Gabapentin Suppresses Ectopic Nerve Discharges and Reverses Allodynia in Neuropathic Rats1
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0022-3565/99/2883-1026$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 288, No. 3
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A.
JPET 288:1026 –1030, 1999
Gabapentin Suppresses Ectopic Nerve Discharges and
Reverses Allodynia in Neuropathic Rats1
HUI-LIN PAN, JAMES C. EISENACH, and SHAO-RUI CHEN
Departments of Anesthesiology, Physiology, and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
Accepted for publication October 8, 1998 This paper is available online at http://www.jpet.org
ABSTRACT
Repetitive ectopic discharges from injured afferent nerves play ated allodynia in nerve-injured rats. Furthermore, gabapentin, in
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an important role in initiation and maintenance of neuropathic the same therapeutic dose range, dose-dependently inhibited
pain. Gabapentin is effective for treatment of neuropathic pain the ectopic discharge activity of 15 injured sciatic afferent nerve
but the sites and mechanisms of its antinociceptive actions fibers through an action on impulse generation. However, the
remain uncertain. In the present study, we tested a hypothesis conduction velocity and responses of 12 normal afferent fibers
that therapeutic doses of gabapentin suppress ectopic afferent to mechanical stimulation were not affected by gabapentin.
discharge activity generated from injured peripheral nerves. Therefore, this study provides electrophysiological evidence
Mechanical allodynia, induced by partial ligation of the sciatic that gabapentin is capable of suppressing the ectopic dis-
nerve in rats, was determined by application of von Frey fila- charge activity from injured peripheral nerves. This action may
ments to the hindpaw. Single-unit afferent nerve activity was contribute, at least in part, to the antiallodynic effect of gaba-
recorded proximal to the ligated sciatic nerve site. Intavenous pentin on neuropathic pain.
gabapentin, in a range of 30 to 90 mg/kg, significantly attenu-
Classical anticonvulsant drugs have a long history of use in of hyperexcitable state of central sensory neurons (Yoon et
treatment of chronic pain, particularly neuropathic pain (Mc- al., 1996). Recently, systemic gabapentin has been shown to
Quay et al., 1995). Gabapentin (Neurontin), a structural an- inhibit spinal dorsal horn neurons in nerve injured rats
alog of g-aminobutyric acid (GABA), is a new anticonvulsant (Chapman et al., 1998). It remains to be determined whether
that is effective for alleviating neuropathic pain in animal therapeutic doses of gabapentin have any effect on sponta-
models as well as in patients (Mellick et al., 1995; Rosner et neous discharges originated from injured peripheral nerves.
al., 1996; Hunter et al., 1997). However, its pharmacological A typical pattern of nerve injury-induced neuroma is repeti-
actions are different from other substances that interact at tive bursting discharge activity, which is similar to electro-
GABA synapses because it does not bind to GABA receptors physiological alterations of central neurons causing epilepsy
or any known neurotransmitter receptors (Rock et al., 1993; (Rock et al., 1993; Wamil and McLean, 1994). Thus, we
Taylor et al., 1998). There has been no substantial evidence wondered whether gabapentin possesses an inhibitory effect
as to the primary site(s) and mechanisms of action that on the ectopic afferent activity generated from injured pe-
contribute to the analgesic effect of gabapentin on neuro- ripheral nerves. The aim of the present study was to examine
pathic pain. the effect of gabapentin on ectopic discharge activity from the
Although the pathogenesis of allodynia (normally innocu- injured sciatic nerve and allodynia in an animal model of
ous stimuli become painful) after a peripheral nerve injury is neuropathic pain.
not fully known, continuous discharges from ectopic foci are
known to contribute to maintenance of neuropathic pain Materials and Methods
(Sheen and Chung, 1993; Matzner and Devor, 1994; Ossipov
et al., 1995). Ectopic discharge activity from injured periph- Male rats (Harlan Sprague-Dawley) weighing 250 to 300 g were
used in this study. Under halothane anesthesia, the right jugular
eral afferent nerves has been proposed as a driving force for
vein was cannulated with PE 50 tubing and the catheter was exter-
sensitization of spinal dorsal horn neurons and maintenance
nalized to the back of the neck. The left sciatic nerve was exposed
and isolated at midthigh and one-third to one-half of the nerve was
ligated tightly with a 5-0 silk suture, according to the method de-
Received for publication July 17, 1998.
1 scribed previously (Seltzer et al., 1990). The animals were allowed to
This study was supported by grant GS-30 (to H.-L.P.) from the American
Heart Association, Mid-Atlantic Affiliate and by Grants HL-60026 (to H.-L.P.) recover for 14 to 18 days before electrophysiological recording or
and GM-35523 (to J.C.E.) from the National Institutes of Health. behavioral testing. The surgical preparations and experimental pro-
ABBREVIATION: GABA, g-aminobutyric acid.
10261999 Gabapentin, Ectopic Afferent Discharge, and Allodynia 1027
tocols were approved by the Animal Care and Use Committee at was recorded for 15 to 30 min. Then, saline or gabapentin was
Wake Forest University School of Medicine. injected i.v. at cumulative doses of 10, 30, 60, and 90 mg/kg (the
To quantify mechanical sensitivity of the paw, rats were placed in actual dose of gabapentin injected was 10, 20, 30, and 30 mg/kg),
individual plastic boxes on a mesh floor and allowed to acclimate for each separated by 15 min. The animals were dosed at an interval
30 min. A series of von Frey filaments (filament numbers 3.61–5.46; identical with that used for the behavioral study. We used the fol-
Stoelting Co., Wood Dale, IL) were applied perpendicularly to the lowing two criteria to ensure that the recorded activity was ectopic
plantar surface of the left paw with sufficient force to bend the discharges originating from the neuromas: 1) recorded nerve fibers
filaments for 6 s. Brisk withdrawal or paw flinching were considered had no receptive field in the peripheral tissue, and 2) at the end of
as positive responses. In the absence of a response, the filament of recording, the ectopic discharge activity was increased by direct
next greater force was applied. In the presence of a response, the stimulation of the neuroma but was not altered by transecting the
filament of next lower force was applied. The tactile stimulus pro- nerve distal to the neuroma site. In addition, after observing the
ducing a 50% likelihood of withdrawal response was calculated by inhibitory effect of gabapentin on the ectopic discharges from the
using the “up-down” method as described in detail before (Chaplan et injured afferents, we determined whether gabapentin had any effect
al., 1994; Pan et al., 1998). Each trial was repeated two to three times on responses of normal Ad- and C-fibers to mechanical stimulation
at approximately 2-min intervals, and the mean value was used as (these normal afferent fibers usually have no spontaneous discharg-
the force to produce withdrawal responses. After baseline thresholds es). Single-unit activity of afferent fibers were recorded from the left
of withdrawal response to von Frey filament stimulation were deter- sciatic nerve in separate, normal rats. The conduction velocity of
mined, animals received i.v. injections of saline (n 5 6) or gabapentin normal afferents and injured afferent fibers was measured by elec-
(n 5 8) at 15-min intervals. The actual dose of gabapentin injected trical stimulation of the sural nerve and the sciatic nerve just prox-
imal to the ligated site, respectively. Conduction time was deter-
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was 10, 20, 30, and 30 mg/kg to yield a cumulative dose of 10, 30, 60,
and 90 mg/kg. Based on a previous study, the elimination half-life of mined by measuring the time interval from the signal of electrical
gabapentin from plasma in rats is about 2 to 3 h after i.v. injection stimulation to recording of the evoked afferent’s action potential,
(Vollmer et al., 1986). The mechanical thresholds were determined displayed on the oscilloscope. C- and Ad-fiber afferents were classi-
every 15 to 30 min after each injection. In five separate normal rats, fied as those with a conduction velocity ,2.5 and 2.5 to 15 m/s,
we injected i.v. 90 mg/kg of gabapentin to determine whether it respectively. After the receptive fields of afferents were precisely
alters the paw-withdrawal response to the application of von Frey located, afferent responses to topical application of calibrated von
filaments (i.e., analgesic effect). Frey filaments were examined before and after i.v. injection of 90
Allodynic conditions were confirmed in all rats before afferent mg/kg of gabapentin. Gabapentin (Parke-Davis Pharmaceutical Re-
nerve recording experiments. Rats were anesthetized with an i.p. search, Ann Arbor, MI) was dissolved in normal saline and injected
injection of sodium phenobarbital (Nembutal, 45 mg/kg). The left in a volume of 0.2 ml followed by a 0.1-ml flush with saline.
carotid artery was cannulated for monitoring the blood pressure. The Data are presented as mean 6 S.E.M. Discharge activity of affer-
trachea was cannulated and the rat was ventilated artificially. Ar- ents was averaged before and after each gabapentin treatment.
terial blood gases were analyzed with a blood gas analyzer and Paw-withdrawal thresholds in response to mechanical stimulation
maintained within physiological limits. Body temperature was main- before and after nerve ligation and evoked responses of normal
tained in the range of 37–38°C with a circulating water heating pad afferents by mechanical stimulation before and after gabapentin
and heat lamps throughout the experiment. treatment were compared by using a paired Student’s t test. The
The fascia and sheath overlying the left sciatic nerve were re- effects of gabapentin on allodynia and afferent activity were deter-
moved carefully. The nerve then was draped on a platform and mined by analysis of variance followed by the Dunnett’s post hoc test.
covered with warm mineral oil. Small nerve filaments were teased P , .05 was considered to be statistically significant.
gently from the nerve segment proximal to the ligated site under an
operating microscope (model M900; D.F. Vasconcellos S.A., São
Paulo, Brazil). Single-unit afferent nerve activity was recorded with Results
a bipolar stainless electrode. The nerve filaments were dissected
gradually until single-unit activity of afferents was isolated. The Behavioral Studies. Paw-withdrawal threshold in re-
action potential of the afferent was amplified and processed through sponse to application of von Frey filaments before sciatic
an audioamplifier (model AM8; Grass Instrument, W. Warwick, RI) nerve ligation was 32.4 6 2.1 g. The mechanical threshold
and an oscilloscope (model 450; Gould, Cleveland, OH). The neuro- decreased significantly (4.1 6 0.7 g, P , .05) within 7 days
gram was recorded on a thermal-sensitive recorder (model K2G; after nerve ligation and remained stable for at least 3 weeks
Astro-Med, W. Warwick, RI). The single unit was identified initially in all animals studied. Three animals were excluded from the
by examining the wave form and the spike amplitude on the oscillo-
study because the withdrawal threshold was .8 g after nerve
scope at a rapid sweep speed as well as by checking the recorded
ligation. I.v. injection of saline did not affect significantly the
sound frequency related to each spike activity. Furthermore, the
signals were digitized at a sampling rate of 20 kHz and recorded into allodynic state (n 5 6, Fig. 1). Intravenous injection of 30 to
a Pentium computer through an analog-to-digital interface card for 90 mg/kg gabapentin increased significantly the withdrawal
subsequent off-line analysis. An amplitude threshold was set for the threshold in eight other rats in a dose-dependent manner
recorded action potential of nerve fibers. When an event was de- (Fig. 1). The threshold after i.v. injection of 90 mg/kg gaba-
tected, the associated wave form (6 ms) would be extracted and pentin was slightly higher than that obtained before nerve
displayed continuously in a separate software oscilloscope window ligation, but such a difference was not statistically signifi-
(DataWave Technology, Inc., Longmont, CO). Single-unit recording cant. Gabapentin administration was not associated with
was ensured by checking the constancy of the shape and polarity of any overt behavioral changes except this increase in with-
the displayed spike wave form. Discharge frequency was quantified
drawal threshold. Only at a high dose (90 mg/kg), gabapentin
by using data acquisition and analysis software (DataWave Technol-
appeared to have a slight calming effect on the animals’
ogy), and a histogram was created for each afferent. Accurate count-
ing of the afferent discharge frequency was verified for each afferent exploratory behavior. In addition, i.v. injection of 90 mg/kg
by comparing the constructed histogram with the hard copy, which gabapentin did not change the mechanical threshold of five
was recorded simultaneously. normal rats. The paw-withdrawal threshold was 35.5 6 6.3
After the spontaneous discharge activity of a single-unit afferent and 34.3 6 6.3 g (P . .05) before and after treatment with
from the injured nerve site was identified, the baseline discharge gabapentin, respectively.1028 Pan et al. Vol. 288
and to the on-off bursting cycle. As the dose increased, gaba-
pentin did not change the interspike intervals. Rather, the
average duration of off-periods lengthened progressively as
that of on-periods shortened gradually (Fig. 2).
In 12 additional rats, i.v. injection of 90 mg/kg gabapentin
did not alter the response of 12 normal afferent fibers to
mechanical stimulation, evoked by application of calibrated
von Frey hairs with bending weights of 2, 5, and 25 g to the
afferents’ receptive fields (Fig. 4). Among 12 normal affer-
ents, 5 were C-fibers with conduction velocities between 0.4
and 1.8 m/s. The remaining seven afferents were Ad-fibers
with conduction velocities between 3.2 and 12.5 m/s. Intra-
venous injection of 90 mg/kg gabapentin did not affect the
conduction velocity of these 12 afferents.
Fig. 1. Effect of i.v. injection of saline (n 5 6) or gabapentin (n 5 8) on
mechanical thresholds determined by paw-withdrawal response to von
Frey filaments. The points labeled with doses indicate values obtained 15 Discussion
min after each injection. Data are presented as mean 6 S. E.M. *P , .05
versus pretreatment control. In the present study, we explored the neurophysiological
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mechanisms of the antiallodynic action of gabapentin in a rat
Electrophysiological Recording Experiments. A total model of neuropathic pain. The major finding of the current
of 25 afferents were recorded from the injured left sciatic study is that the ectopic discharge activity from injured pe-
nerve in 25 additional rats. These afferents exhibited typical ripheral afferent nerve is suppressed by therapeutic doses of
spontaneous bursting discharge activity (Fig. 2), as charac- gabapentin. We observed that i.v. gabapentin, at a range of
terized in detail previously (Matzner and Devor, 1994). The 30 to 90 mg/kg, dose-dependently reversed allodynia caused
conduction velocity was measured in 17 of 25 afferents stud- by partial sciatic nerve ligation. Furthermore, we found that
ied. There were 13 Ad-fibers with a conduction velocity rang- similar doses of gabapentin significantly inhibited the dis-
ing from 3.0 to 13.8 m/s. The four C-fibers had a conduction charge activity recorded from injured afferent fibers but had
velocity of between 0.6 and 1.5 m/s. Repeat i.v. injection of no effect on the conduction velocity and the response of nor-
saline did not affect the ectopic discharge frequency of 10 mal afferents to mechanical stimulation. Therefore, these
separate afferents during the entire recording period from 1 data provide new electrophysiological evidence suggesting
to 3 h (Fig. 3). Intavenous injection of 10 mg/kg gabapentin that the peripheral action of gabapentin on ectopic discharge
failed to influence the spontaneous discharge frequency of activity from injured afferent fibers may constitute an addi-
afferents. In a cumulative dose range of 30 to 90 mg/kg, tional mechanism by which gabapentin produces an antial-
gabapentin significantly inhibited the discharge activity of lodynic effect on neuropathic pain.
15 afferents in a dose-dependent fashion (Figs. 2 and 3). At A prominent feature of central sensitization is allodynia, a
the cumulative dose of 30, 60, and 90 mg/kg, gabapentin state in which normally innocuous input is perceived as pain
suppressed completely the spontaneous discharge activity of (Gracely et al., 1992; Yoon et al., 1996). Previous studies
three, four, and eight afferent fibers, respectively. We paid indicate that sustained high-frequency discharge from ec-
attention to changes in interspike intervals of afferent firing topic sites in the peripheral nerve after nerve injury causes
enhanced responsiveness of spinal dorsal horn neurons,
which contributes toward the pathogenesis of neuropathic
pain states (Kajander and Bennett, 1992; Matzner and De-
vor, 1994; Yoon et al., 1996). Neuropathic pain syndromes
after peripheral nerve injuries are often poorly relieved by
two major classes of analgesics: nonsteroidal anti-inflamma-
tory drugs and opioids (MacFarlane et al., 1997). In the
search for alternative treatment, anticonvulsants have be-
come the more commonly used interventions (McQuay et al.,
1995; MacFarlane et al., 1997). Among these agents, gaba-
pentin has been shown to be effective in animals models of
neuropathic pain as well as in chronic pain patients (Mellick
et al., 1995; Rosner et al., 1996; Field et al., 1997; Rosenberg
et al., 1997). It has a much lower incidence of side effects
compared with other anticonvulsants (Rosner et al., 1996;
Rosenberg et al., 1997). However, the mechanisms and site(s)
of its antinociceptive action are largely unclear. Although it
has been demonstrated that systemic as well as intrathecal
administration of gabapentin has antinociceptive effects in
Fig. 2. Original representative neurograms (each tracing is 30 s of re- various pain models (Hunter et al., 1997; Hwang and Yaksh,
cording) showing dose-dependent inhibitory effect of i.v. gabapentin on 1997), previous studies have not examined the action of gaba-
single-unit ectopic discharge activity from an injured sciatic afferent
fiber. The neurograms were sampled between 12 and 14 min after injec- pentin on injured peripheral afferents. Chapman et al. (1998)
tion of each dose. recently reported that s.c. injection of 30 to 100 mg/kg gaba-1999 Gabapentin, Ectopic Afferent Discharge, and Allodynia 1029
Fig. 3. Effect of i.v. injection of saline
(n 5 10, A) or gabapentin (n 5 15, B) on
spontaneous discharge activity re-
corded from injured afferent fibers.
Note that in B, the points represent
averaged total discharges during the
entire recording period between doses.
Data are presented as mean 6 S. E.M.
*P , .05 versus pretreatment control.
Downloaded from jpet.aspetjournals.org at ASPET Journals on February 4, 2015
(Carlton and Zhou, 1998). As demonstrated in the present
study, therapeutic doses of gabapentin are capable of sup-
pressing ectopic discharge activity generated from injured
afferent nerve sites. Thus, in addition to its effect on sensi-
tized spinal dorsal horn neurons caused by nerve injury, the
effect of gabapentin on ectopic afferent activity may contrib-
ute to its antinociceptive action by directly eliminating noci-
ceptive afferent input to the spinal cord. We recognize that
the antiallodynic effect of gabapentin may occur over a longer
period of time after i.v. injection. Our data indicate that
gabapentin has a rapid effect on ectopic discharges, which is
consistent with its effect on allodynic behavior. There are two
possible explanations for this observation. The allodynia pro-
duced in this model (partial sciatic nerve ligation) may be
highly dependent on the ectopic afferent barrage. Thus, elim-
Fig. 4. Lack of effect of i.v. injection of 90 mg/kg of gabapentin on the
responses of normal afferents (n 5 12) elicited by topical application of ination of abnormal input by gabapentin rapidly reversed the
von Frey filaments (VFH). Data are presented as mean 6 S. E.M. Recep- allodynic condition. Alternatively, the effect of i.v. gabapen-
tive fields of all afferents were located in the left hindpaw. tin on ectopic discharges may not account entirely for its
antiallodynic effect. The quick antiallodynic effect of gaba-
pentin inhibits the spontaneous activity of spinal dorsal horn pentin may be a result of its combined central and peripheral
neurons in rats with L5/L6 spinal nerve ligation, suggesting a effects. Data from this study provide a new rationale for the
spinal site of action of this agent. Other studies have found use of systemic gabapentin as an analgesic agent in neuro-
that administration of the monoclonal antibody anti-GD2 pathic pain.
ganglioside induces ectopic discharge activity from primary Both voltage-activated Na1 channels and voltage-sensitive
afferent fibers, which causes allodynia in rats (Xiao et al., Ca11 channels are closely related to the generation of ectopic
1997). Because i.v. injection of 30 to 300 mg/kg gabapentin discharge activity of injured nerves (Devor et al., 1992;
reverses allodynia caused by this antibody, the peripheral Matzner and Devor, 1994). It is not yet known which channel
action of gabapentin has been proposed (Gillin and Sorkin, is functionally relevant to the inhibitory actions of gabapen-
1998). A recent behavioral study has shown that local injec- tin on allodynia and ectopic discharges from injured afferent
tion of gabapentin attenuates Formalin-induced nociception nerves. Recent studies have shown that gabapentin has a
in rats, also indicating a peripheral action of gabapentin high affinity to the a2d-subunit of voltage-sensitive Ca111030 Pan et al. Vol. 288
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Acknowledgments Xiao W-H, Yu AL and Sorkin LS (1997) Electrophysiological characteristics of pri-
mary afferent fibers after systemic administration of anti-GD2 ganglioside anti-
We thank Dr. Charles Taylor of Parke-Davis Pharmaceutical Re- body. Pain 69:145–151.
search for the generous donation of gabapentin used in this study. Yoon YW, Na HS and Chung JM (1996) Contributions of injured and intact afferents
to neuropathic pain in an experimental rat model. Pain 64:27–36.
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[3H]gabapentin-binding protein/alpha 2 delta Ca21 channel subunit from porcine thesiology, Wake Forest University School of Medicine, Medical Center
brain: Development of a radioligand binding assay for alpha 2 delta subunits using Boulevard, Winston-Salem, NC 27157-1009. E-mail: hpan@wfubmc.edu
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