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Vol. 292, Issue 2, 743-751, February 2000
Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois.
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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In the present study, we investigated the effects of intrathecal gabapentin on nociceptive behaviors and the numbers of spinal Fos-like immunoreactive (Fos-LI) neurons evoked by injection of 0.25 to 2.5% formalin in the hindpaw of the rat. Pretreatment with gabapentin dose dependently decreased flinches and weighted pain scores in phase 2, but not phase 1, at each concentration of formalin. The highest dose of gabapentin (100 µg) shifted the EC50 values of formalin for both flinches and weighted pain scores to the right by 2.5-fold, suggesting that formalin was perceived to be significantly less noxious. Gabapentin also decreased phase 2 behaviors when administered after formalin but was only one third as potent. Unlike its inhibition of formalin-evoked nociceptive behaviors, the effect of gabapentin on the expression of Fos-like immunoreactivity in the spinal cord was highly dependent on the concentration of formalin. Intrathecal pretreatment with 100 µg of gabapentin did not decrease the numbers of Fos-LI neurons evoked by 0.5% formalin, yet this dose decreased the numbers of Fos-LI neurons in laminae I-II and VII-X of rats that received 1.25% formalin and uniformly decreased by 50% the numbers of Fos-LI neurons in all laminae of rats that received 2.5% formalin. These latter findings suggest that gabapentin neither nonselectively decreases the excitability of spinal cord neurons nor uniformly inhibits the release of all neurotransmitters from primary afferent terminals. Rather, its effects may be preferential for those neurotransmitters released by higher, more noxious concentrations of formalin and for conditions in which there is a greater induction of central sensitization.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Shortly
after its introduction for the treatment of partial seizures refractory
to conventional therapies (Goa and Sorkin, 1993
), gabapentin
(Neurontin) was reported to alleviate pain of neuropathic origin
(Mellick and Mellick, 1995; Segal and Rordorf, 1996; Samkoff et al.,
1997). These case reports were subsequently confirmed by a
retrospective case review (Rosenberg et al., 1997) and by prospective
double-blind, placebo-controlled studies (Backonja et al., 1998;
Rowbotham et al., 1998). Although the clinical efficacy of gabapentin
is well established, the sites and mechanisms responsible for its
antihyperalgesic and antiallodynic effects remain unclear (Taylor et
al., 1998). Studies in rats indicated that systemically administered
gabapentin was effective in many different models of neuropathic (Xiao
and Bennett, 1996; Hunter et al., 1997; Field et al., 1999; Pan et al.,
1999), inflammatory (Singh et al., 1996; Field et al., 1997b), or
tissue injury (Field et al., 1997a; Jones and Sorkin, 1998) pain.
However, gabapentin was essentially ineffective in models of acute pain
(Field et al., 1997b; Hunter et al., 1997; Partridge et al., 1998). The
spinal cord was proposed to be a principal site of action because
gabapentin readily crossed the blood-brain barrier (Welty et al., 1993)
and was also effective after intrathecal (i.t.) administration (Xiao
and Bennett, 1996; Hwang and Yaksh, 1997; Shimoyama et al., 1997; Field
et al., 1999).
In the present study, we sought to more thoroughly characterize the
effects of i.t. gabapentin. We first compared the effects of
pretreatment or post-treatment i.t. gabapentin in the formalin test, a
model of inflammatory nociception that is thought to involve central
sensitization mediated by
N-methyl-D-aspartate (NMDA) receptors
(Coderre and Melzack, 1992). Gabapentin may interact indirectly with
NMDA receptors because: 1) its effects are antagonized by
D-Ser, an agonist of the strychnine-insensitive
glycine site of the NMDA receptor (Singh et al., 1996; Partridge et
al., 1998); 2) it suppresses NMDA-induced thermal hyperalgesia
(Partridge et al., 1998); and 3) it is most effective in animal models
of central sensitization, which is mediated by NMDA receptors. As a
functional NMDA receptor antagonist, gabapentin could be expected to
preferentially suppress phase 2 behaviors in the formalin test and to
be effective only when administered as a pretreatment (Coderre and
Melzack, 1992; Yamamoto and Yaksh, 1992; Vaccarino et al., 1993). We
also examined the ability of gabapentin to suppress nociceptive
behaviors evoked by different concentrations of formalin. The extent to
which a drug shifts the concentration-response function of formalin to
the right can provide insight into its relative efficacy. Finally, we
examined whether i.t. pretreatment with gabapentin suppressed the
formalin-evoked expression of Fos-like immunoreactivity (Fos-LI) by
spinal cord neurons as reported for other antinociceptive agents.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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These experiments were conducted under a protocol approved by the Institutional Animal Care and Use Committee of the University of Chicago and in accordance with the "Guide for Care and Use of Laboratory Animals" of the National Institutes of Health.
Animals. Male Sprague-Dawley rats (Sasco, Kingston, NY; 300-350 g) were anesthetized with halothane. One end of a PE-10 catheter was introduced through a slit in the atlantooccipital membrane. In rats that were used for the behavioral analyses, the catheter was threaded caudally for 8.5 cm to position its tip at the L4-L5 segment of the spinal cord. In rats that were used for determination of Fos-LI, the catheter was threaded caudally for 7 cm to position its tip at the L1-L2 segment of the spinal cord and thereby avoid nonspecific induction of Fos-LI in the L4-L5 segments. The other end of the catheter was tunneled s.c. and externalized at the top of the head. The rats were housed individually after surgery and allowed 5 to 7 days to recover before testing.
Formalin Test.
Animals were placed individually in Plexiglas
testing chambers and allowed to acclimate for at least 1 h. A
mirror was situated behind the chamber and another was situated below
the floor of the chamber to allow an unobstructed view of the rat's
paws. Saline or gabapentin (30 or 100 µg) was injected i.t. either 10 min before or 7 to 8 min after the s.c. injection of 100 µl of 0.25, 0.5, 1.25, or 2.5% formalin in the plantar surface of the left
hindpaw. The weighted pain score and the number of flinches that
occurred during the next 60 min were then recorded in 5-min intervals
as previously described (Kaneko and Hammond, 1997). The weighted pain
score was calculated by multiplying the amount of time spent in each of
four categories by its assigned weight, summing these products, and
then dividing by the total time in each 5-min block of time. The four
categories of behavior and their respective weights were as follows:
normal weight bearing by the injected paw, 0; limping or resting the
paw lightly on the floor, 1; elevation of the injected paw with at most
the tip of the nails in contact with the floor, 2; and licking, biting,
or shaking the injected paw, 3. Animals were used only once in this
study and received only one dose of drug and one concentration of
formalin. Doses of gabapentin higher than 100 µg were not
administered due to the occurrence of moderate muscle weakness in the
hindlimbs (M.K., C.M., E.H.S., and D.L.H., unpublished observations;
Hwang and Yaksh, 1997; Partridge et al., 1998).
). The significance of differences in the
EC50 values for formalin in gabapentin- and
saline-treated rats was determined by ANCOVA. A value of
P 
.05 was considered significant.
Immunohistochemistry. The immunohistochemical study was restricted to an analysis of the effect of i.t. pretreatment with either 100 µg of gabapentin or saline on the expression of Fos-LI by injection of either 0.5, 1.25, or 2.5% formalin in the plantar surface of the left hindpaw. Comparison of the antinociceptive effect of 100 µg of gabapentin in these rats, which were outfitted with a slightly shorter catheter, with its antinociceptive effect in rats outfitted with the conventional length catheter revealed no significant differences (data not shown). Thus, the use of the slightly shorter catheter to facilitate visualization of Fos-LI did not pose a confound for this study.
Rats were deeply anesthetized with 60 mg/kg pentobarbital i.p. 90 min after the injection of formalin and perfused intracardially with 50 ml of 0.05 M PBS, pH 7.4, at 37°C, followed by 400 ml of 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, at 4°C. The spinal cord was removed from the vertebral canal and placed in fresh fixative at 4°C for an additional 90 min. The tissue was then cryoprotected in 0.1 M phosphate buffer containing 30% sucrose for at least 48 h. Transverse sections (25 µm) were cut every 250 µm through the L2, L3, L4, and L5 segments of the spinal cord such that eight sections were collected for each segment. The sections were rinsed twice in 0.1 M PBS, incubated for 20 min in 1.67% hydrogen peroxide in 50% methanol, and washed four times in 0.1 M PBS. The sections were then exposed to 1% sodium borohydride for 30 min, followed by four washes in 0.1 M PBS. After immersion in PBS containing 2% normal rabbit serum and 0.3% Triton X-100 for 30 min, the sections were incubated for 48 h at 4°C in a sheep polyclonal antiserum directed against amino acids 2-17 of the protein product of the human c-fos gene (OA-11-824; Genosys Biotechnologies, The Woodlands, TX) at a dilution of 1:3000 in PBS containing 2% normal rabbit serum and 0.3% Triton X-100. This antibody recognizes Fos and Fos-related antigens. After incubation in the primary antibody, the tissue was washed three times in 0.1 M PBS and then transferred to a rabbit anti-sheep biotinylated secondary IgG complex for 2 h at room temperature. After three washes in 0.1 M PBS, the sections were then exposed to the ABC complex (Elite Vectastain; Vector Laboratories; Burlingame, CA) for 1 h at room temperature. The chromagen was developed using diaminobenzidine and hydrogen peroxide (DAB Substrate Kit; Vector Laboratories). Tissue sections were thoroughly rinsed with 0.1 M phosphate buffer, mounted from distilled water onto gelatin-coated slides, air dried, dehydrated in a series of graded alcohols, cleared in xylenes, and coverslipped. For the quantification of Fos-LI, each section of the spinal cord was divided into four regions of interest: 1) the superficial laminae (laminae I, IIo, and IIi), 2) the nucleus proprius (laminae III and IV), 3) the neck of the dorsal horn (laminae V and VI), and 4) the ventral horn (laminae VII-X). Three sections from each of the four segments of the spinal cord were randomly selected for quantification of Fos-LI by a person with no knowledge of the treatment conditions. The number of Fos-LI neurons in a particular region and segment for that rat was determined by averaging the counts in the three sections. The counting was also done by a person with no knowledge of the treatment conditions. For statistical analysis, the number of Fos-LI neurons in each region and segment of the spinal cord was expressed as the mean ± S.E. of these values in all the rats in that treatment group. Two-way ANOVAs were used to compare the effects of different concentrations of formalin on the number of Fos-LI neurons in the different regions of a particular segment of the spinal cord or on the number of Fos-LI neurons in the same region from different segments of the spinal cord. These analyses revealed that there were no significant differences in the numbers of Fos-LI neurons in the corresponding regions of the L4 and L5 segments and that Fos-LI neurons were predominantly restricted to the L4 and L5 segments. The data from the L4 and L5 segments were therefore pooled, and the numbers of Fos-LI neurons were estimated from a total of six sections spanning the L4 and L5 segments of the spinal cord. Two-way ANOVAs were used to compare the effects of gabapentin and saline on the number of Fos-LI neurons. Post hoc comparisons of individual mean values were made with a Newman-Keuls test. A value of P .05 was considered statistically significant.
Drugs and Injections. Gabapentin (free base, lot 45) was provided by Dr. Charles Taylor (Parke-Davis/Warner-Lambert Co., Ann Arbor, MI). Drug solutions were made fresh, adjusted to pH 6.8-7.1, and injected i.t. in a volume of 10 µl followed by a 10 µl volume of saline to clear the catheter. The location of the catheter was verified by direct visualization of the tip of the catheter after laminectomy. In rats used only for the behavioral analysis, proper placement of the catheter was determined by the occurrence of hindlimb paralysis after an i.t. injection of 10 µl of 2% tetracaine hydrochloride.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Effect of i.t. Pretreatment with Gabapentin on Formalin-Evoked
Nociceptive Behaviors.
The i.t. pretreatment with either 30 or 100 µg of gabapentin produced a dose-dependent decrease in the number of
flinches and in the weighted pain scores in phase 2 at each
concentration of formalin compared with saline-treated rats (Figs.
1 and 2). This antinociceptive effect was also apparent as a respective 1.8- and
2.5-fold rightward shift in the concentration-response relationship of
formalin for the number of flinches (Fig.
3A) and a respective 1.7- and 2.6-fold
rightward shift in the concentration-response relationship of formalin
for weighted pain score in phase 2 (Fig. 3C and Table
1). These results indicate that formalin
was significantly less noxious in the presence of gabapentin.
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Effect of i.t. Post-Treatment with Gabapentin on Formalin-Evoked
Nociceptive Behaviors.
Intrathecal post-treatment with 100 µg of
gabapentin significantly decreased both the number of flinches and the
weighted pain score in phase 2 compared with saline-treated rats (Figs. 4 and 5).
It also shifted the concentration-response relationship of formalin to
the right in both measures (Fig. 3 and Table 1). Interestingly, the
EC50 values of formalin for rats in which 100 µg of gabapentin was administered 7 to 8 min after formalin were equivalent to that obtained when 30 µg of gabapentin was administered 10 min before formalin (Table 1). This result indicates that 100 µg
of gabapentin was about one third as potent when administered as a
post-treatment than as a pretreatment. Intrathecal post-treatment with
30 µg of gabapentin did not decrease either the number of flinches or
weighted pain scores in phase 2. Consistent with this finding, the
concentration-effect curves for formalin in rats that received 30 µg
of gabapentin did not differ from those of saline-treated rats (Fig. 3
and Table 1).
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Effect of i.t. Pretreatment with Gabapentin on Formalin-Evoked Fos-LI in Spinal Cord. Although a systematic analysis was not undertaken, examination of the numbers of Fos-LI neurons in the contralateral spinal cord indicated that the basal expression of Fos-LI was low despite the presence of the i.t. catheter. For example, Fos-LI neurons rarely exceeded one per section in the superficial laminae, three per section in the nucleus proprius, and five per section in laminae V-VI or VII-X in the contralateral spinal cord of saline-treated rats that received the lowest concentration of formalin (0.5%). Gabapentin by itself did not induce the expression of Fos-LI in spinal cord neurons. Thus, similar numbers of Fos-LI neurons (<3 neurons/region) were observed in the contralateral L2 and L3 segments of the spinal cord (at the tip of the catheter) of gabapentin- and saline-treated rats that received 0.5% formalin.
The s.c. injection of 100 µl of 0.5, 1.25, or 2.5% formalin in one hindpaw of saline-treated rats induced a concentration-dependent increase in the number Fos-LI neurons in the spinal cord (Figs. 6-8). Fos-LI neurons were predominantly restricted to the ipsilateral spinal cord, although the highest concentration of formalin also evoked a small but significant number of Fos-LI neurons (8-10 neurons/region) in the contralateral spinal cord. For each concentration of formalin, the largest numbers of Fos-LI neurons occurred in the L4 and L5 spinal segments. Within these segments, the largest numbers of Fos-LI neurons were clustered in the medial aspects of laminae I-II and distributed throughout the mediolateral extent of laminae V-VI, with significantly fewer labeled neurons in the nucleus proprius or ventral horn (Fig. 6). Fewer Fos-LI neurons were present in the L3 segment and even fewer were present in the L2 segment of the spinal cord (data not shown).
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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 confirmed that i.t. pretreatment with gabapentin
dose dependently inhibits nociceptive behaviors in phase 2, but not
phase 1, of the formalin test (Shimoyama et al., 1997; Yoon and Yaksh,
1999). Additionally, this study assessed the ability of gabapentin to
inhibit the nociceptive behaviors elicited by formalin concentrations
ranging from 0.25 to 2.5%. This approach enabled the construction of a
concentration-effect relationship for formalin and a quantitative
estimate of the perceived noxious intensity of this stimulus (Kaneko
and Hammond, 1997). The extent to which a drug shifts the
concentration-effect relationship of formalin to the right (i.e.,
renders the formalin less noxious) can provide an estimate of its
relative efficacy as an antinociceptive agent. It can also be used to
compare efficacies within and among different pharmacological classes
of antinociceptive agents. The 2.5-fold rightward shift in the
EC50 value for formalin indicates that it was
perceived to be about one half as noxious a stimulus after the i.t.
administration of 100 µg of gabapentin.
This study also determined that gabapentin was effective when
administered 7 to 8 min after the injection of formalin, when phase 1 nociceptive behaviors are fully expressed. Post-treatment with 100 µg
of gabapentin shifted the concentration-effect relationship of formalin
by 1.7-fold to the right, which was equivalent to that produced by
pretreatment with 30 µg of gabapentin. This finding suggests that
gabapentin is one third as potent when administered as a
post-treatment. The ability of gabapentin to suppress formalin-evoked pain behaviors when administered after formalin is consistent with its
reversal of established thermal hyperalgesia and tactile allodynia in
the carrageenan model of inflammatory nociception (Field et al.,
1997b). The ability of gabapentin to suppress formalin-evoked nociceptive behaviors when administered as either a pretreatment or
post-treatment distinguishes it from NMDA receptor antagonists, which
are ineffective when administered after formalin (Coderre and Melzack,
1992; Yamamoto and Yaksh, 1992; Vaccarino et al., 1993). This
difference in time dependence is indirect evidence that gabapentin does
not interact directly with the NMDA receptor (Taylor et al., 1998).
The present study determined that progressively higher concentrations
of formalin induced increasing numbers of Fos-LI neurons in the spinal
cord. This observation is consistent with previous reports that the
expression of Fos-LI by spinal cord neurons is dependent on the
intensity of the noxious stimulus (Abbadie et al., 1994; Honoré
et al., 1995; Willcockson et al., 1995) and supports the idea that
these concentrations of formalin produce different intensities of
nociception. Behaviorally, 1.25% formalin elicited more flinches and
nociceptive behaviors than 0.5% formalin, which itself elicited more
flinches and nociceptive behaviors than 0.25% formalin. At 2.5%
formalin, there was a much smaller increase in the number of flinches
and nociceptive behaviors relative to 1.25% formalin such that the
concentration-response curve began to plateau (present study; Kaneko
and Hammond, 1997). Because the number of Fos-LI neurons was
significantly greater in rats that received 2.5% compared with 1.25%
formalin, the plateau in the behavioral responses to 1.25 and 2.5%
formalin probably reflects limitations on the number of flinches and
the duration of lifting and licking that an animal can exhibit in a
5-min period.
The effects of gabapentin on the expression of Fos-LI by spinal cord
neurons were highly dependent on the concentration of formalin.
Although gabapentin suppressed nociceptive behaviors evoked by 0.5%
formalin, it did not decrease the numbers of Fos-LI neurons in any
region or segment of the spinal cord at this concentration. Such a
dissociation between the occurrence of behavioral antinociception and
the lack of inhibition of Fos-LI in the spinal cord, particularly in
the superficial laminae, has been previously noted with opioid receptor
agonists (Gogas et al., 1996a; Hammond et al., 1998). Given that
gabapentin did not inhibit the expression of Fos-LI evoked by a low
concentration of formalin, it was surprising that it inhibited the
expression of Fos-LI evoked by higher, more noxious concentrations of
formalin. Indeed, gabapentin appeared to be more effective as the
concentration of formalin increased. The mechanism for this effect is
unclear, but the data do permit speculation. The uniform decrease in
numbers of Fos-LI neurons in all laminae of rats that received 2.5%
formalin could result from a nonselective reduction in the excitability
of all spinal cord neurons. Were that the case, then gabapentin would
have uniformly decreased the numbers of Fos-LI neurons in all laminae
regardless of the concentration of formalin. Moreover, the inhibition
of Fos-LI neurons evoked by the lower concentrations of formalin would
have been proportionately greater. Alternatively, the uniform decrease in numbers of Fos-LI neurons in rats that received 2.5% formalin suggests that gabapentin may act "early" in the afferent pain pathway to reduce afferent drive at the first synapse and thereby effectively diminish the activation of all neurons subsequent in the
pathway. If this were the case, then the numbers and distribution of
Fos-LI neurons evoked by 2.5% formalin in rats pretreated with 100 µg of gabapentin should approximate the numbers and distribution of
Fos-LI neurons in saline-treated rats that received 1.25% formalin. This prediction is based on the behavioral data, which suggest that
formalin is one half as noxious in the presence of 100 µg of
gabapentin. This prediction was borne out by the data. In rats pretreated with 100 µg of gabapentin, the numbers of Fos-LI neurons evoked by 2.5% formalin in laminae I-II, III-IV, V-VI, and VII-X of the L4 and L5 segments were 21.1 ± 2.9, 10.2 ± 2.6, 25.1 ± 4.3, and 15.6 ± 2.8, respectively. By comparison,
the numbers of Fos-LI neurons evoked by 1.25% formalin in
saline-treated rats in these same laminae were 28.6 ± 1.8, 11.6 ± 1.2, 36.6 ± 3.3, and 26.6 ± 2.8, respectively.
In rats that received 1.25% formalin, gabapentin selectively decreased
the numbers of Fos-LI neurons only in the superficial laminae and in
the ventral horn. The differential effects of gabapentin at 0.5%
(i.e., no effect), at 1.25% (selective reduction), and at 2.5%
(uniform reduction) formalin suggest that gabapentin does not uniformly
inhibit the release of all primary afferent neurotransmitters but may
preferentially inhibit the release of those evoked by highly noxious
stimuli that evoke prolonged, high-frequency discharges in
small-diameter primary afferents and induce significant central
sensitization and windup. The above proposals are based on the premise
that similar pharmacological mechanisms subserve the nociceptive
behaviors evoked by 0.5, 1.25, and 2.5% formalin. However, the
differential effects of gabapentin could be alternately interpreted to
indicate that different pharmacological mechanisms subserve the
nociceptive behaviors evoked by the different concentrations of
formalin. Under this premise, delineation of the specific mechanisms
that mediate nociceptive behaviors evoked by 0.5, 1.25, and 2.5%
formalin could very well identify, albeit indirectly, the mechanisms
that mediate the antihyperalgesic and antiallodynic effects of gabapentin.
Finally, many studies have examined the effects of different
pharmacological classes of antinociceptive agents on the numbers of
Fos-LI neurons evoked by a thermal or chemical noxious stimulus. A
common finding is that the lowest doses of these agents that produce
antinociception generally decrease numbers of Fos-LI in the deep dorsal
horn to a greater extent than in the superficial laminae (Presley et
al., 1990; Tölle et al., 1990; Pertovaara et al., 1993; Chapman
et al., 1995; Honoré et al., 1995; Gogas et al., 1996b). Unlike
these agents, gabapentin preferentially decreased Fos-LI neurons in the
superficial laminae and in the ventral horn in rats treated with 1.25%
formalin but did not affect those in the nucleus proprius or the deep
dorsal horn. In this respect, gabapentin bears some resemblance to i.t.
NMDA receptor antagonists, which appear to preferentially decrease the
numbers of Fos-LI neurons in the superficial laminae (Kehl et al.,
1991; Huang and Simpson, 1999). The present study also differs from previous studies in its use of a range of stimulus intensities. Previous studies of drug effects on Fos-LI have exclusively used a
nociceptive stimulus of fixed intensity and have varied the dose of the
drug. By comparison, the present study used the inverse approach, in
which the effect of a single, maximally tolerated dose of drug was
examined against a range of stimulus intensities. The resulting data
indicate that the effects of gabapentin are highly stimulus-dependent.
Whether this pattern of differential suppression of Fos-LI neurons is
unique to gabapentin and others of its pharmacological class or is an
as-yet-unrecognized action of other pharmacological classes of
antinociceptive agents remains to be determined.
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Acknowledgments |
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We thank Dr. Aldric Hama for his assistance in the initial studies to establish the optimal conditions for the Fos immunohistochemistry.
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Footnotes |
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Accepted for publication November 8, 1999.
Received for publication August 4, 1999.
1 This work was supported by an unrestricted grant from Parke-Davis/Warner Lambert.
2 These authors contributed equally to this work.
3 Current address: Neuroscience Program, University of Arizona, 611 Gould-Simpson Bldg., P.O. Box 210077, Tucson, AZ 85721.
4 Department of Toxicology, Pfizer, Z1 Poce-sur-Cisse BP159, Amboise 37401, France.
Send reprint requests to: Donna L. Hammond, Ph.D., Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Ave., MC 4028, Chicago, IL 60637. E-mail: dh15{at}midway.uchicago.edu
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Abbreviations |
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i.t., intrathecal; Fos-LI, Fos-like immunoreactive(ity); NMDA, N-methyl-D-aspartate.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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and µ opioid receptor agonists on formalin-evoked nociception and the expression of Fos-immunoreactivity in the spinal cord of the rat.
J Pharmacol Exp Ther
284:
378-387
-aminobutyric acid block secondary hyperalgesia.
Brain Res
810:
93-99[Medline].-aminobutryic acidA receptors in formalin-induced nociception in the rat.
J Pharmacol Exp Ther
282:
928-938-aminobutyric acid on substance P-induced thermal hyperalgesia.
Anesthesiology
88:
196-205[Medline].This article has been cited by other articles:
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) or
with 30 (
) or 100 (
) µg of gabapentin on the number of flinches
evoked by 0.25, 0.5, 1.25, or 2.5% formalin. Saline or gabapentin was
administered i.t. 10 min before s.c. injection of formalin (arrow) into
the plantar surface of one hindpaw. Each symbol represents the
mean ± S.E. of determinations made in four or five rats.
). Data are expressed
as the mean ± S.E. of determinations in three or four rats for
each treatment condition.