JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (23)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hara, K.
Right arrow Articles by Kosaka, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hara, K.
Right arrow Articles by Kosaka, Y.
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
Top
 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
Top
 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.



View larger version (12K):
[in this window]
[in a new window]
  		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.

 


View larger version (15K):
[in this window]
[in a new window]
  		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.



View larger version (18K):
[in this window]
[in a new window]
  		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).


View this table:
[in this window]
[in a new window]
  		Table 1. Motor Function Score
 

   Discussion
Top
 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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Désarmenien M, Feltz P, Occhipinti G, et al. Coexistence of GABAA and GABAB receptors on A{delta} and C primary afferents. Br J Pharmacol 1984;81:327–33.[Web of Science][Medline]
  2. Price GW, Wilkin GP, Turnbull MJ, Bowery NG. Are baclofen-sensitive GABAB receptors present on primary afferent terminals of spinal cord? Nature 1984;307:71–4.[Medline]
  3. Lin Q, Peng YB, Willis WD. Role of GABA receptor subtypes in inhibition of primate spinothalamic tract neurons: difference between spinal and periaqueductal gray inhibition. J Neurophysiol 1996;75:109–23.[Abstract/Free Full Text]
  4. Hammond DL, Washington JD. Antagonism of L-baclofen-induced antinociception by CGP 35348 in the spinal cord of the rat. Eur J Pharmacol 1993;234:255–62.[Web of Science][Medline]
  5. Roberts LA, Beyer C, Komisaruk BR. Nociceptive responses to altered GABAergic activity at the spinal cord. Life Sci 1986;39:1667–74.[Web of Science][Medline]
  6. Aley KO, Kulkarni SK. GABAergic agents-induced antinociceptive effects in mice. Exp Clin Pharmacol 1989;11:597–601.
  7. Andree T, Kendall DA, Enna SJ. THIP analgesia: cross tolerance with morphine. Life Sci 1983;32:2265–72.[Web of Science][Medline]
  8. Luger TJ, Hayashi T, Weiss CG, Hill HF. The spinal potentiating effect and the supraspinal inhibitory effect of midazolam on opioid-induced analgesia in rats. Eur J Pharmacol 1995;275:153–62.[Web of Science][Medline]
  9. Suh H-W, Soug D-K, Kim Y-H, et al. Differential modulation by muscimol and baclofen on antinociception induced by morphine, ß-endorphin, D-Pen2,5-enkephalin and U50,488H administered intracerebroventricularly in the mouse. Schmiedebergs Arch Pharmacol 1995;352:614–9.
  10. Todd AJ, Spike RC, Russell G, Johnston HM. Immunohistochemical evidence that Met-enkephalin and GABA coexist in some neurons in rat dorsal horn. Brain Res 1992;584:149–56.[Web of Science][Medline]
  11. Barber RP, Vaughn JE, Saito K, et al. GABAergic terminals are presynaptic to primary afferent terminals in the substantia gelatinosa of the rat spinal cord. Brain Res 1978;141:35–55.[Web of Science][Medline]
  12. Gong L-W, Ding Y-Q, Wang D, et al. GABAergic synapses on µ-opioid receptor-expressing neurons in the superficial dorsal horn: an electron microscope study in the cat spinal cord. Neurosci Lett 1997;227:33–6.[Web of Science][Medline]
  13. Ness TJ, Gebhart GF. Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat. Brain Res 1988;450:153–69.[Web of Science][Medline]
  14. Wang RA, Randic M. Activation of µ-opioid receptor modulates GABAA receptor-mediated currents in isolated spinal dorsal horn neurons. Neurosci Lett 1994;180:109–13.[Web of Science][Medline]
  15. Carter BD, Medzihradsky F. Go mediates the coupling of the µ-opioid receptor to adenylyl cyclase in cloned neural cells and brain. Proc Natl Acad Sci USA 1993;90:4062–6.[Abstract/Free Full Text]
  16. Porter NM, Twyman RE, Uhler MD, Macdonald RL. Cyclic AMP-dependent protein kinase decreases GABAA receptor current in mouse spinal neurons. Neuron 1990;5:789–96.[Web of Science][Medline]
  17. Holz GG, Rane SG, Dunlap K. GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels. Nature 1986;319:670–2.[Medline]
  18. Holz GG IV, Kream RM, Spiegel A, Dunlap K. G proteins couple {alpha}-adrenergic and GABAb receptors to inhibition of peptide secretion from peripheral sensory neurons. J Neurosci 1989;9:657–66.[Abstract]
  19. Fox S, Krnjevic K, Morris ME, et al. Action of baclofen on mammalian synaptic transmission. Neuroscience 1978;3:495–515.[Web of Science][Medline]
  20. Malcangio M, Bowery NG. {gamma}-Aminobutyric acidB, but not {gamma}-aminobutyric acidA receptor activation, inhibits electrically evoked substance P-like immunoreactivity release from the rat spinal cord in vitro. J Pharmacol Exp Ther 1993;266:1490–6.[Abstract/Free Full Text]
  21. Hoehn K, Reid A, Sawynok J. Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen. Eur J Pharmacol 1988;146:65–72.[Web of Science][Medline]
  22. Malcangio M, Ghelardini C, Giotti A, et al. CGP35348, a new GABAB antagonist, prevents antinociception and muscle-relaxant effect induced by baclofen. J Pharmacol 1991;103:1303–8.
  23. Feldman RG, Kelly-Hayes M, Conomy JP, Foley JM. Baclofen for spasticity in multiple sclerosis. Neurology 1978;28:1094–8.[Abstract/Free Full Text]
  24. Herman RM, D’Luzansky SC, Ippolito R. Intrathecal baclofen suppresses central pain in patients with spinal lesions. Clin J Pain 1992;8:338–45.[Web of Science][Medline]
  25. Dapas F, Hartman SF, Martinez L, et al. Baclofen for the treatment of acute low-back syndrome: a double-blind comparison with placebo. Spine 1985;10:345–9.[Web of Science][Medline]
  26. Fromm GH, Terrence CF, Chattha AS. Baclofen in the treatment of trigeminal neuralgia: double-blind study and long-term follow-up. Ann Neurol 1984;15:240–4.[Web of Science][Medline]
  27. Terrence CF, Fromm GH, Tenicela R. Baclofen as an analgesic in chronic peripheral nerve disease. Eur Neurol 1985;24:380–5.[Web of Science][Medline]
  28. Gordon NC, Gear RW, Heller PH, et al. Enhancement of morphine analgesia by the GABAB agonist baclofen. Neuroscience 1995;69:345–9.[Web of Science][Medline]
  29. Stenseth R, Sellevold O, Breivik H. Epidural morphine for postoperative pain: experience with 1085 patients. Acta Anaesthesiol Scand 1985;29:148–56.[Web of Science][Medline]
Accepted for publication April 13, 1999.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
K. Hara, Y. Saito, Y. Kirihara, and S. Sakura
The Interaction Between Gamma-Aminobutyric Acid Agonists and Diltiazem in Visceral Antinociception in Rats
Anesth. Analg., May 1, 2004; 98(5): 1380 - 1384.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
C.-R. Lin, L.-C. Yang, H.-L. You, C.-T. Lee, M.-H. Tai, P.-H. Tan, M.-W. Lin, and J.-T. Cheng
Antinociceptive Potentiation and Attenuation of Tolerance by Intrathecal Electric Stimulation in Rats
Anesth. Analg., June 1, 2003; 96(6): 1711 - 1716.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
J. N. Sengupta, B. K. Medda, and R. Shaker
Effect of GABAB receptor agonist on distension-sensitive pelvic nerve afferent fibers innervating rat colon
Am J Physiol Gastrointest Liver Physiol, December 1, 2002; 283(6): G1343 - G1351.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. Nakamura, M. Kakinohana, Y. Taira, H. Iha, and K. Sugahara
The Effect of Gamma-Aminobutyric Acid (GABA) Receptor Drugs on Morphine-Induced Spastic Paraparesis After a Noninjurious Interval of Spinal Cord Ischemia in Rats
Anesth. Analg., November 1, 2002; 95(5): 1389 - 1395.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. M. Walker, L. C. Goudas, M. J. Cousins, and D. B. Carr
Combination Spinal Analgesic Chemotherapy: A Systematic Review
Anesth. Analg., September 1, 2002; 95(3): 674 - 715.
[Full Text] [PDF]

Home page
 J PsychopharmacolHome page
M. Mahmoudi and M.-R. Zarrindast
Effect of intracerebroventricular injection of GABA receptor agents on morphine-induced antinociception in the formalin test
J Psychopharmacol, January 1, 2002; 16(1): 85 - 91.
[Abstract] [PDF]

Home page
 Pharmacol. Rev.Home page
D. Le Bars, M. Gozariu, and S. W. Cadden
Animal Models of Nociception
Pharmacol. Rev., December 1, 2001; 53(4): 597 - 652.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (23)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hara, K.
Right arrow Articles by Kosaka, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hara, K.
Right arrow Articles by Kosaka, Y.

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press