Seiya Nakamura

The Antinociceptive Effect of Intrathecal Administration of Glycine Transporter-2 Inhibitor ALX1393 in a Rat Acute Pain Model

BACKGROUND: Glycinergic neurons in the spinal dorsal horn have been implicated in the inhibition of spinal pain processing in peripheral inflammation and chronic pain states. Neuronal isoform glycine transporter-2 (GlyT2) reuptakes presynaptically released glycine and regulates the glycinergic neurotransmission. In this study, we examined whether a selective GlyT2 inhibitor, ALX1393, elicits an antinociceptive effect in a rat acute pain model. METHODS: Male Sprague-Dawley rats were implanted with a catheter intrathecally. The effects of intrathecal administration of ALX1393 (4, 20, or 40 &mgr;g) on thermal, mechanical, and chemical nociception were evaluated by tail flick, hot plate, paw pressure, and formalin tests. Furthermore, to explore whether ALX1393 affects motor function, a rotarod test was performed. RESULTS: ALX1393 exhibited antinociceptive effects on the thermal and mechanical stimulations in a dose-dependent manner. The maximal effect of ALX1393 was observed at 15 min after administration, and a significant effect lasted for about 60 min. These antinociceptive effects were reversed completely by strychnine injected immediately after the administration of ALX1393. In the formalin test, ALX1393 inhibited pain behaviors in a dose-dependent manner, both in the early and late phases, although the influence was greater in the late phase. In contrast to antinociceptive action, ALX1393 did not affect motor function up to 40 &mgr;g. CONCLUSIONS: This study demonstrates the antinociceptive action of ALX1393 on acute pain. These findings suggest that the inhibitory neurotransmitter transporters are promising targets for the treatment of acute pain and that the selective inhibitor of GlyT2 could be a novel therapeutic drug.

Propofol reduces spinal motor neuron excitability in humans.

IMPLICATIONS 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.

Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity

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 [ED50 of 0.44 μg (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.

Influence of the Descending Thoracic Aortic Cross Clamping on Bispectral Index Value and Plasma Propofol Concentration in Humans

Background:In this study, the authors investigated changes in Bispectral Index (BIS) values and plasma propofol concentrations (Cp) after aortic cross clamping in the descending thoracic aortic aneurysm repair surgery during propofol anesthesia. Methods:Prospectively, in 10 patients undergoing thoracic aortic surgery during total intravenous anesthesia with propofol, BIS values were recorded during cross clamping of the descending thoracic aorta. In this study, the rate of propofol infusion was controlled to keep the BIS value between 30 and 60 throughout surgery. Simultaneously, Cp values in the blood samples taken from the right radial artery (area proximal to cross clamping) and the left femoral artery (area distal to cross clamping) were measured. Results:Approximately 15 min after initiating aortic cross clamping, BIS values in all cases started to decrease abruptly. Cp values of samples taken from the radial artery after cross clamping of the aorta were significantly (P < 0.05) increased compared with pre–cross clamp values (1.8 ± 0.4 &mgr;g/ml), and the mean Cp after aortic cross clamping varied between 3.0 and 5.3 &mgr;g/ml. In addition, there were significant differences in the Cp values between radial arterial and femoral arterial blood samples throughout aortic cross clamping. Cp values in samples from the radial artery were approximately two to seven times higher than those from the femoral artery. Conclusions:This study showed that Cp values increased and BIS values decreased rapidly after aortic cross clamping in thoracic aortic aneurysm repair surgery during propofol anesthesia. These findings suggested that all anesthesiologists should control the infusion rate carefully, taking the abrupt changes in its pharmacokinetics into consideration, especially during cross clamping of the descending thoracic aorta.

Intravenous Infusion of Dexmedetomidine Can Prevent the Degeneration of Spinal Ventral Neurons Induced by Intrathecal Morphine After a Noninjurious Interval of Spinal Cord Ischemia in Rats

BACKGROUND:In recent studies, we demonstrated that neuraxial morphine after noninjurious spinal cord ischemia in the rat could induce spastic paraplegia and degeneration of selective spinal ventral neurons. Our objective was to investigate the impact of dexmedetomidine infusion on the degeneration of spinal ventral neurons induced by intrathecal (IT) morphine after spinal cord ischemia. METHODS:Male Sprague-Dawley rats were given repetitive doses of IT morphine (40 &mgr;g × 2) at 1 and 5 h after a noninjurious interval (6 min) of spinal cord ischemia. The animals were assigned to one of the following four groups after the first IT injection (n = 8/group): Group S, IV infusion of saline (mL/h); Group Dex 0.1, dexmedetomidine (0.1 &mgr;g · kg−1 · h−1); Group Dex 1, dexmedetomidine (1 &mgr;g · kg−1 · h−1); Group Dex 3, dexmedetomidine (3 &mgr;g · kg−1 · h−1). Follow-up evaluation included a sedation scale, the Motor Deficit Index to determine neurological dysfunction and histopathology of the spinal cord at 72 h of reperfusion. RESULTS:IV dexmedetomidine produced a dose-dependent increase in the sedation index. Repetitive IT morphine injection induced paraplegia and degeneration of the spinal ventral neurons. IV dexmedetomidine at a sedative dose in comparison with saline significantly attenuated neurological dysfunction and histopathological consequences. CONCLUSION:These data show that repetitive administration of IT morphine can induce paraplegia with degeneration of spinal ventral neurons, which can be attenuated by IV dexmedetomidine at a sedative dose. The use of dexmedetomidine may provide beneficial effects on neurological outcome after IT morphine after spinal cord ischemia in rats.

Emergence from propofol anesthesia in a nonagenarian at a Bispectral Index of 52.

In this case report, we describe a nonagenarian patient who could respond completely to verbal commands at a Bispectral Index (BIS) value of 52 after epidural lidocaine and IV propofol anesthesia. Measured blood lidocaine and propofol concentrations were 0.69 microg/mL and 0.74 microg/mL, respectively. Intraoperative awareness even in the recommended BIS range of 40-60 remains possible.

Intrathecal morphine, but not buprenorphine or pentazocine, can induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat.

In this study, we sought to determine the effect of intrathecal (IT) pentazocine or buprenorphine on the neurological outcome after a short interval of spinal cord ischemia in rats. Although IT morphine (30 &mgr;g) induced spastic paraparesis after 6 min of aortic occlusion, neither pentazocine (150 &mgr;g) nor buprenorphine (4 &mgr;g) produced neurological dysfunction. Our results indicate that the effect of various opioids on the motor function after a noninjurious interval of spinal cord ischemia is opioid-specific.

The effect of gamma-aminobutyric acid (GABA) receptor drugs on morphine-induced spastic paraparesis after a noninjurious interval of spinal cord ischemia in rats.

We have previously demonstrated that intrathecal morphine given after a noninjurious interval of spinal cord ischemia induced transient spastic paraparesis in a rodent model. However, the mechanism of this paraparesis is unknown. We hypothesized that morphine inhibits &ggr;-aminobutyric acid (GABA)ergic interneurons that control the tonus of spinal cord &agr;-motoneurons and that inhibition of spinal cord interneurons may cause spastic paraparesis. In this study, we investigate interactions between morphine and GABAergic agonists or antagonists on motor function after spinal cord ischemia and then clarified the mechanism of the spastic paraparesis induced by intrathecal morphine. Spinal cord ischemia was induced by aortic occlusion lasting 6 min. We first determined whether intrathecally administered GABA agonists (muscimol or baclofen) improve the spastic paraparesis in this model. GABA agonists did not improve the paraparesis. Next, we examined the effect of GABA antagonists (bicuculline or 5-aminovaleric acid) and determined the interaction between morphine and GABA antagonists. In an isobolographic analysis, the 50% effective dose decreased below the theoretical additive line, indicating a synergistic interaction between morphine and GABA antagonists. These results indicate that the spastic paraparesis induced by intrathecal morphine may be mediated in part by GABA receptors.

Appropriate method of administration of propofol, fentanyl, and ketamine for patient-controlled sedation and analgesia during extracorporeal shock-wave lithotripsy

AbstractPurpose. The aim of this study was to identify the appropriate method for administering propofol, fentanyl, and ketamine (PFK) for patient-controlled sedation and analgesia (PCSA) during extracorporeal shock-wave lithotripsy (ESWL). Methods. Twenty-one unpremedicated patients were randomly assigned to three groups that received different drug administration regimens. (group 1: low loading dose and high demand bolus, group 2: high loading dose and demand bolus, group 3: high loading dose and low demand bolus). Results. The patients in all groups were hemodynamically stable during ESWL. Oxygen desaturation was recognized in all groups, but was avoided by 2 l·min−1 of oxygen supply via a nasal prong. The total administration dose of the drugs was significantly higher (P < 0.05) in group 2 than in groups 1 and 3. The median level of sedation was the same, but the episodes of oversedation were not recognized in group 3 (P < 0.05). A significant difference in the frequency of episodes of oversedation was found between groups 2 and 3 (P < 0.05). The results were good or excellent for almost all patients, and were assessed as fair by only one patient in group 2. Conclusion. We concluded that the method used for group 3 is the most appropriate for administering PFK for PCSA during ESWL.

Intrathecal nicorandil and small-dose morphine can induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat.

We investigated the interaction between nicorandil, a K+ATP channel opener, and morphine on motor function after a noninjurious interval of spinal cord ischemia in the rat. Spinal ischemia was induced by aortic occlusion for 6 min with a balloon catheter in Sprague-Dawley rats. All animals received intrathecal (IT) injection of morphine (1–60 &mgr;g) 1 h after ischemia. In addition to IT injection of morphine, group M (control), group MN (combination of morphine and nicorandil), and group MNG (combination of morphine, nicorandil, and glibenclamide) received IT saline, nicorandil (10 &mgr;g), and both glibenclamide (10 &mgr;g) and nicorandil (10 &mgr;g) after 150 min of reperfusion, respectively. A quantal bioassay for the effect of IT morphine on neurological function after ischemia was performed to calculate 50% effective dose values (ED50) for inducing paraparesis at 3 h of reperfusion. The ED50 in group M and group MN was 15.1 ± 4.9 &mgr;g and 2.9 ± 1.0 &mgr;g of IT morphine, respectively (P < 0.05). In Group MNG, the dose-response curve shifted back to the right and the ED50 for inducing paraparesis was 11.6 ± 4.7 &mgr;g of IT morphine. The present study demonstrates that IT small-dose morphine combined with nicorandil induces spastic paraparesis after noninjurious interval of spinal cord ischemia in the rat.