Anesth Analg 2007; 105:1086-1093
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000278641.90190.8d
NEUROSURGICAL ANESTHESIOLOGY
Section Editor:
Adrian W. Gelb
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
Manabu Kakinohana, MD, PhD*,
Masakatsu Oshiro, MD*,
Satoko Saikawa, MD*,
Seiya Nakamura, MD, PhD*,
Tatsuya Higa, MD*,
Kenneth J. Davison, MD ,
Martin Marsala, MD , and
Kazuhiro Sugahara, MD, PhD*
From the *Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan; Department of Anesthesiology, Massachusetts General Hospital, Boston, Massachusetts; and Department of Anesthesiology, University of California, San Diego, California.
Address correspondence and reprint requests to Manabu Kakinohana, MD, PhD, Department of Anesthesiology, Facutly of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0125, Japan. Address e-mail to mnb-shk{at}ryukyu.ne.jp.
Abstract
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 µg x 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 µg · kg–1 · h–1); Group Dex 1, dexmedetomidine (1 µg · kg–1 · h–1); Group Dex 3, dexmedetomidine (3 µg · 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.
Opiates are commonly administered into intrathecal (IT) or epidural spaces to produce analgesia in the postoperative period. IT morphine has been used for pain control after thoracoabdominal aortic aneurysm repair operation (1), in which spinal cord ischemia could be a complication of aortic cross-clamping. Our previous case report (2) showed that spastic paraparesis may have been induced by 4 mg of epidural morphine for postoperative pain relief after thoracoabdominal aortic aneurysm repair. In our studies (2,3), we demonstrated that neuraxial morphine after a noninjurious period of spinal cord ischemia in the rat could induce transient spastic paraplegia and degeneration of selective spinal ventral neurons. Fuchigami et al. (4) also demonstrated that repetitive administration of IT morphine after a noninjurious interval of spinal cord ischemia in rats gave rise to irreversible paraplegia and selective spinal ventral neuronal death. According to two clinical cases reported by Acher and Wynn (5), it is likely that not only neuraxial administration of opioids but also systemic administration can exacerbate neurological dysfunction after thoracoabdominal aortic aneurysm repair surgery.
Several studies indicated that large-dose opioids, such as alfentanil (6), fentanyl (7) and remifentanil (8), produce an increased metabolic rate in the limbic system, seizures, and brain damage by activation of glutamate receptors in the rat (9). We have also reported that the concentration of cerebrospinal fluid (CSF) glutamate was increased by administration of IT morphine after a noninjurious period of spinal cord ischemia, and that this increase may be associated with these degenerative changes of spinal ventral neurons for which the activation of N-methyl-d-aspartate (NMDA) receptor (10) may also be a contributing factor.
Dexmedetomedine, one of the  2 adrenoreceptor agonists, is useful for postoperative sedation (11,12) and can reduce opioid consumption (13) by its analgesic property. Dexmedetomedine has been reported to provide neuroprotective effects against ischemia in the central nervous system (14–16) and this neuroprotective effect was likely to result from the reduction of glutamate release (17,18). We, therefore, speculated that dexmedetomidine could attenuate the degeneration of spinal ventral neurons induced by IT morphine after a noninjurious period of spinal cord ischemia. If so, clinical use of dexmedetomidine after thoracoabdominal aortic surgery would be advantageous because of its neuroprotective effects and because of its ability to enable the reduction of morphine consumption. In the present study, we investigated the effect of IV infusion of dexmedetomidine on the degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia in rats.
METHODS
The following investigations were performed under a protocol approved by the Institutional Animal Care Committee, University of the Ryukyus. Male Sprague-Dawley rats (300–400 g) were used. IT catheters were implanted according to a previously described method (19). After implantation, animals were allowed to recover for 5 days before induction of spinal ischemia. Rats showing motor weakness or signs of paresis upon recovery from anesthesia were immediately killed with intraperitoneal injection of pentobarbital (100 mg/kg). All animals displaying normal feeding and drinking behavior without any neurological disorders were used in this study.
Induction of Spinal Ischemia
Details of the aortic occlusion model have been reported previously (20). In brief, animals previously implanted with IT catheters were anesthetized in a Plexiglas box with 4% isoflurane in room air. After induction, rats were maintained with 1%–2% isoflurane delivered by an inhalation mask. For infusion of IV dexmedetomidine, a PE-10 cannula was inserted into the right external jugular vein. A PE-50 was inserted into the tail artery for monitoring of distal arterial blood pressure and for taking blood samples to monitor pH, Pao2, Paco2, HCO3– and glucose. For induction of spinal ischemia, the left femoral artery was isolated and a 2F Fogarty catheter was placed into the descending thoracic aorta so that the tip of the catheter reached the level of the left subclavian artery. To control the proximal arterial blood pressure at 40 mm Hg during the period of aortic occlusion, a 20-G Teflon catheter connected to an external blood reservoir (37.5°C) was inserted to the left carotid artery. To monitor paravertebral muscle temperature, a thermocouple probe was placed in the paravertebral muscle at the level of T10. To control and maintain the degree of paravertebral muscle temperature during aortic occlusion, water (38.5°C–38.8°C) was perfused through the heat exchanger at 100 mL/min (21). At the completion of all cannulations, heparin (200U) was injected into the tail artery. To induce spinal ischemia, the balloon catheter was inflated with 0.05 mL of saline and blood was allowed to flow into the external reservoir. The efficiency of the occlusion was evidenced by an immediate and sustained loss of any detectable pulse pressure and decrease of distal arterial pressure. After ischemia, the balloon was deflated and the blood was reinfused over a period of 60 s. Protamine sulfate (4 mg) was then administered subcutaneously. All arterial lines were then removed, incisions were closed and animals were allowed to recover. During the reperfusion period, a rectal temperature was monitored periodically. All animals were kept in the Plexiglas box under a heating lamp to avoid hypothermia.
Experimental Groups and Design
All animals were administered two doses of IT morphine (40 µg x 2) at 1 and 5 h after 6 min of spinal cord ischemia. Then, 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, IV infusion of small-dose dexmedetomidine (0.1 µg · kg–1 · h–1); Group Dex 1, IV infusion of medium-dose dexmedetomidine (1 µg · kg–1 · h–1); Group Dex 3, IV infusion of large-dose dexmedetomidine (3 µg · kg–1 · h–1). The dosing was based on pilot studies to find a range of levels of sedation from none to deep sedation.
Drug Administration
Dexmedetomidine was dissolved in 0.9% NaCl. The IV infusion was started at 1 h after the beginning of the reperfusion period. Dexmedetomidine was administered at 1 µg/kg for 30 min followed by an 8-h infusion either at a dose of 0.1 µg · kg–1 · h–1 (Dex 0.1), 1 µg · kg–1 · h–1 (Dex 1) or 3 µg · kg–1 · h–1 (Dex 3). Control rats (S) received an IV infusion of 0.9% NaCl at 3 mL/h for 8 h followed by a 1-mL infusion for 30 min. The number of rats in each experimental Group was 8 (32 in total).
Assessment of Sedation
Animals were monitored continuously, and at 2-h intervals were scored for arousal (22): 0, normal behavior, alert to the environment, standing or grooming; 1, sitting quietly, no spontaneous movement, but moved if touched; 2, no spontaneous movement, did not move when touched; and 3, loss of righting reflex, unresponsive.
Assessment of Neurological Motor Function
During reperfusion, recovery of motor function was assessed by a previously described grading system (3,4,18) that quantified ambulation and placing and stepping responses that could be used for statistical analysis. Ambulation (walking with lower extremities) was graded as follows: 0, normal; 1, toes flat under the body when walking, but ataxia present; 2, knuckle walking; 3, movement in lower extremities but unable to knuckle walk; or 4, no movement or drags lower extremities. The placing or stepping reflex was assessed by observing the animal dragging the dorsum of the hindpaw over the edge of a surface, which normally evokes a coordinating lifting and placing response (e.g., stepping). Grading was as follows: 0, normal; 1, weak; and 2, no stepping. A Motor Deficit Index (MDI) was calculated for each rat at each time interval. The final MDI was the sum of the scores (walking with lower extremities plus placing and stepping reflex). To show the condition of muscle tone (spastic or flaccid) during the infusion of dexmedetomidine or saline, an electromyogram (EMG) was recorded at 6 h after the first IT injection of morphine with a pair of Teflon-coated stainless-steel wires inserted into the right femoral muscle, filtered at 150 Hz–3 kHz, and monitored on an oscilloscope. Occasionally, the signals were digitalized at 4 kHz and stored on a hard disk.
Perfusion Fixation and Histopathological Analysis
Rats were killed with pentobarbital (100 mg/kg, IP) 72 h after spinal cord ischemia and were then transcardially perfused with 100 mL of heparinized saline followed by 150 mL of 4% paraformaldehyde in phosphate buffer (pH = 7.4). Then, 24 h later, the spinal cords were removed and post-fixed in the same fixative for 2–14 days. After this period, the spinal cords were removed from the fixative and segments of the spinal lumbar enlargement were dissected and cryoprotected in 30% sucrose solution. Frozen transverse sections (20–30 µm) were then prepared and stained by the Nissl method. For analysis, three representative sections were taken from the upper, middle, and lower segments of the spinal lumbar enlargement with 200-µm interspaces. They were coded for each animal and then subjected to a systematic examination. Cells that contained Nissl substance in the cytoplasm, loose chromatin, and prominent nucleoli were considered to be normal neurons. The number of normal-appearing spinal ventral neurons was counted in each of the upper, middle, and lower segments by an observer without the knowledge of the treatment groups.
Statistical Analysis
Physiologic data are expressed as mean ± sd. Results of the sedation index and MDI are expressed as the median. Statistical analyses of physiologic data and the number of normal neurons in the spinal cord were performed by one-way analysis of variance for multiple comparison followed by the Dunnett post hoc test. For analysis of neurological outcome in each group, significant overall values were obtained by the Friedman test followed by the Wilcoxon’s signed rank test. Specific comparisons between experimental groups at individual time points after reflow were made with the Kruskal-Wallis test followed by the Tukey-Kramer test. A P value of <0.05 was considered significant. Statistical analyses were done using the SPSS software 8.0.1 for Windows from the SPSS Institute (Chicago, IL).
RESULTS
Physiologic Data
During the pre- and postischemic period, there were no significant differences among the groups in any of the physiologic variables examined except for mean arterial blood pressure at 9 h of reperfusion, which was significantly higher in Group Dex 3 than in group S (Table 1). Arterial blood gas analysis revealed that IV dexmedetomidine infusion was unable to induce respiratory depression in comparison with saline infusion (Group S). Paravertebral muscular temperature during the intraischemic period ranged from 38.0°C to 38.2°C, which was not significantly different among these groups. Additionally, during the reperfusion period, there were no statistically significant differences in the rectal temperature among the groups.
Sedative Conditions
IV infusion of dexmedetomidine produced a dose-dependent increase in the sedation index (Table 2). At 8 h after IV infusion of dexmedetomidine, a significant increase in the sedation index was seen in Groups Dex 1 and Dex 3, but not in Group Dex 0.1 in comparison with Group S.
Neurological Function
All animals had modest and transient motor weakness (median MDI = 3) 30 min after reperfusion (before IT injection). In Groups S and Dex 0.1, the first IT injection of morphine resulted in a gradual development of spasticity and near complete loss of the ability to stand, walk, or step (MDI = 5 or 6) (Fig. 1). Although this spastic paraplegia slightly recovered at 4 h after the first IT morphine injection, it returned after the second IT injection of morphine and this paraplegia did not improve throughout this experiment. In Group Dex 1, three animals with a sedation scale score of 1 also showed complete paraplegia 2 h after the first IT morphine administration. In Group Dex 3, however, neurological motor function could not be assessed because all animals had a sedation index 2 or 3. According to the EMG recorded from the right femoral muscle in Groups S and Dex 0.1, IT administration of morphine after spinal cord ischemia always elicited EMG activity, indicating the presence of spontaneous activity of the skeletal muscles (spasticity). Conversely, Groups Dex 1 and 3 rats had no significant background EMG activity, indicating a lack of spontaneous activity of the skeletal muscles (Fig. 2). At 24 h after spinal cord ischemia, the majority of rats in Groups Dex 1 and Dex 3 regained motor function and had the ability to stand, walk, or step (MDI = 3-0). At 72 h after spinal cord ischemia, there were significant differences in neurological motor function between Group S and Group Dex 1 or Group Dex 3.
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Figure 1. Motor Deficit Index (MDI) assessed at 30 min to 24 h in animals after the first intrathecal (IT) injection of morphine. The second IT injection was at 4 h after the first IT injection. In Groups S and Dex 0.1, the second IT injection of morphine resulted in development of paraplegia (P < 0.01, compared with before the first IT injection), which did not improve throughout this experiment (irreversible paraplegia). In Groups Dex 1 and Dex 3, however, neurological motor function could not be assessed because almost all animals displayed a sedation index of 2 or 3. At 24 and 72 h after spinal cord ischemia, there were significant differences in neurological motor function between Group S and Group Dex 1 or group Dex 3 (P < 0.01). **Difference in comparison of MDI with that before the first IT injection is statistically significant (P < 0.01). ##Difference in MDI compared with Group S is statistically significant (P < 0.01). Data are presented as median. Group S, IV infusion of saline (mL/h); Group Dex 0.1, dexmedetomidine (0.1 µg · kg–1 · h–1); Group Dex 1, dexmedetomidine (1 µg · kg–1 · h–1); Group Dex 3, dexmedetomidine (3 µg · kg–1 · h–1).
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Figure 2. Electromyograms (EMG) recorded from the right femoral muscles at 6 h after the first intrathecal (IT) injection of morphine. Animals in Groups S and Dex 0.1 showed EMG activity. No significant background EMG activity could be seen in Groups Dex 1 and 3. Group S, IV infusion of saline (mL/h); Group Dex 0.1, dexmedetomidine (0.1 µg · kg–1 · h–1); Group Dex 1, dexmedetomidine (1 µg · kg–1 · h–1); Group Dex 3, dexmedetomidine (3 µg · kg–1 · h–1).
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Histopathological Analysis
Systematic histopathological analysis of the spinal lumbar enlargement in Group S and Group Dex 0.1 at the end of 72 h of survival showed advanced signs of degenerative changes expressed by the absence of spinal ventral neurons or the presence of small fragments of their disintegrated bodies (Fig. 3). In contrast, histopathological analysis of spinal cords in Group Dex 1 revealed the occasional presence of dark-stained spinal ventral neurons. In animals that displayed nearly complete recovery in Group Dex 3, most neurons in Laminae IX had a normal appearance. The number of normal spinal ventral neurons 72 h after spinal cord ischemia was significantly greater in Group Dex 1 and Dex 3 than in Groups S and Dex 0.1 (Fig. 4).
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Figure 3. Light microphotograph of transverse sections. (A, B) Transverse section of spinal cord taken from the lumbar spinal segment from an animal in Group S with complete paraplegia (Motor deficit index: 6) at 72 h after spinal cord ischemia. (C, D) Transverse section of spinal cord taken from the lumbar spinal segment from a rat in Group Dex 3 with normal motor function (Motor deficit index: 0) at 72 h after spinal cord ischemia. Normal appearance of spinal ventral neurons is evident. Arrows indicate the ventral horn in the spinal cord. Group S, IV infusion of saline (mL/h); Group Dex 0.1, dexmedetomidine (0.1 µg · kg–1 · h–1); Group Dex 1, dexmedetomidine (1 µg · kg–1 · h–1); Group Dex 3, dexmedetomidine (3 µg · kg–1 · h–1).
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Figure 4. Number of normal spinal ventral neurons at 72 h after spinal cord ischemia. Each symbol represents data for each animal. **Significant difference from Group S (P < 0.01). Group S, IV infusion of saline (mL/h); Group Dex 0.1, dexmedetomidine (0.1 µg · kg–1 · h–1); Group Dex 1, dexmedetomidine (1 µg · kg–1 · h–1); Group Dex 3, dexmedetomidine (3 µg · kg–1 · h–1).
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DISCUSSION
The present study showed that repetitive IT administration of morphine could induce irreversible paraplegia and the degeneration of spinal ventral neurons after a noninjurious interval of spinal cord ischemia in the rat, which was consistent with previous data (4). The present data also provided further evidence that IV infusion of dexmedetomidine after IT morphine during the reperfusion period could improve neurological outcome in a dose-dependent manner. In particular, a sedative dose of dexmedetomidine was shown to inhibit the degeneration in the spinal ventral neurons induced by IT morphine after a noninjurious interval of spinal cord ischemia. These data suggest that dexmedetomidine at a sedative dose may be neuroprotective against morphine-induced paraplegia after spinal cord ischemia.
Our previous study (2) is the first experimental report of paraparesis induced by neuraxial morphine after a noninjurious interval of aortic occlusion. In our previous reports (2–4), we speculated on the following mechanisms by which IT morphine can induce spasticity after a noninjurious interval of spinal ischemia. The first is increased sensitivity to morphine in the ischemic spinal cord. Ting et al. (23) demonstrated a two- to threefold increase in binding sites of brain µ,  , and  agonists during the early reperfusion period after temporary focal cerebral ischemia in the cat. From this report, it can be considered that through an increase in the concentration of spinal opioid receptors during the reperfusion period, sensitivity to morphine should be increased by an ischemic insult to the spinal cord. Second,  -aminobutyric acid (GABA) and glycinergic interneurons may be blocked by morphine. As for the interaction between morphine and GABA or glycinergic interneurons, it was reported that opiate alkaloids, including morphine, seemed to inhibit GABA and glycinergic interneuronal function in the spinal cord (24,25). From these results and suggestions, it can be speculated that the increase in opioid sensitivity after a spinal ischemic insult might enhance the effect of IT morphine, and therefore might block the inhibitory systems’ input (GABA or glycinergic) to spinal ventral neurons, leading to increased spasticity in the hindlimb. In the present study, our EMG data also indicated that IT morphine after spinal cord ischemia induced an increase of spontaneous activity in the skeletal muscles, suggesting an increase in the excitability of spinal ventral neurons.
The mechanisms by which degeneration of spinal ventral neurons was induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia are not clear. As for the vulnerability in the spinal cord to ischemic insults, the features of neuronal degeneration after spinal cord ischemia are different from those induced by postischemic neuraxial morphine. It was reported that the most vulnerable area to spinal cord ischemia in the rat was the anterior or anterolateral columns (Laminae V-IX), in which inhibitory interneurons are predominantly located (20). In contrast, spinal ventral neurons were likely to be the most vulnerable to morphine-inducing paraplegia (2,4). A microdialysis study showed that the concentration of glutamate in CSF increased significantly after neuraxial morphine after spinal ischemia, and these data suggested that this increase in the concentration of CSF glutamate may be associated with the degenerative changes of spinal ventral neurons through the activation of NMDA receptors (10). Our behavioral observations (Fig. 1) and EMG data (Fig. 2) indicated that IT morphine after a noninjurious interval of spinal cord ischemia may induce spasticity, suggesting inappropriate increases in excitability of the spinal ventral neurons. An inappropriate increase in excitability of neurons can allow an influx of calcium through voltage-gated Ca2+ channels activated by a prolonged depolarization (26). This can combine with the activation of NMDA receptors, resulting in excessive and prolonged increases of Ca2+ and subsequent mitochondrial membrane dysfunction and cell death (27).
In previous studies, dexmedetomidine was shown to have a neuroprotective effect in various cerebral ischemic models such as the gerbil (14), rabbit (15), and rat (16). Of interest to us, the 2-adrenoreceptor agonist was demonstrated to reduce glutamate release (17,18), early peak calcium changes, and cell damage in ischemia-vulnerable neurons in hippocampal slices during hypoxia (17). Considering that morphine-induced paraplegia is associated with an increase in glutamate release and subsequent activation of NMDA receptors in the spinal cord (10), it is likely that these effects of 2 adrenoreceptor activation may contribute to the neuroprotection by dexmedetomidine in the present study. Other publications, however, did not support this mechanism as a major factor in neuroprotection by dexmedetomidine; therefore the neuroprotective mechanism in this study remains unclear. Future studies should investigate, by microdialysis, whether dexmedetomidine can suppress the increase in glutamate concentration in CSF after IT morphine after spinal cord ischemia. The 2-adrenoreceptor agonist is used in the treatment of spasticity. This effect seems to be caused by inhibition of polysynaptic reflex at the supraspinal and spinal level (28), which can subsequently suppress overexcitability of the spinal ventral neurons. Our EMG data also demonstrated that dexmedetomidine, at a sedative dose, seemed to inhibit an overexcitability of the spinal ventral neurons induced by IT morphine after spinal cord ischemia. This suppression of overexcitability of the spinal ventral neurons by dexmedetomidine may also contribute in part to its neuroprotection in this study.
In clinical situations, if the present data can be extrapolated, the use of dexmedetomidine after thoracoabdominal aortic surgery may have two advantages for postoperative management. One is, as shown in the present study, that it might be able to prevent the degeneration of spinal ventral neurons induced by postischemic neuraxial or systemic administration of morphine. The second is that dexmedetomidine can reduce morphine consumption during the postoperative period (13). Our previous report (3) demonstrated a dose-response effect of neuraxial morphine to induce parapresis after a noninjurious interval of spinal cord ischemia in rats. Hence, the reduction of morphine consumption could be one of the most important strategies to prevent the morphine-induced paraplegia, if it occurs clinically.
Although it remains unclear whether dexmedetomidine administration can provide neuroprotection against ischemic spinal cord injury, the present study clearly suggests that repetitive administration of IT morphine after a noninjurious interval of aortic occlusion can produce paraplegia with degeneration of spinal ventral neurons in the rat, and that this neuronal degeneration was prevented by administration of dexmedetomidine at a sedative dose.
Footnotes
Accepted for publication June 6, 2007.
Supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan (Nos. 16591551, 17591479).
This work has been attributed mainly to the Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus.
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