Using a rat model of ischemic paraplegia, we examined the expression of spinal AMPA receptors and their role in mediating spasticity and rigidity. Spinal ischemia was induced by transient occlusion of the descending aorta combined with systemic hypotension. Spasticity/ rigidity were identified by simultaneous measurements of peripheral muscle resistance (PMR) and electromyography (EMG) before and during ankle flexion. In addition, Hoffman reflex (H-reflex) and motor evoked potentials (MEPs) were recorded from the gastrocnemius muscle. Animals were implanted with intrathecal catheters for drug delivery and injected with the AMPA receptor antagonist NGX424 (tezampanel), glutamate receptor 1 (GluR1) antisense, or vehicle. Where intrathecal vehicle had no effect, intrathecal NGX424 produced a dose-dependent suppression of PMR [ED 50 of 0.44 g (0.33-0.58)], as well as tonic and ankle flexion-evoked EMG activity. Similar suppression of MEP and H-reflex were also seen. Western blot analyses of lumbar spinal cord tissue from spastic animals showed a significant increase in GluR1 but decreased GluR2 and GluR4 proteins. Confocal and electron microscopic analyses of spinal cord sections from spastic animals revealed increased GluR1 immunoreactivity in reactive astrocytes. Selective GluR1 knockdown by intrathecal antisense treatment resulted in a potent reduction of spasticiy and rigidity and concurrent downregulation of neuronal/astrocytic GluR1 in the lumbar spinal cord. Treatment of rat astrocyte cultures with AMPA led to dose-dependent glutamate release, an effect blocked by NGX424. These data suggest that an AMPA/kainate receptor antagonist can represent a novel therapy in modulating spasticity/rigidity of spinal origin and that astrocytes may be a potential target for such treatment.

Background Spasticity and rigidity are serious complications associated with spinal traumatic or ischemic injury. Clinical studies show that Tizanidine (Tiz) is an effective anti-spasticity agent, however, the mechanism of this effect is still not clear. Tiz binds not only to α2-adrenoreceptors (AR) but also to imidazoline (I) receptors. Both receptor systems (AR+I) are present in the spinal cord interneurons and α-motoneurons. The aim of the present study was to evaluate the therapeutic potency of systematically or spinally (intrathecally) delivered Tiz on stretch reflex activity (SRA) in animals with ischemic spasticity, and to delineate supraspinal or spinal sites of Tiz action. Methods Animals were exposed to 10 min of spinal ischemia to induce an increase in SRA. Increase in SRA was identified by simultaneous increase in recorded EMG activity and ankle resistance measured during computer-controlled ankle dorsiflexion (40°/3 sec) in fully awake animals. Animals with increased SRA were divided into several experimental subgroups and treated as follows: i) Tiz administered systemically at the dose of 1 mg kg-1, or intrathecally (IT) at 10 μg or 50 μg delivered as a single dose; ii) Treatment with systemic Tiz was followed by the systemic injection of vehicle, or by non-selective AR antagonist without affinity for imidazoline receptors; Yohimbine (Yoh), α2A AR antagonist; BRL44408 (BRL), α2B AR antagonist; ARC239 (ARC), non-selective AR and I1 receptor antagonist; Efaroxan (Efa), or non-selective AR and I2 receptor antagonist; Idazoxan (Ida); iii) Treatment with IT Tiz was followed by the IT injection of selective α2A AR antagonist; Atipamezole (Ati). In a separate group of spastic animals the effect of systemic Tiz treatment (1 mg/kg) or isoflurane anesthesia on H-reflex activity was also studied. Results Systemic and/or IT treatment with Tiz significantly suppressed SRA. This Tiz-mediated anti-SRA effect was reversed by BRL (5 mg kg-1), Efa (1 mg kg-1) and Ida (1 mg kg-1). No reversal was seen after Yoh (3 mg kg-1) or ARC (5 mg kg-1) treatment. Anti-SRA induced by IT Tiz (50 μg) was reversed by IT injection of Ati (50 μg). Significant suppression of H-reflex was measured after systemic Tiz treatment (1mg/kg) or isoflurane (2%) anesthesia, respectively. Immunofluoresecene staining of spinal cord sections taken from animals with spasticity showed upregulation of α-2A receptor in activated astrocytes. Conclusions These data suggest that α2A AR and I receptors, but not α2B AR primarily mediate the Tiz-induced anti-spasticity effect. This effect involves spinal and potentially supraspinal sites and likely targets α2A receptor present on spinal neurons, primary afferents and activated astrocytes Further studies using highly selective antagonists are needed to elucidate the involvement of specific subtypes of the AR and imidazoline receptors in the anti-spasticity effect seen after Tiz treatment.

We investigated in humans whether changes in spinal motor neuron excitability correlate with the predicted propofol concentration (Cpt) achieved by a target-controlled infusion system. Propofol suppressed F-wave persistence in a Cpt-dependent manner, indicating that propofol depresses spinal motor neuron excitability at clinically relevant concentrations.

These results suggest that the effect of various opioids on motor function after a short period of spinal cord ischaemia depends upon individual opioid receptor subtypes.