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Anesth Analg 1999;89:422
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

The Interaction of Antinociceptive Effects of Morphine and GABA Receptor Agonists Within the Rat Spinal Cord

Kaoru Hara, MD, Yoji Saito, MD, Yumiko Kirihara, DVM, Yuko Yamada, MD, Shinichi Sakura, MD, and Yoshihiro Kosaka, MD

Department of Anesthesiology, Shimane Medical University, Izumo, Shimane, Japan

Address correspondence to Y. Saito, MD, Department of Anesthesiology, Shimane Medical University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan. Address e-mail to ysaito{at}shimane-med.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Previous reports indicate that there may be an interaction between {gamma}-aminobutyric acid receptors and opioid receptors systems within the spinal cord, the antinociceptive effects of which have not been elucidated. We examined the effects of intrathecally coadministered morphine and muscimol or baclofen on somatic and visceral antinociception in rats. The tail flick (TF) test and colorectal distension (CD) test were used to assess somatic and visceral antinociceptive effects, respectively. Motor function was also assessed. The measurements were performed for 180 min after the intrathecal administration of morphine (0.1–10 µg), muscimol (0.2–10 µg), baclofen (0.03–1 µg), combination of morphine and muscimol or baclofen, or saline. Morphine, muscimol, or baclofen increased both TF latency and CD threshold in a dose-dependent fashion. Although morphine 0.1 µg, muscimol 0.2 µg, or baclofen 0.03 µg alone did not significantly increase TF latency and CD threshold, the combination of morphine 0.1 µg and muscimol 0.2 µg or baclofen 0.03 µg significantly increased both TF latency and CD threshold. The coadministration of muscimol or baclofen increased the antinociceptive effects of morphine in intensity and duration. None of the rats showed motor dysfunction after the coadministration of morphine and muscimol 0.2 µg, although muscimol produced motor paralysis of the lower limbs in a dose-dependent fashion. Those results suggest a clinical relevance of the coadministration of µ-opioids and GABA receptor agonists for pain control.

Implications: We examined the antinociceptive interaction between morphine and muscimol or baclofen at the spinal level in rats. Intrathecal muscimol or baclofen potentiated both somatic and visceral antinociceptive effects of morphine.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
|gg-Aminobutyric acid (GABA) is a major inhibitory amino acid neurotransmitter in the central nervous system, and its actions are mediated by at least two receptor subtypes, GABAA and GABAB (1), which are located on primary afferents and dorsal horn neurons (1,2) and contribute to inhibitory control at the spinal level (3). GABAA agonists, such as muscimol or 4,5,6,7-tetrahydroisoxazolo[5,4,-c]pyridin-3-ol (THIP), and GABAB agonists, such as baclofen, have antinociceptive effects at the level of spinal cord (4,5). However, most previous studies have focused on somatic antinociceptive effects (4,5), not on visceral antinociceptive effects.

Although there are complex mechanisms of action associated with GABA, at least part of the antinociceptive action may be the result of interactions with opioid systems. The antinociceptive effect of baclofen is reversed by naloxone pretreatment (6), and there is cross-tolerance between a GABAA agonist and morphine (7). Systemically administered muscimol or baclofen potentiates morphine-induced antinociception (6). Benzodiazepines, which mainly act on GABAA receptors, enhance opioid-induced antinociception at the spinal level (8). In contrast, the intracerebroventricular administration of GABA agonists counteracts the antinociceptive effect of opioids (9).

Yet, morphological studies have demonstrated the coexistence of immunoreactivity for GABA and enkephalin in superficial dorsal horn neurons (10) and the existence of GABAergic neurons connected to primary afferents in the dorsal horn (11). Gong et al. (12) showed that some µ-opioid receptor-expressing neurons in the superficial dorsal horn are postsynaptic to GABAergic axon terminals. Those observations support the existence of an antinociceptive interaction of GABA receptors with opioid receptors. However, the interactions between GABA receptor agonists and opioids on antinociceptive effects at the spinal level have not been elucidated.

We examined the interaction between morphine and muscimol or baclofen on somatic and visceral antinociception at the level of spinal cord in the rat.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This protocol was approved by our animal research and use committee. Male Sprague-Dawley rats weighing 300–400 g were used. Rats were maintained on a 12-h light/dark schedule and were housed individually with free access to food and water. To reduce the influences of handling on nociceptive responses, all animals were handled and trained in the test situation for at least 5 days before intrathecal catheterization. Under pentobarbital (40 mg/kg) anesthesia, intrathecal catheters (PE-10 joined to PE-20) were implanted in the rostral direction from the level of the L4-5 intervertebral space. After catheterization, at least 5 days were allowed for recovery before studies were begun. Rats that had motor deficits as a result of catheter placement, infection, or other health problems were excluded.

The tail flick (TF) test was used to measure responses to noxious somatic stimuli by monitoring latency to withdrawal from a heat source focused on the dorsal surface of the tail approximately 5 cm from the tip. The site on the tail that was stimulated was systematically varied so that the same portion of the tail was not repeatedly exposed to the light source. Lack of the tail flick response by 10 s resulted in termination of the stimulus, and the 10-s interval was assigned as the cutoff time to avoid damage to the tail.

The colorectal distension (CD) test was used to measure responses to noxious visceral stimuli (13). Colorectal distension involves inflation with air of an 8-cm, flexible, latex balloon. The system consists of two parts: a large proximal stimulating balloon and a small distal sensing balloon. Both stimulating and sensing balloon pressures were continuously monitored and recorded via in-line pressure transducers. The balloons were inserted via the anus into the colon and rectum under light halothane anesthesia. Animals were tested awake after a minimal 20 min recovery from halothane anesthesia. Pressure within the intracolonic-stimulating balloon was steadily increased at a rate of 2.5 mm Hg/s beginning at 0 mm Hg until a rapid increase of pressure in the sensing balloon was detected. The pressure in the stimulating balloon at which the increase of the pressure in the sensing balloon was triggered was defined as the threshold response for CD. A cutoff distension pressure of 60 mm Hg was used to prevent tissue damage. TF and CD tests were performed sequentially at the same time point with a 90-s interval between each test sequence.

Motor function after intrathecal drug injection was assessed by bilaterally grading the motor block in the upper and lower limbs as follows: 0 = none, 1 = partially blocked, and 2 = completely blocked. Motor blockade was graded as none when the rat had no visible limb weakness and normal gait; as partially blocked when the limb was able to move but not able to support normal posture; and as completely blocked when the limb was flaccid, with no detectable resistance to extension of the limbs. The normal score was 0, and the score with bilateral complete blockade in the upper or lower limbs would have been 2 + 2 = 4.

The drugs administered in this study were morphine hydrochloride, muscimol hydrobromide, and baclofen. After the baseline response values were determined, rats received an intrathecal injection of morphine (0.1, 0.3, 1, 10 µg), muscimol (0.2, 1, 3, 10 µg), baclofen (0.03, 0.1, 0.3, 1 µg), a combination of morphine and muscimol or baclofen, or saline. There were seven rats per experimental condition. Drugs were dissolved in sterile saline. All drug injections were given in a volume of 10 µL, followed by 10 µL of saline to flush the catheter. The investigators were blinded to the injected solutions. Measurements of TF latency and CD threshold and evaluation of motor function were performed 5, 10, 15, 20, 30, 60, 90, 120, and 180 min after the injection. At the end of an experiment, each rat received an intrathecal injection of 2% lidocaine (10 µL). Data obtained from rats in which paraplegia was not seen after lidocaine administration were not included in the data analysis. Some rats were tested on multiple days (not more than three) but never received the same dose of drug twice, and only rats that recovered completely were used. Each rat received only one dose of drug on any one day.

The antinociceptive effects were evaluated by transforming latency or threshold to the percent of maximal possible effect (%MPE) = (postdrug value - baseline value)/(cutoff value - baseline value) x 100%. Motor function scores are presented as median (10th–90th percentiles), and the other data are mean ± SEM. Analysis of variance for repeated measures, followed by Scheffé’s F-test, was used to evaluate the statistical significance of TF latency and CD threshold. The Kruskal-Wallis test, followed by the Mann-Whitney U-test, was used to assess motor function tests. Differences were considered to be significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Intrathecally administered morphine, muscimol, or baclofen alone produced a significant prolongation of TF latency and an increase in CD threshold in a dose-dependent fashion (Fig. 1). Intrathecally administered saline produced no significant change in either test (Fig. 2). The 50% effective dose (ED50) values of antinociceptive effects in the TF and CD tests were 0.46 µg and 0.55 µg in the morphine group, 0.55 µg and 2.5 µg in the muscimol group, and 0.12 µg and 0.15 µg in the baclofen group.



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  		Figure 1. Dose-response effects of morphine (MOR), muscimol (MUS), and baclofen (BAC) in tail flick (TF) and colorectal distension (CD) tests. The data points represent the percent maximal possible effect (%MPE) 10 min after the intrathecal administration of drugs. n = 7 for each point. Data are presented as means ± SEM.

 


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  		Figure 2. Time course effects on percent maximal possible effect (%MPE) in tail flick (TF) and colorectal distension (CD) tests after the intrathecal administration of saline (SAL), morphine 0.1 µg (MOR 0.1), morphine 0.1 µg + baclofen 0.03 µg (MOR 0.1 + BAC 0.03), or morphine 0.1 µg + muscimol 0.2 µg (MOR 0.1 + MUS 0.2). n = 7 for each group. Data are presented as means ± SEM. *P < 0.05 compared with morphine alone.

 
When administered alone, morphine 0.1 µg, muscimol 0.2 µg, or baclofen 0.03 µg produced a slight prolongation of TF latency that was not significant, and produced no increase in CD threshold (Fig. 2). The combination of 0.1 µg morphine and 0.03 µg baclofen produced a significant change in both the TF and CD tests compared with saline or morphine alone. The combination of 0.1 µg morphine and 0.2 µg muscimol produced a significant prolongation of TF latency compared with saline or morphine alone. However, there was no change in CD threshold. These potentiations returned to baseline level within 30 min.

In addition to the ability of drug combinations to produce an increase in the intensity of the antinociception, we also examined the effects of combinations on duration of effect. Morphine 1 µg significantly increased mean %MPE for 90 min (with a peak effect of 96%MPE at 20 min) in the TF test and for 30 min (with a peak effect of 53%MPE at 20 min) in the CD test (Fig. 3). The combination of 1 µg morphine and 0.2 µg muscimol or 0.03 µg baclofen produced significant prolongation of TF latency and an increase in CD threshold compared with morphine 1 µg alone (Fig. 3). Both combinations showed similar time course effects on each test. Maximal TF latency was reached by the first observation time and remained near that level for 90 min. Peak effects of combinations of 1 µg morphine in the CD test were observed 10 or 15 min after intrathecal administration. The significant increase of TF latency and CD threshold caused by the combination continued for 90 or 120 min compared with morphine 1 µg alone.



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  		Figure 3. Time course effects on percent maximal possible effect (%MPE) in tail flick (TF) and colorectal distension (CD) tests after the intrathecal administration of morphine 1 µg (MOR 1), morphine 1 µg + baclofen 0.03 µg (MOR 1 + BAC 0.03), or morphine 1 µg + muscimol 0.2 µg (MOR 1 + MUS 0.2). n = 7 for each group. Data are presented as means ± SEM. *P < 0.05 compared with morphine alone.

 
No effects on motor function were seen after the intrathecal injection of morphine and baclofen. Intrathecal muscimol produced motor paralysis of the lower limbs in a dose-dependent fashion, but muscimol 0.2 µg produced no apparent paralysis (Table 1). None of the rats showed motor dysfunction after the intrathecal injection of the combinations of morphine 0.1 µg or 1 µg and muscimol 0.2 µg or baclofen 0.03 µg (Table 1).


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  		Table 1. Motor Function Score
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We found that intrathecally administered muscimol or baclofen produced antinociceptive effects to both somatic and visceral noxious stimuli. These data coincide with results in previous reports in which the intrathecal administration of GABAA agonists or GABAB agonists increased TF latency or hotplate latency in rats (4,5). Coadministered GABAA agonists, as well as GABAB agonists, potentiated the somatic and visceral antinociceptive effects produced by morphine. This suggests that GABAA and GABAB receptor systems work together to produce a final common effect with µ-opioid receptors at the spinal level. However, the combination of opioid receptor systems with GABAA receptor systems, and the combination of opioid receptor systems with GABAB receptor systems, may have different mechanisms in potentiating antinociception, because GABAA and GABAB receptors have different inhibitory mechanisms in the sensory pathway (3).

There are many ways that opioid and GABA systems could interact within the spinal cord. One possible way would be through actions on cAMP. GABAA receptor-mediated currents are potentiated by µ-opioid receptor agonists in spinal dorsal horn neurons (14). Th activation of µ-opioid receptors inhibits cAMP formation through a pertussis toxin-sensitive mechanism (15). The reduction in cAMP-dependent protein kinase activity may result in enhanced antinociception because activated protein kinase decreases GABAA receptor-mediated responses in most cell types, including spinal neurons (16). These results support the potentiation of morphine antinociception by muscimol in the present study.

The activation of GABAB receptors inhibits voltage-dependent calcium channels via G-protein–coupled adenylate cyclase in dorsal root ganglion cells (17,18) and reduces the release of excitatory amino acids from primary afferent terminals (19) and substance P from the rat spinal cord (20). Hoehn et al. (21) demonstrated that morphine- and baclofen-induced spinal antinociception was abolished by intrathecal pretreatment with pertussis toxin, which suggests the involvement of pertussis toxin-sensitive G proteins in both morphine and baclofen antinociception. The formation of cAMP through pertussis toxin-sensitive G proteins, as a common pathway of GABAB receptors and µ-opioid receptors, may contribute to an interaction between morphine and baclofen. Thus, by acting on cAMP, opioids and GABA may interact in a positive way to produce spinal analgesia.

An additional finding was that visceral pain was also influenced by the tested drug combinations. The control of visceral pain is clinically important because visceral pain plays a large part in many kinds of pain. However, the analgesic effects of morphine on visceral pain are limited, or a large amount of morphine is required to produce satisfactory analgesia on visceral pain, despite the popular use of epidural or intrathecal morphine for relieving postoperative and cancer pain. We confirmed the visceral antinociception of GABA agonists at the spinal level. Visceral antinociceptive effects of systemically administered GABA agonists were previously shown in animal studies (22). Furthermore, the coadministration of GABA agonists significantly potentiated morphine-induced antinociception. These results suggest that such combination may be useful in the clinical treatment of visceral pain.

Baclofen has been used clinically for many years as a muscle relaxant or an antispastic drug (23). Baclofen has also been used for relieving intractable pain (24). Despite the significant analgesic effects of GABAB agonists in animal studies, their analgesic effects in clinical studies are conflicting. For example, the administration of baclofen produced analgesic effects on pain associated with low-back disorders (25), trigeminal neuralgia (26), or spinal lesions (24), but not on postoperative pain, postherpetic neuralgic pain, or neuropathic pain (27). However, the present results support the possible use of the combination of GABA agonists and opioids in the clinical setting after a demonstration of safety. Oral baclofen enhances the analgesic effect of IV morphine in postoperative patients, which supports the clinical usefulness of the combination (28). An additional benefit is the ability to reduce the side effects of each drug by using smaller doses of each in combination.

The clinical uses of baclofen are limited because large doses of GABA agonists produce motor dysfunction. Large doses of opioids also cause adverse effects, including pruritus, nausea, and urinary dysfunction (29). However, we demonstrated that the intrathecal coadministration of GABA agonists and morphine was more effective than the intrathecal administration of GABA receptor agonists or morphine alone, and that it did not produce increased side effects. These results strongly support the concept that the intrathecal or epidural coadministration of GABA receptor agonists and µ-opioids is a possible method to produce good analgesia while reducing the incidence of side effects.

In conclusion, the intrathecal administration of a small and ineffective dose of a GABA receptor agonist, muscimol or baclofen, in combination with morphine potentiated morphine-induced antinociception and did not potentiate motor paralysis. These results suggest that the coadministration of GABA receptor agonists and opioids could have clinical relevance.


   Acknowledgments
 
Supported in part by a grant-in-aid for exploratory research from the Ministry of Education, Science, Sports and Culture.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 13, 1999.




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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