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Vol. 280, Issue 2, 1031-1037, 1997
Department of Anatomy and Brain Science, Kobe University School of Medicine (H.O.), Kobe 650, Japan, and Departments of Anesthesiology (T.M.), Anatomy (C.Y.) and Dental Science (T.N.), Kyoto Prefectural University of Medicine, Kyoto 602, Japan
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Abstract |
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 Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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Intracisternal 6-hydroxydopamine treatment to newborn rats caused massive and permanent damage of brain dopaminergic neurons, and many of these animals show self-injurious behavior (SIB) when loaded by systemic injection of L-dihydroxyphenuylalanine (L-DOPA) or D1 agonist, SKF-38393. SIB occurred at life-long time in neonatal 6-hydroxydopamine-lesioned rats, because SIB confirmed rats at 4 to 6 wk all showed SIB at 3 to 5 mo and at 12 to 13 mo after L-DOPA loading. To elucidate the brain locus important for the induction and cessation of SIB, in our study, we microinjected dopamine agonists and antagonists into various dopamine neuron innervating areas. L-DOPA-induced SIB was inhibited by the injection of a D1 antagonist, SCH-23390 (5 µg), into the bilateral substantia nigra, but not into the bilateral caudate-putamen or nucleus accumbens. The microinjection of YM-09151-2 (10 µg), a D2 antagonist, into these regions could not stop SIB. For examining the important area for the induction of SIB, we microinjected SKF-38393, D1 agonist, and/or LY-141865, D2 agonist (each 1 µg) into bilateral (or ipsilateral) caudate-putamen and substantia nigra. SIB was induced only in the case of D1 and D2 receptors in both the bilateral caudate putamen and bilateral substantia nigra being stimulated simultaneously by the mixed application of SKF-38393 and LY-141865. SIB was not induced by the sole injection of SKF-38393 into bilateral caudate-putamen or bilateral substantia nigra. These observations suggest that both caudate-putamen and nigral D1- and D2-like receptors are important for the induction of SIB, but, for cessation of SIB, up-regulated nigral D1 receptor is crucial.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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To examine the
dopamine-related neuronal circuits involving the SIB in neonatal
6-OHDA-treated dopamine-depleted rats, we performed immunocytochemistry
of TH and in vitro receptor autoradiography of
tritium-labeled D1 and D2 ligands. We found
that the destruction of both nigro-dorsal striatal (caudate-putamen)
and VTA-ventral striatal (nucleus accumbens and tuberculum olfactorium)
dopaminergic systems and, at the receptor level, the up-regulation of
nigral D1 receptors on terminals of the strionigral pathway
in the SNR were unique to SIB-manifesting rats (Yokoyama and Okamura,
1997
) (see table 1). It is generally accepted that
ventral and dorsal striatum receive respective information with
extensive and highly organized projections from the limbic and
somatosensory cortex, and arrange this information under the influence
of dopaminergic input in the striatum, and relay down to the pallidal
structures and SNR (Alexander and Crutcher, 1990; Hattori et
al., 1975). Thus our findings suggest that the above motor and
limbic information processing systems were impaired in L-DOPA-induced
SIB manifesting rats.
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To elucidate the important areas for the induction or cessation
of SIB, in our study, we performed a microinjection study of
dopaminergic agonists and antagonists into above impaired limbic and
motor information processing system in the caudate-putamen, nucleus
accumbens and substantia nigra. Because D1- and
D2-like dopamine receptors were extremely concentrated in
these loci, the application of D1 and D2
agonists are highly predicted as modulators of SIB induced by L-DOPA.
Before performing the brain microinjection study, we reexamined the
behavioral characteristics of SIB after the systemic injection of
D1 and D2 agonists and L-DOPA, by which some of
new behavioral findings were presented complementarily to the
description by Breese et al. (1984).
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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Animals
Progeny of pregnant Wistar rats was used. Neonatal rats were first given desipramine (20 mg/kg i.p.), and then 6-OHDA (100 µg/5 µl in saline containing 0.1% ascorbic acid) intracisternally on postnatal day 1 and day 3 under deep cold anesthesia. The protocol of this research was accepted by the Committee for Animal Research in Kyoto Prefectural University of Medicine.
Systemic Injection Study
At the age of 4 to 6 wk, L-DOPA (100 mg/kg i.p.) was loaded 30 min after Ro 4-4602 (50 mg/kg i.p.), and the behavior was evaluated, and the onset of SIB was examined. The repeated holding of their skin between their teeth was referred to SIB. Animal behavior was observed for 150 min in a clear plastic cage. Once SIB was confirmed, we stop the behavior immediately by injecting SCH-23390.
Previously SIB manifesting rats by systemic L-DOPA loading at young age (4-6 wk) were reexamined at their adult (3-5 mo) and older age (12-13 mo), to examine whether SIB is persistent for a life-long period. After habituation of these rats in a clear plastic cage for 30 to 60 min, L-DOPA (100 mg/kg) administered via i.p. route after 30 min of the pretreatment of Ro-4-4602 (50 mg/kg i.p). Animal behavior was observed for 150 min in a clear plastic cage.
Rats with SIB confirmed previously at a young age (4-6 wk) were used at their adult stage (3-5 mo) to examine the effect of dopamine agonists and antagonists. After habituation of these rats in a clear plastic cage for 30 to 60 min, apomorphine (0.25 mg/kg), SKF-38393 (10 mg/kg) or LY-141865 (1 mg/kg, 10 mg/kg) were administered via i.p. route. The inhibiting potentials of dopamine antagonists on the induction of SIB were also examined. SCH-23390 (1 mg/kg, 3 mg/kg) or YM-09151-2 (0.015 mg/kg, 0.5 mg/kg) was pretreated 15 min before the L-DOPA (100 mg/kg) treatment. Animal behavior was observed for 150 min in a clear plastic cage.
Intracerebral Microinjection
At 3 to 5 mo of age, selected L-DOPA-induced SIB manifesting
rats were deeply anesthetized with pentobarbital and ether. Guide and
dummy cannullae were implanted into 1) bilateral caudate-putamen (stereotaxic coordination: Bregma +0.7 mm, ML ± 2.0 mm, depth -4.2 mm from the surface) (n = 4), 2) bilateral nucleus
accumbens (Bregma +2.0 mm, ML ± 1.5 mm, depth -7.0 mm)
(n = 3), 3) bilateral substantia nigra (Bregma -5.3 mm,
ML ± 2.6 mm, depth -7.2 mm) (n = 14), 4) both
bilateral caudate-putamen and bilateral substantia nigra
(n = 12) (Bregma +0.7 mm, ML ± 2.0 mm, depth -4.2 mm; Bregma -5.3 mm, ML ± 2.6 mm, depth -7.2 mm), 5) both
bilateral nucleus accumbens and bilateral substantia nigra
(n = 8) (Bregma +2.0 mm, ML ± 1.5 mm, depth -7.0 mm; Bregma -5.3 mm, ML ± 2.6 mm, depth -7.2 mm). Injection to
substantia nigra was aimed to its lateral part, since the up-regulation
of D1-like receptor was more prominent in lateral half than
medial half in SIB(+) rats (Yokoyama and Okamura, 1997). After 8 to 96 hr when the anesthetic wears off, intracerebral injections were
performed. Three to 10 injection trials (average 5.75 trials) were
performed in each rat. Because rats showing SIB were exhausted, more
than one load of L-DOPA was not performed in a day. The order of
injection was not settled to avoid the effect of previous treatment.
However, in 30 of 41 experiments, we used SKF-38393 and SCH-23390 in
the rear of the treatment, because microinjection of these drugs
sometimes cause the tissue damage in preliminary experiment.
Cessation of L-DOPA induced SIB by microinjection of D1 and/or D2 antagonists. After 5 min of the SIB induction by the i.p. injection of L-DOPA (100 mg/kg), D1 antagonists (SCH-23390, 5 µg), D2 antagonist (YM-09151-2, 10 µg) or both [SCH-23390 (5 µg) plus YM-09151-2 (10 µg)] were injected into ipsilateral and bilateral caudate-putamen, nucleus accumbens and substantia nigra. Although the total amount of drugs was not changed, drugs were dissolved with different volumes (5 and 1 µl) of artificial cerebrospinal fluid (1.2 mM CaCl2, 2.4 mM KCl; 138.0 mM NaCl, 7.5 mM ascorbic acid; pH 7.0). The injection volumes were determined by the spread and the toxicity of the injected drugs. To decrease the toxicity, the concentration should be low. For the injection of caudate-putamen, large volume (5 µl) was chosen because the size of this area (diameter 3-3.5 mm) is very large. For the injection into smaller areas (substantia nigra and nucleus accumbens), we performed the injection of small (1 µl) volume to limit the drug effect more locally, in addition to large volume (5 µl). Injection was performed at the rate of 0.5 µl/min for 5 µl injection, and of 0.1 µl/min for 1 µl injection. Rats were observed for 2 hr after the injection.
Induction of SIB after microinjection of D1 and/or D2 agonists. D1 agonist (SKF-38393, 1 µg) and D2 agonist (LY-141865, 1 µg) were injected into 1) caudate putamen, 2) nucleus accumbens, 3) substantia nigra, 4) caudate-putamen and substantia nigra and 5) nucleus accumbens and substantia nigra. Similar to the above cessation experiment, drugs were dissolved in two different volumes (5 µl and 1 µl) of artificial cerebrospinal fluid, although the total drug dose was not changed. Animal behavior was observed at least for 120 min. After these observations, animals were decapitated, and each brain was fixed in 4% paraformaldehyde in 0.1 M phosphate-buffered saline. Brain sections were made with a cryostat to observe the injection region.
Reagents
YM-09151-2 was a gift from the Yamanouchi-Pharmaceutical Company (Tsukuba, Japan), and Ro-4-4602 from Roche-Japan (Tokyo, Japan). Apomorphine was purchased from Sigma (St. Louis, MO), SKF-38393, SCH-23390 and LY-141865 were purchased from Research Biochemicals Inc., MA). The guide cannulae (C315G, 26 gauge), internal cannulae (C315I, 33 gauge) and dummy cannulae (C315DC, 26 gauge) were purchased from Neuroscience Inc. (Tokyo, Japan).
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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Systemic Injection Study
The impairment of motor behaviors such as rigidity and tremor was not found in neonatal 6-OHDA-treated rats not only during developmental age, but also in adults. However, L-DOPA injection induced a tremendous behavioral change to these rats. We first challenge L-DOPA injection to all of rats at the age of 4 to 6 wk, and some of them were rechallenged at 3 to 5 mo and at 12 to 13 mo. In SIB-manifesting rats, the biting targets were toward their own body, not to other animals. SIB was different from the attack behavior such as muricide because SIB manifesting rats did not pay attention to nearby mice.
At 4 to 6 wk of age, 71 of 103 rats exhibited SIB following the L-DOPA loading. To examine the age dependent change of biting behavior, we reexamined the SIB rats at 3 to 5 mo and 12 to 13 mo. We found that all rats which showed SIB at 4 to 6 wk demonstrated SIB at 3 to 5 mo after L-DOPA loading (positive/total; 9/9) and at 12 to 13 mo (3/3).
The onset time of biting behavior was examined at 4 to 6 wk. The
beginning of SIB differed in each rat from 20 to 150 min. The maximal
induction time is 30 to 60 min after the L-DOPA loading (fig.
1). After 150 min, no rats initiated SIB.
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Rats with SIB confirmed previously at a young age (4-6 wk) were used at their adult stage (3-5 mo) for examining the effect of dopamine agonists and antagonists. Apomorphine (0.25 mg/kg), a mixed D1/D2 agonist, induced SIB at 33% (positive/total; 2/6). In case of SKF-38393 (10 mg/kg) administration, 83% (5/6) of rats showed SIB. LY-141865 (1 mg/kg, 10 mg/kg) could not induce SIB (0/4 and 0/2, respectively). One mg/kg pretreatment of SCH-23390 almost inhibited [SIB-positive was only 11% (1/9)], and 3 mg/kg administration of the drug completely suppressed the L-DOPA-induced SIB (0%; no positive per nine trials). Pretreatment of YM-09151-2 (0.015 mg/kg, 0.5 mg/kg) could not inhibit the induction of SIB by L-DOPA (all positive in 5 and 4 trials, respectively).
Microinjection Study
To directly test the possibility of importance of basal ganglia on the induction of SIB, we performed intracerebral microinjection studies (tables 2 and 3). We implanted the canula into bilateral striatum (or bilateral nucleus accumbens) and bilateral substantia nigra (lateral part; fig. 2) of the rat brain at 3 to 5 mo of age, in which SIB was previously confirmed.
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Cessation of L-DOPA induced SIB by microinjection of D1 and/or D2 antagonists. We performed i.p. L-DOPA loading (100 mg/kg) into canula-implanted rats. After the induction of SIB was confirmed, we microinjected D1 antagonist SCH-23390 or D2 antagonist YM-09151-2 into the previously implanted canula (table 2). Among the cases of unilateral or bilateral microinjections, only bilateral nigral SCH-23390 injections could stop SIB. Unilateral nigral injections of SCH-23390 could not stop SIB. Injections of SCH-23390 into bilateral caudate-putamen, bilateral nucleus accumbens, unilateral nucleus accumbens could not stop SIB, although the combination of bilateral nucleus accumbens and bilateral substantia nigra could stop SIB. None of the injection of YM-09151-2 into unilateral caudate-putamen, bilateral caudate-putamen, unilateral substantia nigra and bilateral substantia nigra could stop SIB. Application of YM-09151-2 into combination of bilateral caudate-putamen and bilateral substantia nigra, and that of the bilateral nucleus accumbens and bilateral substantia nigra, could not stop SIB.
Induction of SIB after microinjection of D1 and/or D2 agonists. To find the area important for the induction of SIB, we injected dopamine receptor agonists to the caudate-putamen, nucleus accumbens and the substantia nigra (table 3). We used SKF-38393 for D1 agonist, LY-141865 for D2 agonist. In all cases of SKF-38393 injection, SIB was not induced, except in one of five cases of SKF-38393 injection into the bilateral caudate-putamen. SIB was not induced by LY-141865 injection. Then we examined the effect of the stimulation of both D1- and D2-like receptors by the combined injection of SKF-38393 and LY-141865. In this case, the combination of bilateral caudate-putamen and bilateral substantia nigra application could induce SIB (9 positive of 11 trials including both 5 and 1 µl injection cases), although the sole application to bilateral caudate-putamen, bilateral substantia nigra or bilateral nucleus accumbens could not induce SIB. The combined applications to bilateral nucleus accumbens and bilateral substantia nigra could not induce SIB.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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Pharmacobehavioral studies using specific agonists and antagonists
have great contributions for understanding the role of dopamine to the
manifestations of SIB. SIB in neonatal 6-OHDA-lesioned rats was induced
by systemic loading of SKF-38393, a D1 agonist, but failed
to induce SIB by systemic loading of LY-141865, a D2 agonist (Breese et al., 1985). They also found that
L-DOPA-induced SIB was inhibited by the systemic injection of
SCH-23390, a D1 antagonist, but difficult to prevent by the
systemic injection of haloperidol, a mixed antagonist of
D1- and D2-like receptors (Breese et
al., 1985; Breese et al., 1984). From these findings it
is evident that L-DOPA-induced SIB is through the D1-like
receptors. We also confirmed these studies, and further found that the
D2-specific antagonist, YM-09151-2, could not inhibit SIB.
Although Breese et al. (1985, 1984) extensively studied the
pharmacobehavioral characteristics of SIB, and discovered that the
behavior is intimately linked to brain D1 receptor
function, the search for brain locus important for L-DOPA-induced SIB
has not been systematically examined. In previous studies, we found unique topography-dependent destruction of dopaminergic neurons, and
the change of dopaminergic receptors in SIB-manifesting rats. Based on
these findings, we applied dopamine agonists and antagonists into
selected brain loci, and examined their effect.
Self-injurious behavior after systemic injection of L-DOPA. Before performing a brain microinjection study, we examined the behavioral characteristics of SIB after the systemic injection of D1 and D2 agonists and L-DOPA. First, we examined whether SIB is a temporal or permanent phenomenon. By the developmental and aging studies, we found that most rats showing SIB at 4 to 6 wk demonstrated SIB again at 3 to 5 mo and 12 to 13 mo of age after L-DOPA loading. This suggests that SIB is not a temporal phenomenon, and the permanent alteration of neuronal transmission of the brain circuit underlies the behavior.
Brain locus important for self-injurious behavior.
To directly
test the possibility of the importance of basal ganglia on the
induction of SIB, we performed intracerebral microinjection studies.
After the induction of SIB by the i.p. L-DOPA loading, we microinjected
the D1 antagonist SCH-23390 or D2 antagonist YM-09151-2, into unilateral or bilateral striatum or substantia nigra.
Although we tried several injection combinations, only bilateral nigral
SCH-23390 injection was successful. This indicates that the striatal
D1-like receptor is not important for the cessation of SIB,
and the up-regulated nigral D1-like receptor is crucial for
the cessation of SIB. In the classical model of Parkinson's disease
using a unilateral 6-OHDA lesion of the substantia nigra, Robertson and
Robertson (Robertson and Robertson, 1989) reported that L-DOPA is
converted to dopamine in significant amounts within the 6-OHDA-lesioned
substantia nigra, and the activation of D1 dopamine
receptor in SNR is well correlated with the L-DOPA-induced circling
behavior.
).
Moreover this finding suggests the importance of caudate-putamen, in
addition to the substantia nigra, for the induction of SIB. Recently,
it is known that the c-fos1, an immediate early gene
indicating the metabolic activation of the cells, is induced in cells
of the caudate-putamen of the neonatal intracranial 6-OHDA treated rats
followed by the L-DOPA challenge (Johnson et al., 1992).
Thus, the activated caudate-putamen D2 expressing cells may
have some role for the induction process of SIB.
Hypothetical brain neuronal circuit important for SIB.
Figure
3 is an hypothetical figure for explaining the induction
and cessation of SIB. In this schema, basic neuronal circuits connecting the caudate-putamen and SNR is shown in the uppermost portion (A). The caudate-putamen receives strong excitatory
glutaminergic input from the cerebral cortex (Divac et al.,
1977; Spencer, 1976). Basal ganglia output neurons in the SNR, having
high ratios of spontaneous discharge, exert a tonic, GABA-mediated,
inhibitory effect on their target nuclei in the thalamus (Chevalier
et al., 1985; Deniau and Chevalier, 1985; Penney and Young,
1981). This inhibitory outflow is modulated by two pathways from the
caudate-putamen to the basal ganglia output nuclei: 1) "direct"
inhibitory pathway containing GABA, substance P and dynorphin (Albin
et al., 1989; Graybiel and Ragsdale, 1983), which activation
tends to disinhibit the thalamic neurons (Chevalier and Deniau, 1990;
Chevalier et al., 1985; Deniau and Chevalier, 1985), 2)
"indirect" pathway, which passes first to the globus pallidus by
phasically activating GABA/enkephalin neurons (Graybiel and Ragsdale,
1983), then from the globus pallidus to the subthalamic nucleus via
tonically active GABAergic neurons, and finally to SNR from the
subthalamic nucleus via an excitatory glutaminergic projection
(Nakanishi et al., 1987; Smith and Parent, 1988).
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).
Dopaminergic dendritic release in SNR (Cheramy et al., 1981)
stimulates the release of GABA from strionigral terminals (Reubi
et al., 1977). GABA release from the terminals of the
strionigral fibers inhibits the tonically active neurons in SNR
(Alexander and Crutcher, 1990), that project to thalamus, superior
colliculus and pedunculopontine nucleus. Contrary to this direct
strionigral pathway, dopamine seemed to exert an inhibitory effect on
striopallidal neurons consisting of "indirect" strionigral pathway.
Suppression of the inhibitory GABA/enkephalin projection from the
caudate-putamen tends to liberate the activity of the inhibitory
pallidal neurons and thereby inhibit the subthalamic nucleus,
decreasing the excitatory drive on the output nuclei and decreasing the
inhibition of efferent targets within the thalamus.
In neonatal 6-OHDA rats nonloaded by dopamine agonists (fig. 3B),
dopamine neurons are severely injured, thus, striatal stimulation and
dendritic release of dopamine may decrease. However, the up-regulation of D1-like receptors in the substantia nigra may have a
contradictory effect on the release of GABA in nigral terminals, and
thus overwhelmed the decrease of the inhibitory drive on SNR neurons.
In addition to the effect on this "direct" pathway, neonatal
dopamine depletion may influence the activity of neurons of the
"indirect" pathway. Because it is known that neonatal 6-OHDA
increased the enkephalin at its mRNA and peptide levels (Sivam et
al., 1987), striopallidal enkephalin/GABA neurons can be said to
be activated by neonatal 6-OHDA treatment, although
electrophysiological activity should be directly measured. Activation
of the inhibitory GABA/enkephalin neurons tends to suppress the
activity of the pallidal neurons and thereby disinhibit the subthalamic
neurons, increasing the excitatory drive on the SNR neurons. This
indirect "activating" influence turns off the exaggerated
"inhibitory" pulses from a direct pathway, and helps to send static
information to thalamic neurons.
In rats showing SIB loaded by dopamine agonists or L-DOPA (fig. 3C),
strionigral neurons are activated through D1- and
D2-like receptors. By stimulation of up-regulated
D1-like receptor in strionigral terminals in SNR by
D1 agonists, the GABA release may be more potentiated,
which inhibits the extrapyramidal output neurons in SNR. The
potentiation of "direct pathway" is not negated by the
"indirect" pathway. L-DOPA or dopamine agonists may suppress the
inhibitory GABA/enkephalin projection from the caudate-putamen, and
liberate the activity of the inhibitory pallidal neurons, and thereby
inhibit the subthalamic nucleus, decreasing the excitatory drive on the
SNR neurons. These changes of neurotransmission in "direct" and
"indirect" pathways may decrease the activity of SNR neurons, and
disinhibit thalamic neurons. Although the release of GABA has not been
measured previously in the SIB state, Breese et al. (1987)
reported that the muscimol, a GABAA receptor agonist, injection to substantia nigra induces SIB.
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Conclusion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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Recently, neurochemical and molecular approaches are becoming popular to complex behaviors such as this self-injurious behavior. The analysis of brain neuronal circuit using dopamine-deficiency model of SIB may be useful for resolving the mechanism. In this rat model, the only neurochemical factor that triggers SIB is dopamine. We tried to analyze the brain dopaminergic system focusing at their regional difference. We have demonstrated the destruction of both nigro-dorsal striatal system and VTA-ventral striatal system, and up-regulation of nigral D1 receptors in rats showing SIB. From these anatomical data, we tried the brain microinjection study, and found that the nigral D1-like receptor is crucial for the cessation, and both striatal and nigral D1- and D2-like receptors are important for the induction. However, no data are available for the factor determining the characteristics of behavior. For one possible candidate, the impairment of limbic striatal function, which is suggested by the destruction of VTA-ventral striatal dopaminergic neuron system, in SIB is interesting. Although SIB having various clinical expressions, will not be caused by a single neurological change, a trial for elucidation of the neuronal circuits of this experimental model, may make way for the therapy to the SIB.
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Acknowledgments |
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The authors thank Prof. Dai-ichiro Nakahara (Hamamatsu-Medical School) for teaching us the stereotaxic microinjection study and Dr. Yukio Ichitani (Tsukuba University School of Education) for useful discussion.
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Footnotes |
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Accepted for publication October 11, 1996.
Received for publication October 3, 1995.
1 This work was supported in parts by grants to H. O. from Uehara Memorial Foundation, Ciba-Geigy Foundation, Smoking Research Foundation, and Ministry of Education, Science and Culture, Japan.
2 Current address: Department of Anatomy, Kawasaki Medical School, Kurashiki 701-01, Japan.
Send reprint requests to: Dr. Hitoshi Okamura, Department of Anatomy and Brain Science, Kobe University School of Medicine, Kusunoki-cho, Chuo-ku, Kobe 650, Japan.
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Abbreviations |
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Acb, nucleus accumbens; 6-OHDA, 6-hydroxydopamine; SIB, self-injurious behavior; SNR, substantia nigra pars reticulata; L-DOPA, L-dihydroxyphenylalanine.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Conclusion
References
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The neonatal-6-OHDA-lesioned rat.
Brain Res. Bull.
25: 477-484, 1990[Medline].This article has been cited by other articles:
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  B. L. Schmidt, C. H. Tambeli, J. Barletta, L. Luo, P. Green, J. D. Levine, and R. W. Gear Altered Nucleus Accumbens Circuitry Mediates Pain-Induced Antinociception in Morphine-Tolerant Rats J. Neurosci., August 1, 2002; 22(15): 6773 - 6780. [Abstract] [Full Text] [PDF]
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