which causes weight gain and glucose intolerance in neurologically intact mice, was tested in mice that had undergone a spinal cord transection at thoracic vertebra 10 (T10) or a sham-transection. At 84 days after surgery, Sham-HFD and SCI-HFD mice showed impaired intraperitoneal glucose tolerance when compared with Sham control (Sham-Con) or SCI control (SCI-Con) mice fed a standard control chow. Glucose tolerance in SCI-Con mice was comparable to that of Sham-Con mice. The mass of paralyzed skeletal muscle, liver, and epididymal, inguinal, and omental fat deposits were lower in SCI versus Sham groups, with lower liver mass present in SCI-HFD versus SCI-Con animals. SCI also produced sublesional bone loss, with no differences between SCI-Con and SCI-HFD groups. The results suggest that administration of a HFD to mice after SCI may provide a model to better understand mechanisms leading to insulin resistance post-SCI, as well as an approach to study pathogenesis of glucose intolerance that is independent of obesity.

Motor Recovery after Chronic Spinal Cord Transection in Rats: A Proof-of-Concept Study Evaluating a Combined Strategy.

The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP). This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers. Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers. Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.

Combining Constitutively Active Rheb Expression and Chondroitinase Promotes Functional Axonal Regeneration after Cervical Spinal Cord Injury

After spinal cord injury (SCI), severed axons in the adult mammalian CNS are unable to mount a robust regenerative response. In addition, the glial scar at the lesion site further restricts the regenerative potential of axons. We hypothesized that a combinatorial approach coincidentally targeting these obstacles would promote axonal regeneration. We combined (1) transplantation of a growth-permissive peripheral nerve graft (PNG) into an incomplete, cervical lesion cavity; (2) transduction of neurons rostral to the SCI site to express constitutively active Rheb (caRheb; a Ras homolog enriched in brain), a GTPase that directly activates the growth-promoting pathway mammalian target of rapamycin (mTOR) via AAV-caRheb injection; and (3) digestion of growth-inhibitory chondroitin sulfate proteoglycans within the glial scar at the distal PNG interface using the bacterial enzyme chondroitinase ABC (ChABC). We found that expressing caRheb in neurons post-SCI results in modestly yet significantly more axons regenerating across a ChABC-treated distal graft interface into caudal spinal cord than either treatment alone. Excitingly, we found that caRheb+ChABC treatment significantly potentiates the formation of synapses in the host spinal cord and improves the animals' ability to use the affected forelimb. Thus, this combination strategy enhances functional axonal regeneration following a cervical SCI.

Effects of pudendal nerve stimulation with different frequency on bladder dysfunction in spinal cord injury dogs

Objective To determine the effects of pudendal ncrve stimulation with different frequency(5 Hz,20 Hz) on bladder dysfunction dogs after spinal cord injury.Methods The study was done in 4 dogs which chronic spinal cord transection at T9-T10 level.All the dogs underwent electrical stimulation of pudendal nerve (5 Hz,20 Hz).Then,bladder capacity,compliance,non-voiding contraction number (NVC) and voiding efficiency before and during stimulation were compared.Results The bladder capacity and the compliance was increased ( 58.9 ± 17.4) ％ and (53.1 ± 4.9 ) ％ ( P ＜ 0.05 ) by pudendal nerve stimulation with low frequency (5 Hz).Detrusor overactivity can be inhibited and the NVC decreased from 1.7 ± 1.3 to 0.9 ± 1.1.Pudendal nerve stimulation with medium frequency ( 20 Hz) can induce bladder contraction and increased voiding efficiency from (5.8 ± 1.0) ％ to ( 16.3 ± 2.6 ) ％ ( P ＜0.05).Conclusions Pudendal nerve stimulation with low frequency can inhibit detrusor overactivity and increase the bladder capacity and compliance in spinal cord injury dogs.Pudendal nerve stimulation with medium frequency can induce bladder contraction and increased voiding efficicncy. Key words: Bladder; Spinal cord injury; Pudendal nerve stimulation; Dogs; Urodynamics

The Inhibitory Effects of Pudendal Nerve Stimulation on Bladder Overactivity in Spinal Cord Injury Dogs: Is Early Stimulation Necessary?

To determine the inhibitory effects of pudendal nerve stimulation (5 Hz) on bladder overactivity at early and late stages of spinal cord injury in dogs. The study was performed in eight dogs with chronic spinal cord transection at the T9-T10 level. Group 1 (four dogs) underwent electrical stimulation of pudendal nerve one month after spinal cord transection. Group 2 (four dogs) underwent stimulation six months after spinal cord transection. The bladders were removed for histological examination of fibrosis after the stimulation. The bladder capacity and the compliance were significantly increased (p < 0.05) by pudendal nerve stimulation in group 1, but not in group 2. The nonvoiding contractions were inhibited in both groups by electrical stimulation. Collagen fiber was increased, while elastic fiber was significantly decreased (p < 0.05) in group 2 when compared with group 1. Pudendal nerve stimulation can increase the bladder capacity and compliance only during the early period before the bladder wall becomes fibrosit and can inhibit the nonvoiding contraction during two stages.

Stress-induced cardiomyopathy in a patient with chronic spinal cord transection at the level of C5: Endocrinologically mediated catecholamine toxicity

Stress-induced cardiomyopathy (SIC) is characterized by transient extensive left ventricular (LV) akinesia in the absence of coronary artery disease of sufficient magnitude to explain the extent of cardiac dysfunction. The typical presentation is that of an akinetic ballooning apex with hypercontractile basal segments. Stress-induced release of catecholamines is believed to trigger cardiac dysfunction, but it is not known whether it is mediated by systemically elevated plasma catecholamines (endocrine hypothesis) or by the sympathetic nervous end (neural hypothesis) [1].

Tail muscle parvalbumin content is decreased in chronic sacral spinal cord injured rats with spasticity

In rats, chronic sacral spinal isolation eliminates both descending and afferent inputs to motoneurons supplying the segmental tail muscles, eliminating daily tail muscle EMG activity. In contrast, chronic sacral spinal cord transection preserves afferent inputs, causing tail muscle spasticity that generates quantitatively normal daily EMG. Compared with normal rats, rats with spinal isolation and transection/spasticity provide a chronic model of progressive neuromuscular injury. Using normal, spinal isolated and spastic rats, we characterized the activity dependence of calcium-handling protein expression for parvalbumin, fast sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA1) and slow SERCA2. As these proteins may influence fatigue resistance, we also assayed the activities of oxidative (citrate synthase; CS) and glycolytic enzymes (glyceraldehyde phosphate dehydrogenase; GAPDH). We hypothesized that, compared with normal rats, chronic isolation would cause decreased parvalbumin, SERCA1 and SERCA2 expression and CS and GAPDH activities. We further hypothesized that chronic spasticity would promote recovery of parvalbumin, SERCA1 and SERCA2 expression and of CS and GAPDH activities. Parvalbumin, SERCA1 and SERCA2 were quantified with Western blotting. Citrate synthase and GAPDH activities were quantified photometrically. Compared with normal rats, spinal isolation caused large decreases in parvalbumin (95%), SERCA1 (70%) and SERCA2 (68%). Compared with spinal isolation, spasticity promoted parvalbumin recovery (ninefold increase) and a SERCA2-to-SERCA1 transformation (84% increase in the ratio of SERCA1 to SERCA2). Compared with normal values, CS and GAPDH activities decreased in isolated and spastic muscles. In conclusion, with complete paralysis due to spinal isolation, parvalbumin expression is nearly eliminated, but with muscle spasticity after spinal cord transection, parvalbumin expression partly recovers. Additionally, spasticity after transection causes a slow-to-fast SERCA isoform transformation that may be compensatory for decreased parvalbumin content.

Nerve-Evoked Constriction of Rat Tail Veins Is Potentiated and Venous Diameter Is Reduced after Chronic Spinal Cord Transection

Despite reduced sympathetic activity below the level of a spinal cord injury (SCI), venoconstriction during autonomic dysreflexia increases venous return to the heart. Here, contractions of isometrically mounted tail veins from rats with spinal transection at T4 performed 8 - 10 weeks earlier are compared with those from sham-operated rats. After SCI, lumen diameter was reduced by ∼30% and the contractions evoked by electrical stimulation of the perivascular axons were larger than control. This augmentation of neurovascular transmission was not associated with enhanced sensitivity to α-adrenoceptor agonists or to adenosine-5'-triphosphate (ATP) although contractions to depolarization with K(+) were larger after SCI. The percentage reduction in nerve-evoked contraction after SCI produced by the α(1)-adrenoceptor antagonist prazosin (10 nM) was unchanged but that by the α(2)-adrenoceptor antagonist rauwolscine (0.1 μM) was reduced. The relative contribution of P2-purinoceptors to nerve-evoked contractions after α-adrenoceptor blockade, revealed by adding suramin (0.1 mM), was unchanged. The greater depolarization-induced contraction and the reduced contribution of α(2)-adrenoceptors to nerve-evoked contraction suggest that changes in the venous smooth muscle underlie the potentiation of neurovascular transmission after SCI. Furthermore, the smaller lumen diameter after SCI will increase the pressure that the veins exert on the luminal contents when they are neurally activated.

Quantification of external urethral sphincter and bladder activity during micturition in the intact and spinally transected adult rat

The goal of this study was to determine the effect of chronic mid-thoracic spinal cord transection on the time course of external urethral sphincter (EUS) and bladder activity associated with micturition events in the rat. Adult female Sprague–Dawley rats, either spinally intact or transected (T 9–T 10), were anesthetized with urethane and set up for continuous flow urodynamic recording of bladder intravesical pressure (BP) and EUS electromyography (EMG). Spinal transections were performed under isoflurane anesthesia 1–8 weeks prior to the terminal experiment. Four major differences between intact and transected rats were observed: 1) While the frequency of micturition events in the intact rat was dependent upon the rate of bladder filling, the bladder contraction and associated EUS activation in transected rats exhibited an intrinsic rhythm that was independent of the rate of bladder filling and post-transection survival time. 2) EUS activation was augmented at the beginning of active bladder contraction in the transected rat, indicating an amplified guarding reflex. 3) Phasic EUS activity at the peak of bladder contraction (EUS bursting) in the intact rat was markedly reduced or absent in the transected rat. 4) The sustained tonic EUS activity following bladder relaxation in the intact rat was absent in the transected rat. These data are discussed in the context of understanding the pathophysiology of spinal cord injury (SCI) induced destrusor-sphincter dyssynergia (DSD).

Muscarinic control of the excitability of hindlimb motoneurons in chronic spinal-transected salamanders

The excitability of spinal motoneurons (MNs) is regulated by acetylcholine via the activation of muscarinic receptors. The objective of the present study was to determine whether this cholinergic modulation of MN excitability is altered following a chronic spinal cord transection. Juvenile salamanders (Pleurodeles waltlii) were spinally transected at the mid-trunk level, and patch-clamp recordings from hindlimb MNs in spinal cord slices were performed 9-30 days after transection, with and without bath application of muscarine (20 mum). Our results showed that the input-output relationship was larger in MNs recorded 2 weeks after spinal transection than in MNs recorded 3-4 weeks after spinal transection. They further revealed that muscarine increased both the gain of MNs and the proportion of MNs that could exhibit plateau potentials and afterdischarges, whereas it decreased the amplitude of the medium afterhypolarizing potential. Moreover, muscarine had no effect on the hyperpolarization-activated cation current (I(h)), whereas it increased the inward rectifying K(+) current (I(Kir)) in MNs recorded > or = 2 weeks after spinal transection. We conclude that following chronic spinal cord injury, the muscarinic modulation of some intrinsic properties of MNs previously reported in acute spinal-transected animals [S. Chevallier et al. (2006)The Journal of Physiology, 570, 525-540] was preserved, whereas that of other intrinsic properties of MNs was suppressed, either transiently (I(Kir)) or definitively (I(h)). These alterations in muscarinic modulation of MN excitability may contribute to the spontaneous recovery of locomotion displayed in long-term chronic spinal-transected salamanders.

Intrathecal delivery of resiniferatoxin (RTX) reduces detrusor overactivity and spinal expression of TRPV1 in spinal cord injured animals

Recently, it has been demonstrated that intrathecal delivery of resiniferatoxin (RTX) produces strong analgesia, even in models of bone cancer pain. RTX has been investigated to treat bladder dysfunction of spinal origin, applied by intravesical instillation. However, RTX delivered by this route was not completely satisfactory in controlling urinary incontinence and high intravesical pressure. Thus, the present study assessed the effects of intrathecal injections of RTX in bladder dysfunction in rats with spinal cord transection (SCT). Bladder function was evaluated in SCT rats 24 h following intrathecal administration of RTX. Detrusor overactivity and intravesical pressure were reduced in a dose-dependent manner. This was accompanied by a decrease in spinal cord TRPV1 and CGRP, but not in IB4 binding sensory fibres. Also, intrathecal RTX induced a dose-dependent reduction in spinal cord activation of the ERK pathway. Overall, our results show that intrathecal administration of RTX effectively reduces detrusor overactivity and reduces intravesical pressure in models of complete chronic spinal cord transection by suppressing the activity of TRPV1 expressing afferent fibres. Also, intrathecal RTX decreases sensory input, as shown by reduced spinal ERK activation. These findings might be relevant for the management of patients with spinal cord injuries.

The Role of Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide in the Neural Pathways Controlling the Lower Urinary Tract

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are expressed in the neural pathways regulating the lower urinary tract. VIP-immunoreactivity (IR) is present in afferent and autonomic efferent neurons innervating the bladder and urethra, whereas PACAP-IR is present primarily in afferent neurons. Exogenously applied VIP relaxes bladder and urethral smooth muscle and excites parasympathetic neurons in bladder ganglia. PACAP relaxes bladder and urethral smooth muscle in some species (pig) but excites the smooth muscle in other species (mouse). Intrathecal administration of VIP in cats with an intact spinal cord suppresses reflex bladder activity, but intrathecal administration of VIP or PACAP in rats enhances bladder activity and suppresses urethral sphincter activity. PACAP has presynaptic facilitatory effects and direct excitatory effects on lumbosacral parasympathetic preganglionic neurons. Chronic spinal cord transection produces an expansion of VIP-IR (cats) and PACAP-IR (rats) in primary afferent axons in the lumbosacral spinal cord and unmasks spinal excitatory effects of VIP on bladder reflexes in cats. Intrathecal administration of PACAP6-38, a PAC1 receptor antagonist, reduces bladder hyperactivity in chronic spinal-cord-injured rats. These observations raise the possibility that VIP or PACAP have a role in the control of normal or abnormal voiding.

Effects of intrathecal administration of pituitary adenylate cyclase activating polypeptide on lower urinary tract functions in rats with intact or transected spinal cords

Effects of intrathecally administered pituitary adenylate cyclase activating polypeptide-38 (PACAP-38, 0.1–30 μg) on lower urinary tract function were examined in unanesthetized, decerebrate rats with an intact spinal cord and after chronic spinal cord transection (SCT). PACAP-38 was also studied in rats with intact or bilaterally transected hypogastric nerves (HGNs), to determine if sympathetic pathways to the bladder influenced responses. In SCT rats with intact HGNs under isovolumetric conditions, 30 μg of PACAP-38 but not lower doses (0.1–10 μg) increased (mean 194%) bladder contraction amplitude (BCA). In SCT rats with sectioned HGNs, 10 μg and 30 μg of PACAP-38 increased BCA by 62% and 195%, respectively. On the other hand, during continuous infusion cystometrograms (CMGs) in SCT rats with intact or sectioned HGNs, PACAP-38 (10 μg and 30 μg) markedly reduced or completely suppressed BCA (60% and 90%, respectively) and reduced external urethral sphincter (EUS) EMG activity (58% and 91%, respectively). During CMGs in spinal cord intact rats, with intact HGNs PACAP-38 30 μg increased BCA (26%) but after HGN section PACAP-38 10 μg and 30 μg increased BCA by 21% and 35%. These results suggest that after SCT, PACAP-38 activates spinal circuitry to facilitate the parasympathetic outflow to the urinary bladder and that the elimination of sympathetic pathways enhances this effect. The decrease in BCA by PACAP-38 during CMGs in SCT rats is most reasonably attributed to a reduction in urethral outlet resistance due to suppression of excitatory EUS reflexes.

Does elimination of afferent input modify the changes in rat motoneurone properties that occur following chronic spinal cord transection?

The purpose of this study was to determine the effects of 6-8 weeks of chronic spinal cord isolation (SI, removal of descending, ascending and afferent inputs), compared with the same duration of spinal cord transection (ST, removal of descending input only) on hindlimb motoneurone biophysical properties. Adult female Sprague-Dawley rats were placed into three groups: (1) control (no removal of inputs), (2) ST and (3) SI. The electrophysiological properties from sciatic nerve motoneurones were recorded from deeply anaesthetized rats. Motoneurones in SI rats had significantly (P < 0.01) lower rheobase currents and higher spike afterhyperpolarization amplitudes and input resistances compared with motoneurones in control rats. A higher percentage (chi2, P = 0.01) of motoneurones in SI than control rats demonstrated frequency-current (f-I) relationships consistent with activation of persistent inward currents. Motoneurone steady state f-I slopes determined by increasing steps of 500 ms current pulses were significantly lower (P < 0.02) in SI than control rats. Motoneurone spike frequency adaptation measured using 30 s square-wave current injections (1.5-3.0 nA above the estimated rhythmic firing threshold), was similar for control and SI motoneurones. Changes in motoneurone properties following SI did not differ from ST. These findings indicate that the removal of afferent and ascending inputs along with descending inputs has little additional affect on motoneurone properties than removal of descending inputs alone. This study is the first to demonstrate that intact ascending and afferent input does not modify the effects of spinal transection on basic and rhythmic firing properties of rat hindlimb motoneurones.

T5 spinal cord transection increases susceptibility to reperfusion-induced ventricular tachycardia by enhancing sympathetic activity in conscious rats

We recently documented that paraplegia (T(5) spinal cord transection) alters cardiac electrophysiology and increases the susceptibility to ventricular tachyarrhythmias induced by programmed electrical stimulation. However, coronary artery occlusion is the leading cause of death in industrially developed countries and will be the major cause of death in the world by the year 2020. The majority of these deaths result from tachyarrhythmias that culminate in ventricular fibrillation. beta-Adrenergic receptor antagonists have been shown to reduce the incidence of sudden cardiac death. Therefore, we tested the hypothesis that chronic T(5) spinal cord transection increases the susceptibility to clinically relevant ischemia-reperfusion-induced sustained ventricular tachycardia due to enhanced sympathetic activity. Intact and chronic (4 wk after transection) T(5) spinal cord-transected (T(5)X) male rats were instrumented to record arterial pressure, body temperature, and ECG. In addition, a snare was placed around the left main coronary artery. The susceptibility to sustained ventricular tachycardia produced by 2.5 min of occlusion and reperfusion of the left main coronary artery was determined in conscious rats by pulling on the snare. Reperfusion culminated in sustained ventricular tachycardia in 100% of T(5)X rats (susceptible T(5)X, 10 of 10) and 0% of intact rats [susceptible intact, 0 of 10 (P < 0.05, T(5)X vs. intact)]. Beta-adrenergic receptor blockade prevented reperfusion-induced sustained ventricular tachycardia in T(5)X rats [susceptible T(5)X 0 of 8, 0% (P < 0.05)]. Thus paraplegia increases the susceptibility to reperfusion-induced sustained ventricular tachycardia due to enhanced sympathetic activity.

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

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.

The spinal cord, anesthesia and immobility: A re-examination

There has been much recent emphasis on the spinal cord as an important site of anesthetic action with respect to immobility. For example, decerebration or spinal cord transection in rats appears to have little effect on minimum alveolar anesthetic concentration (MAC) needed to produce immobility. Likewise, selective delivery of isoflurane, halothane or thiopental to the brain circulation necessitates increased anesthetic concentrations to provide immobility. However, we have observed that chronic spinal cord transection or acute spinal cooling results in lower MAC and reduced force of limb movement. Others have shown that discrete drug microinjections at various brain sites (gabazine in tuberomammillary nucleus or pentobarbital in the pontine tegmentum) alter anesthetic requirements or produce anesthesia. Collectively, these data suggest that, while the spinal cord is a major site of action for the immobilizing properties for anesthetics, supraspinal sites still play an important role in determining MAC.

Spastic long-lasting reflexes in the awake rat after sacral spinal cord injury.

Following chronic sacral spinal cord transection in rats the affected tail muscles exhibit marked spasticity, with characteristic long-lasting tail spasms evoked by mild stimulation. The purpose of the present paper was to characterize the long-lasting reflex seen in tail muscles in response to electrical stimulation of the tail nerves in the awake spastic rat, including its development with time and relation to spasticity. Before and after sacral spinal transection, surface electrodes were placed on the tail for electrical stimulation of the caudal nerve trunk (mixed nerve) and for recording EMG from segmental tail muscles. In normal and acute spinal rats caudal nerve trunk stimulation evoked little or no EMG reflex. By 2 wk after injury, the same stimulation evoked long-lasting reflexes that were 1) very low threshold, 2) evoked from rest without prior EMG activity, 3) of polysynaptic latency with >6 ms central delay, 4) about 2 s long, and 5) enhanced by repeated stimulation (windup). These reflexes produced powerful whole tail contractions (spasms) and developed gradually over the weeks after the injury (< or =52 wk tested), in close parallel to the development of spasticity. Pure low-threshold cutaneous stimulation, from electrical stimulation of the tip of the tail, also evoked long-lasting spastic reflexes, not seen in acute spinal or normal rats. In acute spinal rats a strong C-fiber stimulation of the tip of the tail (20 x T) could evoke a weak EMG response lasting about 1 s. Interestingly, when this C-fiber stimulation was used as a conditioning stimulation to depolarize the motoneuron pool in acute spinal rats, a subsequent low-threshold stimulation of the caudal nerve trunk evoked a 300-500 ms long reflex, similar to the onset of the long-lasting reflex in chronic spinal rats. A similar conditioned reflex was not seen in normal rats. Thus there is an unusually long low-threshold polysynaptic input to the motoneurons (pEPSP) that is normally inhibited by descending control. This pEPSP is released from inhibition immediately after injury but does not produce a long-lasting reflex because of a lack of motoneuron excitability. With chronic injury the motoneuron excitability is increased markedly, and the pEPSP then triggers sustained motoneuron discharges associated with long-lasting reflexes and muscle spasms.

Enhanced hypotensive response to intravenous apomorphine in chronic spinalized, conscious rats: role of spinal dopamine D 1 and D 2 receptors

Intravenous (i.v.) treatment with apomorphine (0.3 mg/kg) in conscious rats with chronic spinal cord transection (at T5–T7) induced a significant hypotension, which was greater than that in sham-operated rats. The present study examined whether such an amplification results from an enhanced spinal dopamine D 1 and/or D 2 receptor-mediated depressor effect. Intrathecal (i.t.) pretreatment with domperidone (40 μg/rat at T9–T10), a dopamine D 2 receptor antagonist that does not cross the blood–brain barrier, blocked nearly 35 and 56% of the maximal apomorphine-induced hypotension in control and spinal rats, respectively. The remaining hypotension after i.v. domperidone (0.5 mg/kg) pretreatment (i.e. the spinal component of the response) was significantly greater in spinal rats than in controls. In the latter animals, apomorphine-induced hypotension was fully abolished by metoclopramide (5 mg/kg, i.v.). However, in spinal rats, the hypotension was only abolished by combined pretreatment with i.v. metoclopramide and i.t. SCH 23390 (27 μg/rat at T9–T10). The results suggest that the enhancing hypotensive effects of i.v. apomorphine by spinal cord section are related to increased spinal dopamine D 1 and D 2 receptor-mediated depressor effects.

Rats with chronic spinal cord transection as a possible model for the at-level pain of paraplegic patients

Patients with complete spinal cord injury (SCI) often suffer from chronic pain which is perceived around the segment of the lesion. The present study tests the hypothesis that chronic SCI pain is due to pathophysiological neuronal activity in the spinal segment just rostral to the SCI. In an animal model with complete chronic SCI, the impulse activity of single dorsal horn neurones was recorded in the segment rostral to the lesion. Following SCI, the neurones exhibited a higher background activity. Some neurones showed an abnormal type of activity which was not present under control conditions. The results support the hypothesis that increased and altered background activity just rostral to the lesion contributes to chronic at-level pain of paraplegic patients.