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Vol. 302, Issue 3, 1168-1175, September 2002
Departments of Pharmacology (T.M.L., G.L.W.), Neuroscience (G.L.W.), Medical School, and Experimental and Clinical Pharmacology (A.K.B.), Epilepsy Research and Education Program, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Macalester College, St. Paul, Minnesota (K.V.T.)
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Some antiepileptic drugs have been shown to be clinically effective in the treatment of neuropathic pain. This study determined whether the new antiepileptic drug tiagabine, a GABA uptake inhibitor, is efficacious in mice in a broad range of nociceptive tests (hot-plate, formalin, and dynorphin-induced chronic allodynia) and compared tiagabine's potency with two other antiepileptic drugs, gabapentin and lamotrigine. Intraperitoneally administered tiagabine, but not lamotrigine, gabapentin, or i.t. tiagabine, produced dose-dependent antinoception in the hot-plate test. A 5-min pretreatment with tiagabine (2-29 nmol i.t.) dose-dependently inhibited both the acute and late phase formalin behaviors; pretreatment with lamotrigine (4-265 nmol i.t.) inhibited only the late phase. In the formalin assay the GABAA antagonist bicuculline reversed the acute phase antinociception, whereas the GABAB antagonist saclofen reversed both the acute and late phase tiagabine-induced antinociception. Tiagabine administered i.p. but not i.t. dose-dependently reduced dynorphin-induced chronic allodynia for 120 min. Gabapentin and lamotrigine produced antinociception administered either i.t. or i.p. in a dose-dependent manner. Thus, we have shown that gabapentin and lamotrigine produced antinociception in two mouse models of pain, whereas tiagabine produced antinociception in all three mouse models of pain.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Enhancement
of GABA neurotransmission may provide an approach to diminish the level
of nociception in various pain states. Several studies have implicated
GABAA and GABAB receptors
in spinal nociceptive circuitry. GABAA but not
GABAB receptor agonists inhibit N-methyl-D-aspartate-induced
nociceptive behaviors (Aanonsen and Wilcox, 1989
), whereas both
GABAA and GABAB receptor
agonists inhibit substance P-induced nociceptive behaviors (Hwang and
Wilcox, 1989). Intrathecal administration of GABA receptor antagonists dose-dependently produced tactile allodynia (Yaksh, 1989), suggesting that inhibiting endogenous GABA can lead to an excited sensory state.
Both GABAA and GABAB
receptor agonists administered i.t. are antinociceptive in the acute
and late phases of the formalin assay (Dirig and Yaksh, 1995; Kaneko
and Hammond, 1997), and dose-dependently attenuate allodynia induced by
peripheral injury (spinal nerve tight ligation) (Hwang and Yaksh,
1997). Peripheral nerve injury (Ibuki et al., 1997) and transient
spinal cord ischemia (Zhang et al., 1994) result in a loss of GABA
expression in the spinal cord dorsal horn, suggesting that the loss of
inhibitory GABA neurons may contribute to exaggerated sensory
processing after nerve injury. Several antiepileptic drugs have been
shown to have either a direct or indirect influence on the GABAergic
transmission in the brain and antiepileptic drugs, such as gabapentin
and lamotrigine, are therapeutic for the management of chronic pain
(McQuay et al., 1995).
Gabapentin (GBP) is a structural analog of GABA whose mechanism of
action is currently unknown, lacking affinity for both the
GABAA and GABAB receptors
and failing to inhibit GABA transaminase (Goldlust et al., 1995) or
GABA uptake (Su et al., 1995), but possibly binding to a subunit common
to most voltage-sensitive calcium channels in brain (Brown and Gee,
1998). Several studies have shown GBP to be antinociceptive. In the
formalin test, GBP has been shown to inhibit the late phase but not the
acute phase (Field et al., 1997; Shimoyama et al., 1997; Carlton and
Zhou, 1998). In addition to its action in acute and inflammatory pain, GBP reverses hyperalgesia and allodynia observed after peripheral nerve
injury (Xiao and Bennett, 1996; Hunter et al., 1997) and suppresses
spontaneous ectopic discharges from injured peripheral nerves (Chapman
et al., 1998; Pan et al., 1999).
Lamotrigine (LTG) is a use-dependent inhibitor of voltage-activated
sodium channels (Leach et al., 1986). It has been suggested that LTG's
inhibition of voltage-activated sodium channels stabilizes the
presynaptic neuronal membrane (Leach et al., 1986), thus preventing the
release of excitatory neurotransmitters (Teoh et al., 1995), and
inhibits sustained repetitive neuronal firing (Cheung et al., 1992).
These qualities of LTG are suggestive of a drug having antinociceptive
properties. LTG inhibited transient prostaglandin E-induced
hyperalgesia and produced analgesia in streptozotocin-induced chronic
hyperalgesia (Nakamura-Craig and Follenfant, 1995). Additionally, LTG
reverses nerve injury-induced cold allodynia but not tactile allodynia
(Hunter et al., 1997). LTG significantly reduced topical mustard oil
but not brush-evoked dorsal horn neuronal activity (Blackburn-Munro and
Fleetwood-Walker, 1997).
Tiagabine (TGB)
[(R-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)
nipecotic acid hydrochloride], a newer antiepileptic drug approved by
the Food and Drug Administration as an adjunctive therapy for partial
seizures, is an inhibitor of neuronal and glial GABA uptake proteins
(Nielsen et al., 1991). TGB increases the concentration of GABA in the
brain (Fink-Jensen et al., 1992). Recently, it has been demonstrated
that systemic administration of tiagabine produces antinociception in
acute nociceptive tests in mice (Giardina et al., 1998; Ipponi et al.,
1999) and nerve ligation-induced tactile allodynia in rats (Giardina et
al., 1998). These past studies have examined TGB's efficacy when given
systemically; however, neither study examined the efficacy after
central drug administration. In the present study, we examine the
nociceptive capability of TGB after central (intrathecal) as well as
systemic (intraperitoneal) drug administration in mice. Additionally,
we compared the antinociceptive efficacy of TGB to two other
antiepileptic drugs (LTG and GBP) in a broad range of nociceptive tests
in mice, ranging from acute (hot-plate) through tonic (formalin assay) to chronic (dynorphin-induced allodynia), and characterized which GABA
receptors are involved in TGB-induced antinociception.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Chemicals and Materials
Bicuculline and 2-hydroxysaclofen (saclofen) were purchased from Sigma/RBI (Natick, MA) and clonidine from Boeringer Ingelheim USA (Ridgefield, CT). Dynorphin A (1-17), and morphine were provided by National Institute on Drug Abuse (Bethesda, MD), tiagabine by Abbott Diagnostics (Abbott Park, IL), lamotrigine by GlaxoSmithKline (Uxbridge, Middlesex, UK), and gabapentin by Parke-Davis (Ann Arbor, MI). Individual von Frey filaments were purchased from North Coast Medical, Inc. (San Jose, CA).
Animals
Male ICR mice (Harlan, Indianapolis, IN) weighing 20 to 30 g were used in all experiments. Mice were maintained in cages with free access to food and water and kept on a 12-h light/dark schedule in the University of Minnesota's Research Animal Resources facilities. The Institutional Animal Care and Use Committee approved these experiments.
Drug Preparation
Drugs were administered either i.t. in a volume of 5 µl to
awake mice, as described previously (Hylden and Wilcox, 1980) or i.p.
in a volume of 200 µl with a 27-gauge needle attached to a 1-ml
disposable syringe. Drugs were diluted in 0.9% saline for all i.t.
injections and systemic injections of GBP. For systemic studies of TGB
and LTG, these drugs were first diluted in dimethyl sulfoxide (DMSO)
and then further diluted with 0.9% saline. The maximum concentration
of DMSO used in this study was 9% after the final drug dilution.
Experimental Design
These studies used mice and compared effects of drugs given i.p. and i.t. on three measures of nociception. The hot-plate assay tested for acute nociception, the formalin assay tested for tonic nociception, and the dynorphin-induced allodynia tested for the antiepileptic drug's effect in chronic nociception. Each mouse was only used once, which means that the mouse was tested with only one nociceptive method and received one drug.
Hot-Plate Assay. The hot-plate assay is a model for acute thermal nociception. This test, along with the tail-flick assay, is a standard test to determine the antinociceptive efficacy of a compound. Mice (281) were placed onto a 53°C metal plate, and latency to either licking of the hind paw or vertical jumping was determined. A maximum cutoff of 60 s was imposed to avoid tissue damage. At least 24 h after two baseline latencies were established, drugs were administered either intrathecally (0.1, 0.2, 7, 14, 29, and 73 nmol for TGB; 0.1, 1, 10, and 100 nmol for GBP; and 0.4, 4, 12, and 39 nmol for LTG) or intraperitoneally (1, 4, and 10 mg/kg for TGB; 10, 30, and 100 mg/kg for GBP; and 0.1, 1, 3, 10, and 100 mg/kg for LTG); then latencies to the hot-plate were measured at 10 (only with intrathecal), 30, 60, and 120 min.
Formalin Assay.
The formalin test was used as a tonic model
of nociception. Two phases of behavior follow injection of formalin
into the hind paw. The first phase consists of intense licking and
biting of the injected paw for the first 5 min followed by a period of
little activity. The second phase spans from 15 to 30 min after the
formalin injection and involves periods of licking and biting of the
injected paw. The first phase is thought to be a model of acute
chemical pain, whereas the second phase reflects a state of central
sensitization driven by the presumed first phase involvement of
excitatory amino acids (Coderre and Melzack, 1992). The testing
environment was maintained at a minimum of 26°C. All together, 163 mice were used for the formalin experiments. Mice were placed into
individual 2-liter beakers for at least 1 h before testing. Mice
were injected with 20 µl of 5% formalin into the dorsal right hind
paw and returned to the beakers for observation. The amount of time
spent licking and biting the injected paw and leg was recorded in 5-min
intervals for 25 to 40 min after the formalin injection. TGB (2, 14, and 29 nmol) or LTG (4, 12, 39, and 265 nmol) were intrathecally
administered 5 min before the intraplantar injection of formalin. In
determining the mechanism of TGB-induced antinociception, bicuculline
(1, 3, 10, or 20 pmol) or saclofen (0.01, 0.1, 1, 10, 100, or 900 nmol)
was coadministered with TGB.
Dynorphin-Induced Allodynia.
For chronic nociception, we
used the dynorphin-induced chronic allodynia model. In this model, a
single i.t. injection of 3 nmol of dynorphin induces allodynia and
hyperalgesia for at least 100 days (Laughlin et al., 1997). Mechanical
allodynia was determined with a set of von Frey filaments modified as
described previously (Laughlin et al., 1997); these filaments are used
to stimulate the dorsal side of the hind paw. The innocuous 2.44 (0.3-0.4 mN) filament was applied to the point of bending three times
to the dorsal surface of the left and right hind paw for a total of six
applications per mouse. This filament elicits paw withdrawal responses
only in mice exposed to allodynia-inducing manipulations such as i.t.
applied dynorphin (Laughlin et al., 1997). For testing, 247 mice were
placed in individual 2-liter bedding-lined beakers and allowed to
adjust to the surroundings for at least 1 h before all behavioral
testing. Allodynia was determined 1 to 3 days after the i.t. injection
of dynorphin; thereafter, only allodynic mice (responding at least 50%
to the 0.4 mN von Frey filament) were used to determine efficacy of the antiepileptic drugs. TGB (0.2, 7, or 24 nmol i.t.; 0.1, 1, or 10 mg/kg
i.p.), LTG (4, 39, or 86 nmol i.t.; 0.1, 1, or 10 mg/kg i.p.), and GBP
(0.1, 30, or 60 nmol i.t.; 0.1, 1, 10, or 100 mg/kg i.p.) were
administered to allodynic mice. Nonallodynic mice (responding less than
50%) were removed from the study, so that approximately 10% of mice
were removed from the study.
Statistical Analysis
Both nonparametric and parametric statistical tests were used to
analyze the data. Both tests yielded the same results; only the
parametric results are reported in the figures. All data were expressed
as the mean ± S.E.M. The allodynia data were converted to
percentage of inhibition of baseline response according to: % inhibition = 100 × (BR 
TR)/BR, where BR is baseline
response to the 2.44 von Frey filament (possible 0 to 6 paw
withdrawals) and TR is the test response to the same filament (possible
0 to 6 paw withdrawals). A mean and S.E.M. were calculated from these values. The data were analyzed using Student's t test only
when two means were compared; otherwise, analysis of variance was used. Statistical differences between groups were further analyzed with Dunnett's test for multiple post hoc comparisons to a control. The
Kruskal-Wallis nonparametric statistical analysis was performed on the
data; this analysis produced the same results as the analysis of
variance. p values of less than 0.05 were considered
statistically significant. The ED50 values [and
95% confidence interval (CI)] were calculated according to the method
of Tallarida and Murray (1987).
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Role of Antiepileptic Drugs in Acute Thermal Nociception.
The
effect of three antiepileptic drugs on acute thermal nociception was
tested using the hot-plate test. Intrathecal administration of TGB
(0.1, 0.2, 2, 7, 14, 29, and 73 nmol), LTG (0.4, 4, 12, and 39 nmol),
and GBP (0.1, 1, 10, and 100 nmol) had no effect on hot-plate latencies
at 10, 30, 60, or 120 min after injection (data not shown).
Systemically administered TGB (1, 4, and 10 mg/kg) dose-dependently
increased latencies compared with a saline-treated group (Fig.
1). The 4-mg/kg dose of TGB induced
antinociception for 30 min; the antinociception induced by 10 mg/kg TGB
lasted at least 120 min, whereas 1 mg/kg TGB had no effect (Fig. 1). Unlike TGB, systemically administered LTG (0.1, 1, 3, 10, and 100 mg/kg) and GBP (10, 30, and 100 mg/kg) had no effect on hot-plate latencies at 30, 60, and 120 min (data not shown).
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Role of Antiepileptic Drugs in Tonic Nociception.
Intrathecal
pretreatment with TGB dose dependently decreased formalin-induced
behaviors; specifically 29 nmol reduced both acute and late phase
behaviors, 14 nmol of TGB inhibited only the acute phase, and 2 nmol of
TGB had no effect compared with the saline control group (Figs.
2 and 3). Unlike TGB,
pretreatment with LTG (4-265 nmol) inhibited only the late phase (Fig.
3). For the acute phase, 12 nmol of LTG significantly enhanced the formalin-induced behaviors, whereas 4, 39, and 265 nmol of LTG had no
effect (Fig. 3A). For the late phase, TGB inhibited the formalin-induced nociceptive behaviors with an
ED50 value of 13 nmol (95% CI = 5-31
nmol), and for LTG the ED50 was 28 nmol (95% CI = 3-274 nmol). To determine whether TGB prevented the
development of central sensitization or acted as an analgesic similar
to morphine, we administered TGB after the acute phase. TGB (29 nmol
i.t.) administered 5 min after the intraplantar injection of formalin still reduced the late phase nociceptive behaviors in a manner similar
to that of the pretreatment (Fig. 4).
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Role of Antiepileptic Drugs in Chronic Thermal Nociception.
Intrathecal administration of morphine (0.3-1 nmol) and clonidine
(0.01-1 nmol) both dose dependently attenuated the dynorphin-induced allodynia (Fig. 7). Neither saline nor
0.03 nmol of morphine had an effect on mechanical allodynia, whereas
0.3 nmol of morphine was effective for 10 min and 1 nmol of morphine
was effective for at least 60 min (Fig. 7A). Both 0.01 and 0.1 nmol of
clonidine produced antinociception for 10 min and 1 nmol of clonidine
for 30 min; saline had no effect (Fig. 7B). For inhibition of allodynia in this model of chronic pain, clonidine had a greater potency than
morphine [clonidine had an ED50 of 5.3 pmol
(95% CI = 1.1-25.9]. Morphine had an ED50
of 120 pmol (95% CI = 50-250) (Table
1) and produced a longer lasting effect
(Fig. 7).
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The present study demonstrates that the antiepileptic drug TGB
produces antinociception in three mouse models of pain (Table 2). TGB, administered i.p. but not i.t.
dose dependently produced antinociception in the hot-plate test. A
5-min pretreatment with TGB (i.t.) dose dependently inhibited both
acute and late phase formalin behaviors, and post-treatment with 29 nmol of TGB was still able to inhibit the late phase formalin
behaviors. The TGB-induced antinociception in the formalin test was
reversed by coadministration with GABA antagonists: saclofen
(GABAB antagonist) reversed inhibition of both
the acute and late phase behaviors, whereas bicuculline (GABAA antagonist) reversed only inhibition of
the acute phase. Finally, we examined the antinociceptive potential of
TGB in dynorphin-induced allodynia. Systemically, but not centrally
(i.t.), administered TGB dose dependently attenuated established
dynorphin-induced allodynia, a model of neuropathic pain, for 30 to 120 min. Thus, systemically administered TGB was effective in the acute
(hot-plate) and chronic (dynorphin-induced allodynia) nociceptive
tests, whereas centrally (i.t.) administered TGB was effective in the
formalin assay.
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The first part of this study examined the ability of the three
antiepileptic drugs to inhibit responses in the hot-plate test, which
evaluates acute nociceptive function. Only systemically administered
TGB was effective in this test. Systemically administered LTG or GBP
had no effect, as did i.t. administered TGB, LTG, and GBP. Our results
agree with previous acute nociceptive studies on normal rodents in
which LTG had no effect in hot-plate or tail-flick tests
(Nakamura-Craig and Follenfant, 1995), and GBP had no effect in paw
pinch (Field et al., 1997), heat-evoked paw withdrawal (Field et al.,
1997), or tail-flick tests (Hunter et al., 1997; Shimoyama et al.,
1997). However, in agreement with our study, both 3 and 10 mg/kg TGB
produced antinociception in the hot-plate test after systemic
administration in mice (Giardina et al., 1998; Ipponi et al., 1999).
These results suggest that antiepileptic drugs have little or no effect
on most measures of normal transient nociceptive signaling, but rather
inhibit sensitized signaling associated with allodynia and
hyperalgesia. This interpretation is supported by the fact that GBP had
no effect on normal afferent fiber activity, but inhibited the ectopic
discharge activity associated with peripheral nerve injury (Pan et al.,
1999).
The second part of this study examined the ability of TGB and LTG in
the formalin test, which is a model of acute chemical pain (acute
phase) and tonic nociception involving central sensitization (late
phase). Several studies have previously demonstrated the ability of GBP
to inhibit the late but not the acute phase of the formalin assay when
administered systemically (Field et al., 1997) or centrally (Shimoyama
et al., 1997). Similarly, in the present study, both TGB and LTG
dose-dependently inhibited late phase formalin behaviors, but only TGB
inhibited the acute phase. Thus, TGB may be affecting acute chemical
nociception as it did thermal nociception in the hot-plate test. For
inhibition of the late phase, TGB and LTG produced comparable
dose-response curves. Unlike TGB, LTG actually enhanced rather that
inhibited the acute phase formalin behaviors. Similar enhancing effects
have been demonstrated with LTG, which facilitates C-fiber-evoked
windup and after discharge of dorsal horn neurons (Chapman et al.,
1997).
TGB is an inhibitor of neuronal and glial GABA uptake proteins. Thus,
we examined whether activation of the GABAA
and/or GABAB receptors was involved in the
antinociceptive effect of TGB. In the acute phase of the formalin
assay, both the GABAA and
GABAB receptor antagonists dose-dependently
reversed TGB-induced antinociception. In the late phase of the formalin
assay, only the GABAB receptor antagonist
reversed TGB-induced antinociception. Thus, central administration of
TGB results in elevated GABA levels, leading to the activation of both
GABAA and GABAB receptors
in the acute phase; activation of GABAB receptors
was apparently involved in the late phase of the formalin test. These
results are consistent with previous demonstrations that
tiagabine-induced acute antinociception is inhibited by a
GABAB receptor antagonist (Ipponi et al., 1999).
The late phase of the formalin assay is believed to derive from acute
phase primary afferent activity and is considered to be a model of
central sensitization (Coderre and Melzack, 1992). Drugs that are
considered analgesics, such as morphine, suppress the afferent input
throughout the time course of the behavior and inhibit the late phase
behaviors when given as either a pre- or post-treatment (Yamamoto and
Yaksh, 1992). On the other hand, drugs that inhibit the development of
central sensitization, such as
N-methyl-D-aspartate receptor
antagonists, are only capable of inhibiting the late phase behaviors
when given as a pretreatment and have no effect when given as
post-treatment (Coderre and Melzack, 1992). In this study, we have
shown that TGB inhibited the late phase behaviors when given as either
a pre- or post-treatment, suggesting that TGB has antinociceptive
activity like that of morphine, suppressing afferent input rather than
blocking the development of central sensitization.
The third part of this study examined the efficacy of the three
antiepileptic drugs in dynorphin-induced allodynia, which was used as a
pharmacological model of neuropathic pain. Previous studies have shown
that LTG (Nakamura-Craig and Follenfant, 1995; Hunter et al., 1997),
TGB (Giardina et al., 1998), and GBP (Xiao and Bennett 1996; Hunter et
al., 1997) reversed behavioral signs of neuropathic pain in animal
models. In this study, systemically administered TGB was the most
potent antiepileptic drug to reduce dynorphin-induced allodynia (Table
1), followed by GBP and LTG; GBP, on the other hand, had the longest
duration of action (120 min) compared with TGB and LTG (30-60 min). By
the i.t. route, GBP was more potent than LTG in attenuating
dynorphin-induced allodynia, whereas TGB was without effect on
dynorphin-induced allodynia. Both GBP and LTG were less potent than
morphine and clonidine (Table 1). Systemic administration of morphine
is also more potent than systemic TGB (Giardina et al., 1998). That
systemic but not central administration of TGB was efficacious in
dynorphin-induced allodynia suggests that TGB evidently exerts its
potent antiallodynic effect at a nonspinal site. This outcome could be
due to the presence of a TGB metabolite. TGB is metabolized by the 3A
isoform subfamily of hepatic cytochromes P450 to 5-oxo-TGB, which is
further glucuronidated. There are also thought to be other unidentified
metabolites because only 2% of the parent drug is excreted after
administration of [14C]TGB to humans (Bopp et
al., 1992).
In conclusion, we have shown that TGB produces antinociception in the hot-plate test, formalin assay, and dynorphin-induced allodynia model of neuropathic pain. Both GABAA receptors (acute phase) and GABAB receptors (acute and late phase) are involved in TGB-induced antinociception in the formalin test. This study presents the first comparison between systemic and intrathecal administration of TGB. In both the hot-plate assay and dynorphin-induced allodynia test, TGB was only effective when administered systemically; i.t. administration lacked any effect in these two tests. On the other hand, i.t.-administered TGB was effective in the formalin assay. The reason for this difference in efficacy across routes of administration remains unclear. Further research is required to determine the mechanisms involved in the systemic versus spinal activity profile of TGB. This study also presents the first comparison of TGB's antinociceptive efficacy to that of other antiepileptic drugs. Of the three antiepileptic drugs, TGB was the only drug efficacious in the hot-plate test. TGB was as effective as LTG in the formalin test, and TGB was the most potent systemically administered antiepileptic drug in the dynorphin-induced chronic allodynia test.
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Footnotes |
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Accepted for publication May 6, 2002.
Received for publication December 18, 2001.
This study was supported by a gift from Abbott Diagnostics and in part by National Institute on Drug Abuse Grants R01-DA-11236 and R01-DA-01933 (to G.L.W.). National Institute on Drug Abuse Training Grant T32-DA-07097 supported T.M.L.
Address correspondence to: Dr. Angela K. Birnbaum, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 7-170 WDH, 308 Harvard St. S.E., Minneapolis, MN 55455. E-mail: birnb002{at}tc.umn.edu
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Abbreviations |
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GBP, gabapentin; LTG, lamotrigine; TGB, tiagabine; DMSO, dimethyl sulfoxide; CI, confidence interval.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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-aminobutyric acid (GABA) uptake inhibitor, tiagabine, increases extracellular brain levels of GABA in awake rats.
Eur J Pharmacol
220:
197-201[CrossRef][Medline].-aminobutyric acidB and substance P in the mouse spinal cord.
J Pharmacol Exp Ther
248:
1026-1033.-aminobutyric acidA receptors in formalin-induced nociception in the rat.
J Pharmacol Exp Ther
282:
928-938-amino acid drug, by system l 
-amino acid transporters: a comparative study in astrocytes, synaptosomes and CHO cells.
J Neurochem
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