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Anesth Analg 2003;96:769-775
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Intrathecal Administration of Morphine, but Not Small Dose, Induced Spastic Paraparesis After a Noninjurious Interval of Aortic Occlusion in Rats

Manabu Kakinohana, MD PhD, Tatsuya Fuchigami, MD PhD, Seiya Nakamura, MD, Takeshi Sasara, MD, Tetsuya Kawabata, MD, and Kazuhiro Sugahara, MD PhD

Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan

Address correspondence and reprint requests to Manabu Kakinohana, MD, PhD, Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa, Japan, 903-0125. Address e-mail to mnb-shk{at}ryukyu.ne.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We sought to investigate the dose-response relationship for the effect of intrathecal morphine on the transient spastic paraparesis after short-lasting spinal ischemia in rats. Spinal ischemia was induced by aortic occlusion for 6 min with a balloon catheter in rats previously implanted with an intrathecal catheter for drug delivery. After ischemia, the animals were allowed to recover, and 3, 10, or 30 µg of morphine or saline was injected intrathecally at 30 min after reperfusion. In a separate group, the quantal bioassay for the effect of intrathecal morphine on neurological function after ischemia was performed to calculate 50% effective dose values for inducing paraparesis at 2 h of reperfusion. Subsequently, histopathology of the spinal cord was assessed at 48 h of reperfusion. Intrathecal injection of 30 or 10 µg of morphine, but 3 µg of neither morphine nor saline, caused a progressive development of hindlimb spasticity. The 50% effective dose values for inducing paraparesis were 16.1 ± 1.5 µg in assessing behavioral analysis at 2 h after intrathecal morphine. Histopathological analysis of spinal cords in the 30-µg group revealed the presence of dark-staining {alpha}-motoneurons in lumbosacral segments. We conclude that spinal administration of a large dose of morphine after transient aortic occlusion may be associated with a potential risk of paraparesis and the corresponding development of neurological dysfunction. Careful attention should be paid when intrathecal morphine is used for pain control after thoracoabdominal aortic aneurysm repair.

IMPLICATIONS: Spinal administration of large-dose morphine after transient aortic occlusion may be associated with a potential risk of irreversible spinal neuronal degeneration and the corresponding development of neurological dysfunction.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Opiates are often administered into intrathecal or epidural spaces to produce powerful analgesia in the postoperative period. Intrathecal morphine has also been used for pain control after thoracoabdominal aortic aneurysm repair operations (1) in which aortic cross-clamping was an essential procedure but possibly induced spinal ischemia. It has been found that a concentration of endogenous opioids (ß-endorphin) in the cerebrospinal fluid (CSF) increased during the reperfusion period after spinal ischemia in the dog (2). On the evidence that intrathecal or IV naloxone can attenuate neurological consequences after spinal injury (3), endogenous opioids might be involved in neuronal injuries in the spinal cord after aortic cross-clamping.

Although spinal neuronal injury after spinal trauma or ischemia appears to be worsened by endogenous opioids, the safety of exogenous opiates in central nervous injury is still unclear. We reported that 30 µg of intrathecal morphine after a noninjurious interval of spinal ischemia in a rodent model induced transient spastic paraparesis that could be reversed completely by intrathecal naloxone, suggesting opioid receptor-coupled effects in the spinal cord (4). In this study, we focused on the dose-related effects of intrathecal morphine after noninjurious spinal ischemia on neurological function during the reperfusion period.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The following investigations were performed under a protocol approved by the Institutional Animal Care Committee, University of the Ryukyus. Male Sprague-Dawley rats (350–400 g) were used. Animals were anesthetized with 2.5% isoflurane in a room air/oxygen mixture (1:1), and the back of the head and neck were shaved. The animals were then placed in a stereotaxic headholder with head flexed forward. Anesthesia was maintained with 1.5% isoflurane delivered by mask. A midline incision was made on the back of the neck, and the muscle was freed at the attachment to the skull and retracted with a flat elevator, exposing the cisternal membrane. The membrane was opened with a stab blade and modestly retracted with small dural hook. A polyethylene-10 catheter was then inserted caudally through the cisternal opening and passed slowly and carefully 9 cm into the intrathecal space. All animals displayed normal feeding and drinking behavior

Details of the aortic occlusion model have been previously reported (5). In brief, animals previously implanted with intrathecal 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 monitoring of distal arterial pressure and injection of heparin, a polyethylene-50 catheter was inserted into the tail artery. For the induction of spinal ischemia, a 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-gauge Teflon catheter connected to an external blood reservoir (37.5°C) was inserted into the left carotid artery. To control and maintain the degree of spinal cord normothermia during aortic occlusion, water (38.5°C–38.8°C) was perfused through the heat exchanger at 100 mL/min (6). At the completion of all cannulations, heparin (200 U) was injected into the tail artery. To induce spinal ischemia, the balloon catheter was inflated with 0.05 mL of saline, and the 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 a decrease of distal arterial pressure. After ischemia, the balloon was deflated, and the blood was reinfused for 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. In sham-operated rats, all surgical procedures were performed as described, but the balloon catheter was not inflated.

During reperfusion, recovery of motor function was assessed. Motor function was quantified by assessment of ambulation and of placing and stepping responses. For statistical purposes, ambulation (walking with the 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, drags lower extremities. The placing/stepping reflex was assessed by dragging the dorsum of the hind paw over the edge of a surface. This normally evokes a coordinating lifting and placing response (e.g., stepping), which was graded as follows: 0, normal; 1, weak; or 2, no stepping. A motor deficit index (MDI) was calculated for each rat at each time interval. The final index (MDI) was the sum of the scores (walking with lower extremities plus placing and stepping reflex). The MDI was calculated by the observers (TF or SN) without knowledge of the treatment group.

In Study 1, for assessment of the effect of intrathecal morphine (30 µg) on neurological outcome after 6 min of aortic occlusion, rats were randomly divided into three groups as follows: 1) control—intrathecal saline injection (10 µL) at 30 min of reperfusion (Group S; n = 6), 2) intrathecal injection of morphine (30 µg) at 30 min of reperfusion (Group M; n = 6), and 3) sham-operated animals receiving intrathecal injection of morphine (30 µg) at 30 min after recovery from anesthesia (Group Sh; n = 6).

In Study 2, for assessment of the effect of various doses of intrathecal morphine on neurological function after 6 min of aortic occlusion, rats were divided into four groups as follows: 1) control—intrathecal saline (10 µL) injection (Group S; n = 6) or 2) intrathecal injection of 3 µg (Group 3M; n = 6), 3) 10 µg (Group 10M; n = 6), or 4) 30 µg (Group 30M; n = 9) of morphine at 30 min of reperfusion.

In Study 3, for quantal bioassay for the effect of intrathecal morphine on neurological function after 6 min of aortic occlusion, the doses of intrathecal morphine were selected to span all grades of neurological function ranging from "walk" (MDI: 0–4) to "paraparesis" (MDI: 5–6). Thirteen rats were used, and the doses of intrathecal morphine for individual rats were varied from 1 to 60 µg.

At the end of the survival period, rats were killed with pentobarbital (100 mg/kg intraperitoneally) and phenytoin (25 mg/kg intraperitoneally). The rats were then transcardially perfused with 100 mL of heparinized saline, followed by 150 mL of 4% paraformaldehyde in phosphate buffer (pH 7.4). Twenty-four hours later, the spinal cords were removed and postfixed in the same fixative for 2–14 days. After this period, the spinal cords were removed, and L3, L4, and L5 spinal segments were dissected and cryoprotected in 30% sucrose solution. Frozen transverse sections (20–30 µm) were then prepared and stained with the Klüver-Barrera method. For systematic analysis, 10 representative sections taken from each segment (L3 to L5; total of 30 sections from each spinal cord) were coded in each animal and then subjected to a systematic examination.

Statistical analysis of physiological data was performed by one-way analysis of variance (ANOVA) for multiple comparisons, followed by Dunnett’s post hoc test. Differences in MDI over time were determined by one-way repeated-measures ANOVA followed by Fisher’s post hoc test. Specific comparisons between experimental groups in individual time points after reflow were done with ANOVA by using multiple means analysis followed by the Bonferroni test. A P value of <0.05 was considered significant.

For quantal bioassay for the effect of intrathecal morphine on neurological function after aortic occlusion, the 50% effective dose (ED50), which represents the dose of morphine associated with a 50% probability of resultant paraplegia, was analyzed and graphically demonstrated by computer construction of a dose-response curve (7). The computer calculated an ED50 that represented the dose of intrathecal morphine that produced paraplegia in 50% of the rats. The quantal dose-response analysis method used in this study has been published previously (8).


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
During the preischemic and intraischemic period, paravertebral muscle temperature ranged between 38.0°C and 38.3°C. Baseline mean arterial blood pressure ranged between 67 and 89 mm Hg and decreased to 3–6 mm Hg at the end of 6 min of aortic occlusion. No significant differences among experimental groups were detected except for Group Sh (Table 1).


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  		Table 1. Demographic Data
 
Study 1 (Fig. 1): In Group S, all rats showed modest and transient motor weakness (median MDI, 3) at 30 min after reperfusion, followed by gradual recovery over 24–48 h of reperfusion. During the initial 8 h after ischemia, motor deficit was expressed as the presence of ataxia (but with preserved ability to walk) and partial weakness in the place-stepping reflex. At 48 h, no significant motor deficit was seen. All rats showed complete recovery, which was comparable with sham-operated animals (Group Sh). Intrathecal saline at 30 min of reperfusion had no detectable effect on continuing recovery of motor function. Intrathecal injection of morphine resulted in a gradual development of spasticity and near-complete loss of the ability of rats to stand, walk, or step. The peak of morphine-induced spasticity was observed at 2 h after morphine administration (median MDI, 6) and persisted through approximately 4 h. Between 24 and 48 h after injection, the majority of animals regained their motor function. In Group Sh, intrathecal morphine had no effect on neurological function, and all rats showed near-normal ambulation after recovery from anesthesia.



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  		Figure 1. Changes of motor deficit index (MDI) before and after intrathecal (IT) injection with 30 µg of morphine after a noninjurious interval of aortic occlusion. Reversible aortic occlusion (6 min) induced modest and transient motor weakness before intrathecal injection. Two hours after intrathecal injection of 30 µg of morphine after spinal ischemia, rats showed significantly more motor dysfunction (median MDI, 5) in the hindlimbs compared with the saline group (median MDI, 3; P < 0.05). In Group Sh, intrathecal morphine had no effect on neurological function. Data are presented as medians. *P < 0.05 versus the saline group; #P < 0.05 versus MDI before the intrathecal injection (0 h); §P < 0.05 versus MDI at preischemia; §§P < 0.01 versus MDI at preischemia. Group S = saline; Group M = morphine; Group Sh = sham.

 
Study 2 (Fig. 2): All animals in Study 2 displayed modest and transient motor weakness (median MDI, 3) at 30 min after reperfusion. Rats treated with intrathecal saline (Group S) showed gradual recovery over the 24- to 48-h period of reflow. In contrast to Group S, intrathecal injection of 30 µg of morphine (Group 30M) resulted in a gradual development of spasticity and near-complete loss of the ability of animals to stand, walk, or step. In Group 10M, a gradual increase of spasticity was observed after intrathecal morphine injection, and the rats displayed significant motor deficit (knuckle walk or spastic paraplegia) between 2 and 4 h of reperfusion. In animals of Group 3M, intrathecal injection of morphine had no significant effects on the neurological function compared with Group S. Between 24 and 48 h after intrathecal injection, the majority of animals regained their motor function, except for a couple of rats in Group 30M. At this time, statistical analysis showed no significant difference between morphine- and saline-injected animals.



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  		Figure 2. Changes of motor deficit index (MDI) before and after intrathecal injection with various doses of morphine after a noninjurious interval of aortic occlusion. Reversible aortic occlusion (6 min) induced modest and transient motor weakness before intrathecal injection. After intrathecal injection of 30 µg of morphine after spinal ischemia, the spasticity of hindlimbs developed gradually and significantly compared with the saline group. Modest spasticity of hindlimbs developed in Group 10M, although no spastic changes were detected in Group 3M. Data are presented as medians. *P < 0.05 versus the saline group; #P < 0.05 versus MDI before intrathecal injection (0 h); §P < 0.05 versus MDI at preischemia; §§P < 0.01 versus MDI at preischemia. 30M = 30 µg of morphine; 10M = 10 µg of morphine; 3M = 3 µg of morphine.

 
Study 3 (Table 2, Fig. 3): The results of the quantal bioassay assessment are shown in Figure 3 and Table 2. The ED50 for paraplegia was 16.1 ± 1.5 µg when behavioral analysis was assessed 2 h after intrathecal morphine administration.


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  		Table 2. The Effect of Intrathecal (IT) Morphine on Neurological Outcome of Rats, Measured 48 Hours After Spinal Cord Ischemia
 


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  		Figure 3. Dose-response curve for the effect of intrathecal (IT) morphine on the probability of paraparesis. Beneath the curve, the normal/paraparesis data ({blacksquare} = individual rat) versus the dose of morphine are displayed. The quantal bioassay assessment showed that the 50% effective dose (ED50) values for inducing paraparesis were 16.1 ± 1.5 µg when behavioral analysis was assessed 2 h after intrathecal morphine administration. Data are presented as mean ± SD.

 
In Group S and Group 3M, systematic histopathological analysis of L3 to L5 spinal segments at the end of 48 h of survival showed no detectable neurodegenerative changes (Fig. 4A). All neuronal pools, including small- and medium-sized interneurons and large {alpha}-motoneurons, showed normal structure, with preserved neuronal membrane, nucleus, and nucleolus. In contrast, in Group 30M, histopathological analysis of spinal cords revealed the occasional presence of dark-staining {alpha}-motoneurons localized in the ventral horn and evenly distributed rostrocaudally in lumbosacral segments (Fig. 4, B and C). Neuronal pools localized in the intermediate zone and in the dorsal horn showed normal structure.



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  		Figure 4. Light photomicrographs of the transverse sections taken from L4 spinal segments of rats subjected to 6 min and 48 h of reperfusion. Rats received intrathecal saline (A) or 30 µg of morphine (B and C) at 30 min of reperfusion. Normally appearing {alpha}-motoneurons (&OV0337;) and interneurons can be seen in (A). In (B) and (C), some dark-staining {alpha}-motoneurons ({image}) localized in a ventral horn can be seen.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrated that intrathecal injection with morphine, but not small dose, could induce transient spastic paraparesis after a noninjurious interval of spinal cord ischemia in rats. In addition, the quantal bioassay assessment showed that the ED50 values for inducing paraparesis were 16.1 ± 1.5 µg when behavioral analysis was assessed two hours after intrathecal morphine administration. Histopathological analysis of spinal cords in Group 30M revealed the presence of dark-staining {alpha}-motoneurons localized in the ventral horn in lumbosacral segments (Fig. 4B).

Intrathecal injection of morphine can produce strong antinociceptive effects in rats. Zahn et al. (9) showed that 1.7 µg of intrathecal morphine (approximately 5 µg/kg) markedly inhibited pain behaviors in the rat model of postoperative pain. Additionally, Brennum et al. (10) demonstrated that 0.3 mg of intrathecal morphine (approximately 4 µg/kg) generally produces postoperative analgesia after surgery in adults. These data suggest that the potency of intrathecal morphine in postoperative patients and in the rat model of postoperative pain are similar. Yamaguchi and Naito (11) showed that the ED50 values of intrathecal morphine were 1.2 µg in the tail-flick test. Our results in the quantal bioassay assessment demonstrated that ED50 values for inducing paraparesis were 16.1 µg; this suggests that the potency of intrathecal morphine for inducing paraparesis is approximately 10 times higher than that for antinociceptive effects. From these data, it appears possible in the clinical situation that more than 10 times the dose of intrathecal morphine for antinociception should be needed to induce neurological dysfunction after short-lasting spinal ischemia. However, Chaney (1) reported that 6 mg of intrathecal morphine, which is approximately 20 times more than that reported by Brennum et al. (10), was good for postoperative pain relief without prolonging mechanical support for respiration after thoracoabdominal aneurysm repair. Our previous case report (4) showed that spastic paraparesis was induced by 4 mg of epidural morphine for postoperative pain relief after thoracoabdominal aneurysm repair. From these reports, it should be kept in mind that intrathecal or epidural morphine, even with clinical doses, might be associated with the potential risk of inducing spastic paraparesis after thoracoabdominal aneurysm repair.

Although this study did not focus on the mechanism by which intrathecal morphine can induce significant spasticity after a noninjurious interval of spinal ischemia, several mechanisms can be speculated. The first is increased sensitivity to morphine in the spinal cord. In Study 1, intrathecal administration with 30 µg of morphine after the sham operation could not induce spastic paraparesis in the hindlimbs, but this was evoked by the same dose of morphine after 6 min of aortic occlusion (Fig. 1). These results suggest that the increased sensitivity to morphine in the spinal cord should be induced by a noninjurious interval of ischemic insults. Accordingly, Ting et al. (12) demonstrated a two- to threefold increase in concentrations of brain µ, {kappa}, and {delta} receptors during the early reperfusion period after temporary focal cerebral ischemia in the cat. Thus, one of the explanations for the increase of sensitivity to morphine in the spinal cord may be associated with the upregulation of opioid receptors in the spinal cord after a noninjurious interval of ischemia.

Second, {gamma}-aminobutyric acid (GABA) and/or glycinergic interneuron may be blocked by morphine. In general, ischemic injury to interneurons may be a primary contributor to decreased presynaptic inhibition, leading to postdenervation hypersensitivity of undamaged motoneurons (13). Homma et al. (14) reported the loss of small interneurons and significant reductions in glycine and GABA concentrations after an injurious interval of spinal cord ischemia; this loss of inhibitory spinal cord circuits could have induced postdenervation hypersensitivity of undamaged motoneurons, leading to spastic paraplegia. In addition, laminae V–VII, in which small- and medium-sized interneurons are typically localized, is the most vulnerable area to ischemic insults by aortic occlusion in the rat (5,13). With respect to the interaction between morphine and GABA and/or glycinergic interneurons, the study (15) in cats using a spinal cord slice showed that morphine reduced the direct and recurrent inhibition of spinal motoneurons in accordance with weak strychnine-like activity as a glycine antagonist. Werz and Macdonald (16) also demonstrated that glycine and GABA were antagonized by opiate alkaloids in murine spinal cord neurons. Taken from these results and suggestions, it is possible that intrathecal morphine after spinal ischemia might block the inhibitory systems’ input to motoneurons, leading to an increase in the spasticity in the hindlimb.

Third, there may be a reduction in recurrent {alpha}-motoneuronal inhibition by morphine. In a study of spinal cord, a comparable reduction in recurrent {alpha}-motoneuronal inhibition (mediated by Renshaw cells) was reported after systemic injection of morphine (5–10 mg/kg IV) (17). Similarly, systemic or intrathecal administration of relatively large doses of morphine (300–500 µg) in the rat triggers myoclonic seizures, loss of motor coordination, or truncal rigidity (18,19). After noninjurious ischemic insults, transient loss of spinal inhibition would be initiated by short-lasting spinal ischemia; this would be further potentiated by opioid receptor activation of "sensitized" Renshaw cells and would be clinically expressed as {alpha}-motoneuronal disinhibition and a corresponding spasticity. Because those speculations are far beyond the scope of this study, further study remains necessary to elucidate our speculations.

These data suggest that transient loss of spinal inhibition, initiated by short-lasting spinal ischemia, is further potentiated by opioid receptor activation. More importantly, a larger dose of morphine in the spinal cord may cause irreversible degeneration of {alpha}-motoneurons even after a noninjurious interval of spinal ischemia, because histopathological analysis of spinal cords in Group 30M revealed the occasional presence of dark-staining {alpha}-motoneurons localized in the ventral horn in lumbosacral segments (Fig. 4, B and C). Furthermore, our previous study (20) clearly demonstrated that prolonged activation of opioid receptors by intrathecal morphine can induce irreversible neurological dysfunction (permanent paraplegia) and histopathological damage in rats after a noninjurious interval of aortic occlusion. Although the mechanism of this degeneration is not clear at present, it may involve excessive release of excitatory amino acids and the corresponding activation of glutamate receptors (e.g., N-methyl-D-aspartic acid (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4, and kainate). In previous studies (21,22), it has been shown that the spinal administration of strychnine (a glycine receptor antagonist) or bicuculline (a GABAA receptor antagonist) is associated with an increase in spinal CSF glutamate release and the development of allodynia, which is effectively blocked by NMDA receptor antagonists. These data support our speculation that the inhibition of small interneurons and significant reductions in glycine and GABA concentrations after intrathecal morphine after spinal cord ischemia would cause excessive release of excitatory amino acids from the spinal cord.

In conclusion, we emphasize that spinal administration of large doses of morphine, when they are administered after transient aortic occlusion, may be associated with the potential risk of spastic paraparesis and the corresponding development of neurological dysfunction. Careful attention should be paid when intrathecal or epidural morphine is used for pain control after thoracoabdominal aortic aneurysm repair operations.


   Acknowledgments
 
This study was supported by a Grant-in-Aid (13770847) for Scientific Research from the Ministry of Education of Japan (TS).


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 7, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press