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Anesth Analg 2002;95:1389-1395
© 2002 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effect of Gamma-Aminobutyric Acid (GABA) Receptor Drugs on Morphine-Induced Spastic Paraparesis After a Noninjurious Interval of Spinal Cord Ischemia in Rats

Seiya Nakamura, MD, Manabu Kakinohana, MD PhD, Yutaka Taira, MD PhD, Hiroshi Iha, MD PhD, and Kazuhiro Sugahara, MD PhD

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

Address correspondence and reprint requests to Seiya Nakamura, MD, Department of Anesthesiology, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903–0215, Japan. Address e-mail to morph{at}ga2.so-net.ne.jp


   Abstract
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 Abstract
Introduction
 Methods and Materials
 Results
 Discussion
 References
 
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 {gamma}-aminobutyric acid (GABA)ergic interneurons that control the tonus of spinal cord {alpha}-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.

IMPLICATIONS: The purpose of this study was to investigate interactions between morphine and GABAergic agonists or antagonists on motor function after spinal cord ischemia and then clarify the mechanism of the spastic paraparesis induced by intrathecal morphine. The spastic paraparesis induced by intrathecal morphine may be mediated in part by GABA receptors.


   Introduction
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 Abstract
 Introduction
Methods and Materials
 Results
 Discussion
 References
 
The spinal cord is supplied by one anterior and two posterior spinal arteries and six to eight medullary arteries (1). Many levels of the spinal cord do not receive feeding medullary branches thus leaving watershed areas that are particularly susceptible to ischemic injury during aortic occlusion or hypotension. Damage may result from either actual surgical dissection of the Adamkiewicz artery (the largest one) or exclusion of origin of the artery by cross-clamps (2).

Spinal cord injury after a successful operation on the thoracic aorta is a disastrous and unpredictable complication in humans. The reported prevalence of spinal cord injury after a successful operation ranges from 0.9% to 40% (3,4). The mechanism of spinal cord injury during operations on the thoracic aorta is thought to be ischemia.

Opiates are often used for relief of pain administered by IV, intrathecal, or epidural routes to produce analgesia during the operative and postoperative period. Among the opiates, morphine is one of the most widely used (5). We have observed in our clinical practice that intrathecal morphine, injected after transient aortic occlusion (for repair of aortic aneurysm), triggered spasticity and that this effect was reversed by subsequent naloxone treatment. It has also been shown that IV fentanyl impaired the recovery of somatosensory evoked potentials after reperfusion in a rat incomplete cerebral ischemia model (6). We found that intrathecal morphine, given after a noninjurious interval of spinal cord ischemia, induced transient spastic paraparesis in a rodent model. The effect lasted for several hours corresponding to the duration of the action of intrathecal morphine, and this effect was completely reversed by naloxone (7), which is similar to our clinical observation. Furthermore, we also demonstrated that repetitive intrathecal morphine induced irreversible paraparesis after spinal cord ischemia in rats (7). However, the mechanism of morphine-induced spastic paraparesis is not known.

Muscle tone and muscle spindles are controlled by spinal motoneurons and inhibitory interneurons (8). Gamma-aminobutyric acid (GABA) is a neurotransmitter of interneurons that controls the activity of spinal {alpha}-motoneurons, especially inhibitory control at the spinal level (9). Biochemical analysis of the spinal cord in animals with fully developed spastic paraparesis showed a significant decrease in tissue glycine and GABA concentration, which suggested that this neuronal loss is likely explained by the loss of glycinergic and GABAergic neurons (10). We hypothesized that morphine induces spastic paraparesis via inhibition of spinal interneurons, and therefore, GABA agonists may attenuate this spastic effect of morphine. The aim of this study was to examine the interaction between morphine and GABAergic drugs after a noninjurious interval of spinal cord ischemia and then to clarify the mechanism of the spastic paraparesis.


   Methods and Materials
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 Abstract
 Introduction
 Methods and Materials
Results
 Discussion
 References
 
All experimental procedures were performed according to a protocol approved by the Animal Care Committee at the University of the Ryukyus, Okinawa, Japan. Male Sprague-Dawley rats (300–400 g) were used. Intrathecal catheters were implanted according to the method described by Yaksh and Rudy (11). Rats were anesthetized with 3.0% isoflurane in a room air/oxygen mixture (1:1). The rats were placed in a stereotaxic headholder, and a midline incision was made on the back of the neck. The cisternal membrane was incised, and a PE-10 catheter was then inserted through the cisternal opening and passed caudally 9 cm. One end of the catheter was exteriorized, and the wound was closed with a suture. All rats were allowed to recover for a minimum of 4–5 days before the induction of spinal cord ischemia. Rats showing motor weakness or signs of paresis upon recovery from anesthesia were excluded.

Details of the aortic occlusion model have been previously reported (12). Rats previously implanted with intrathecal catheters were anesthetized and maintained with 1.0%–2.0% halothane delivered by an inhalation mask. A 24-gauge TeflonTM catheter was inserted to the tail artery for monitoring of distal arterial pressure. For the induction of spinal cord 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. A 20-gauge Teflon catheter connected to an external blood reservoir (38.0°C) was inserted into the left carotid artery. At completion of all cannulations, heparin (200 U) was injected into the tail artery. To induce spinal cord ischemia, the balloon catheter was inflated with 0.05 mL of saline, and the blood was allowed to flow to the external reservoir to control the proximal arterial blood pressure (i.e., more than the level of aortic occlusion) at 40 mm Hg during the period of aortic occlusion. The efficiency of occlusion was confirmed by an immediate and sustained loss of any detectable pulse pressure and decrease of distal arterial pressure (i.e., less than the level of aortic occlusion). In this study, 6 min of spinal cord ischemia was chosen on the basis of our previous experiments, which showed minimal or no deleterious effect on spinal neuronal function, with nearly complete recovery observed after 24–48 h of reperfusion (7). The paravertebral muscle temperature was maintained at 38.0°C ± 0.3°C throughout anesthesia, using a feedback controlled heating pad. After ischemia, the balloon was deflated, and the blood was reinfused over 60 s. Protamine sulfate (4 mg) was subcutaneously administered. All arterial lines were then removed, incisions were closed, and rats were allowed to recover for 3 days.

Drugs for intrathecal administration were mixed, such that all doses were delivered in a total volume of 10 µL, followed by 10 µL of saline to flush the catheter. The following drugs were used: morphine (morphine sulfate), muscimol (muscimol hydrobromide), baclofen ((±)-baclofen), bicuculline ([-]-bicuculline methciloride, 1[S], 9[R]), and 5-aminovaleric acid (5-AA). All drugs were further diluted in physiologic saline (0.9% wt/vol).

During reperfusion recovery, motor function was assessed with a standardized grading system. Motor function was quantified by assessment of ambulation and placing and stepping responses. For statistical purposes, 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 and drags lower extremities. The placing/stepping reflex was assessed by dragging the dorsum of the hide 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 the sum of the scores (walking with lower extremities plus placing and stepping reflex). The MDI was calculated for each rat at each time interval (after ischemia at 30 min, 1, 2, 4, 8, 24, 48, and 72 h). The presence of spasticity or flaccidity was determined by the presence of an exaggerated flexion response to a pinch of the hind paw. Flaccidity was defined as no tone in response to limb extension or pinch.

The investigation consisted of two major components. Table 1 summarizes the groups associated with each component.


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  		Table 1. Experimental Design
 
Experiment 1
This experiment was conducted to examine whether GABA agonists attenuate the spastic paraparesis induced by morphine. Rats were randomly assigned to the following groups (Table 1). In Group 1 (n = 6; 6-min ischemia control group), intrathecal normal saline 20 µL was administered at 30 min after reperfusion. In Group 2 (n = 6), the effect of intrathecal morphine on the motor function was assessed in rats in which normal saline (10 µL each) or morphine (30 µg each) were injected intrathecally 30 min after reperfusion (i.e., morphine spasticity group). We used 30 µg of morphine, which induced complete or near complete paraparesis (MDI = 5 or 6) in almost all the rats in our previous experiments (7). To assess the effect of intrathecal GABAA agonist or GABAB agonist on the spastic paraparesis induced by intrathecal morphine, 0.3, 1, or 3 µg/10 µL of muscimol (GABAA agonist) and morphine (30 µg) were injected in Group 3 (n = 6), and 1, 3, or 10 µg/10 µL of baclofen (GABAB agonist) and morphine (30 µg) were injected in Group 4 (n = 6), intrathecally 30 min after reperfusion. Then motor function was assessed. The maximum doses used in this study (3 µg for muscimol and 10 µg for baclofen) were the maximal doses that did not cause significant respiratory depression in our experimental system.

Experiment 2
In Experiment 2, we examined whether GABA antagonists induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat similar to morphine and, if so, to examine the characteristics of interactions between morphine and GABA antagonists in this model. After reperfusion from 6-min spinal cord ischemia, rats were randomly assigned to a treatment group (Groups 5–9; Table 1). Each group had six rats. The 50% effective dose (ED50) of morphine or GABA antagonists alone was determined by using the dose-response curve from the respective area under the MDI curve (sum of 1–8 h), because in the present study, spastic paraparesis induced by morphine lasted 1–8 h. To examine the characteristics of interaction between morphine and GABA antagonists, isobolograms were constructed by plotting ED50 values of the single drugs on x and y axis (plural) and by plotting the experimentally derived ED50 values of the combination dosage on the same axis. The isobologram provides a convenient graphical display of the respective doses to represent equi-effective pairs of doses of drugs x and y, respectively (13). We used the combination ED50 dosage of morphine, and each GABA antagonist applied one third and three times that dose, respectively (Table 1).

Statistical analysis of physiological data was performed by one-way analysis of variance. For analysis of neurological outcome in the individual groups of Experiment 1, values were compared with the Kruskal-Wallis test. Specific comparisons between experimental groups were performed with the Bonferroni post hoc tests. For analysis of neurological outcome in the individual groups of Experiment 2, specific comparisons between experimental groups were performed with the Mann-Whitney U-test for independent means. A value of P < 0.05 was considered significant. Data were expressed as mean ± SEM.


   Results
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 Abstract
 Introduction
 Methods and Materials
 Results
Discussion
 References
 
During the experiments, paravertebral muscle temperature ranged between 37.4°C and 38.1°C. Baseline distal arterial pressure was 84 ± 6 mm Hg and decreased to 6 ± 1 mm Hg at the end of the 6-min aortic occlusion in all the experiments. No significant differences among experimental groups were detected in physiological data.

Experiment 1
The intrathecal injection of morphine had a significant effect on motor function; in the control group (Group 1), all rats showed modest and transient motor weakness (MDI = 2–4) at 1 h after the reperfusion, followed by gradual recovery over 24–48 h and showed almost normal ambulation at 24 h. All rats in the intrathecal morphine group (Group 2) displayed a gradual development of spastic paraparesis in their hind limbs after the intrathecal morphine injection, with the peak motor deficit observed between 1 to 4 h after intrathecal morphine. Although there were significant MDI differences at 2 and 5 h after reperfusion, the MDI recovered at the same rate as the control group. The MDI in this group was the same as that of the control group at 8 h after reperfusion and diminished over 24 h after the injection. In the muscimol and morphine group (Group 3), we did not observe improvement of the MDI compared with that of Group 2 (Fig. 1). We had almost the same result with the baclofen and morphine group (Group 4; data not shown). However, the type of paraparesis in Group 3 and Group 4 was flaccid in five of six rats injected by morphine 30 µg and muscimol 3 µg or baclofen 10 µg and spastic in all rats injected by morphine 30 µg and muscimol 0.3 µg or baclofen 1 µg. These results suggest that GABA agonists did not attenuate the spastic paraparesis induced by intrathecal morphine, but instead augmented the effect.



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  		Figure 1. Mean motor deficit index (MDI) of intrathecal morphine and muscimol. MDI as a function of time after 6-min spinal cord ischemia in intrathecal morphine and {gamma}-aminobutyric acid (GABA)A agonist muscimol groups. Note the spasticity potentiating effect of intrathecal morphine seen at 2–8 h after injection in the morphine 30 µg plus normal saline (N/S) 10 µL group compared with the control group (intrathecal N/S 20 µL). In the muscimol and morphine group, we did not observe the improvement of MDI compared with that of the intrathecal morphine group. *P < 0.05 versus the N/S 20 µL group.

 
Experiment 2
Morphine-induced spastic paraparesis after a noninjurious interval of spinal cord ischemia showed a dose-dependent increase of MDI (Fig. 2A), as we previously demonstrated (7). The ED50 value of morphine alone was 10 µg (Fig. 2B). GABA antagonists (bicuculline or 5-AA) also induced spastic paraparesis in all rats and persisted 1–24 h, with the peak motor deficit observed at 4 h after reperfusion. Bicuculline or 5-AA produced a dose-dependent increase of MDI (Fig. 3A), with ED50 values of 4 µg (Fig. 3B) and 70 µg (data not shown), respectively. In the isobolographic analysis, the ED50 calculated (Fig. 4B) was below the theoretical additive line, indicating a synergistic interaction between morphine and bicuculline (Fig. 4A and 5) or 5-AA (data not shown).



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  		Figure 2. Intrathecal (IT) morphine dose response curve. (A) Mean motor deficit index (MDI) as a function of time after 6-min spinal cord ischemia in each dose of IT morphine. N/S = normal saline. (B) Dose-response curve for IT morphine on the noninjurious period of spinal cord ischemia model. The response presented as percent maximal possible effect (%MPE; y axis) and time course curve (x axis). Each point on the graph represents the mean ± SEM of six rats.

y= 29.252 Ln(x) - 18.879; R2 = 0.9074; 50% effective dose (ED50) = 10.54 µg; 100% area under the curve (AUC) = 27.7 MDI*h; N/S = normal saline.

 


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  		Figure 3. Intrathecal (IT) bicuculline dose response curve. (A) Mean motor deficit index (MDI) as a function of time after 6-min spinal ischemia in each dose of IT bicuculline. (B) Dose-response curve for IT bicuculline on the noninjurious period of spinal ischemia model. The response presented as percent maximal possible effect (%MPE; y axis) and time course curve (x axis). Each point on the graph represents the mean ± SEM of six rats.

y= 15.731 Ln(x) + 30.119; R2 = 0.9035; 50% effective dose (ED50) = 3.54 µg; 100% area under the curve (AUC) = 27.7 MDI*h. N/S = normal saline.

 


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  		Figure 4. Intrathecal (IT) morphine and bicuculline combination dose-response curve. (A) Mean motor deficit index (MDI) as a function of time after 6-min spinal cord ischemia in each combination dose of IT morphine and bicuculline. (B) Each point on the graph (A, B, and C) express the combination dose: (morphine:bicuculline; µg) mean A (1:0.34), B (3:1), and C (10:3.4) and represents the mean ± SEM.

y= 25.014 Ln(x) + 20.698; R2 = 0.9238. Calculated morphine 50% effective dose (ED50) = 3.23 µg and bicuculline ED50 = 1.12 µg. %MPE = percent maximal possible effect.

 


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  		Figure 5. Isobologram of morphine and bicuculline. Isobolographic plot of the interaction of the spastic paraparesis of intrathecal (IT) morphine combined with the {gamma}-aminobutyric acid (GABA)A antagonist bicuculline after a noninjurious period of spinal cord ischemia. The 50% effective dose (ED50) values for the single drugs are plotted on the x and y axis, respectively, and the heavy lines represent SEM. The dashed line connecting these points is the theoretical additive line. The experimental point and SEM for morphine and bicuculline combination decreased below the theoretical additive point, and statistical significance using t distribution (P < 0.05) indicated a synergistic interaction (i.e., more than additive effect). *ED50 of morphine and bicuculline combination (10.28:3.54 µg).

y= 25.014 Ln(x) + 20.698; R2 = 0.9238.

 

   Discussion
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
References
 
The development of myoclonic activity or neuroexcitation has been observed as a toxic side effect of opioids when injected into the intrathecal or epidural space in humans and animals (14–16). Although the overall incidence of paraplegia after descending and thoracoabdominal aneurysmectomy varies between 5% and 21% (17), we observed that the intrathecal administration of morphine, if injected after aortic cross-clamp in humans, triggered motor dysfunction that had a rapid onset and was effectively reversed by naloxone. However, the mechanism of transient spasticity observed by morphine is not completely understood. Previous studies have demonstrated that transient spinal cord ischemia is associated with a selective loss of small interneurons localized between laminae V-VII and a significant decrease in spinal cord glycine and GABA concentrations (10). Opioid administration has a potent inhibitory effect on target neurons in several brain and spinal cord regions, and this effect is thought to be mediated by decreased neurotransmitter release or by hyperpolarization of target cells (18). Systemic administration of morphine has been reported to trigger neuronal excitation in the hippocampus, which may be mediated by the inhibition of GABAergic interneurons (19). We hypothesized that blockade of inhibitory neurotransmitter receptor was responsible for morphine-induced spastic paraparesis.

In the present study, we demonstrated that GABA agonists did not attenuate the spastic paraparesis induced by intrathecal morphine after a noninjurious interval of spinal cord ischemia in our rodent model. We also demonstrated that GABA antagonists produced a dose-dependent increase of MDI (Fig. 3A) similar to morphine (Fig. 2A) and that with an isobolographic analysis, morphine and GABA antagonists have a synergistic interaction on spastic paraparesis. These results suggest that the spastic paraparesis induced by intrathecal morphine may be mediated in part by GABA receptors.

GABA is a major inhibitory amino acid neurotransmitter in the central nervous system (20), and its action is mediated by at least two receptor subtypes, GABAA and GABAB, which are located on primary afferents and dorsal horn neurons (21) and contribute to inhibitory control at the spinal cord level (22). The GABAA agonist muscimol and the GABAB agonist baclofen have antinociceptive effects at the level of spinal cord (23). Therefore, we examined the effect of GABA agonists on the spastic paraparesis induced by intrathecal morphine and found that GABA agonists did not attenuate this spastic paraparesis. Although there are complex mechanisms of action associated with GABA, it is unlikely that the spastic paraparesis induced by morphine is because of the inhibition of GABAergic interneurons. Hara et al. (23) demonstrated that the co-administration of muscimol or baclofen increased the antinociceptive effects of morphine in intensity and duration in rats but did not potentiate motor paralysis. Thus, the morphine-induced spastic paraparesis might be mediated by a different mechanism from that of its antinociceptive action.

However, GABA antagonists, bicuculline or 5-AA, produced a dose-dependent increase of MDI (Fig. 3A) similar to morphine (Fig. 2A), and the combination of morphine and GABA antagonists (bicuculline or 5-AA) also produced a further increase of MDI. In addition, morphine and GABA antagonists have a synergistic, not an additive, interaction in producing spastic paraparesis. These synergistic interactions may depend upon events that occur as a result of a functional interaction between two separate systems influenced by their receptors (24). Further investigation would be interesting to verify the functional interaction of these drugs. However, these results suggest that the spastic paraparesis induced by intrathecal morphine may be mediated in part by inhibition of GABAergic interneurons. This type of paraparesis might be a transient symptom because the motor deficit caused by morphine administered after a noninjurious spinal cord ischemia disappeared by at least 48–72 hours in our study. However, we have demonstrated the histopathological changes of spinal cord after morphine-induced paraparesis (7). Therefore, the co-administration of opioids and GABA antagonists administered after transient aortic occlusion could worsen spinal neuronal injury and corresponding development of neurological dysfunction.

In conclusion, we demonstrated that GABA agonists did not attenuate spastic paraparesis but induced flaccidity after a noninjurious interval of spinal cord ischemia. We also demonstrated that GABA antagonists produced a dose-dependent increase of MDI similar to morphine and have a synergistic interaction with morphine, which indicates that the spastic paraparesis induced by intrathecal morphine may be mediated in part by inhibition of GABAergic interneurons.


   Acknowledgments
 
Supported, in part, by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.


   Footnotes
 
Presented, in part, at the 1999 International Anesthesiology Research Society 73rd Clinical and Scientific Congress, March 12–16, Beverly Hills, Los Angels, California.


   References
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press