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Hemodynamic Effects of Gabapentin in Rats
Gabapentin has been known to elicit the antinociceptive effect. However, little has
been known about the effect of gabapentin on the cardiovascular system. The author’s
Department of Anesthesiology and Pain Medicine
aim of this experiment was to examine the hemodynamic effects of gabapentin. Male
Chonnam National University, Medical School,
Sprague-Dawley rats were used. Intrathecal or intracerebroventricular catheters were
implanted and gabapentin was delivered through each catheter or directly into theperitoneal cavity. For hemodynamic measurements, catheters were inserted into
the tail artery. Blood pressure and heart rate were measured over 60 min following
administration of gabapentin. Intrathecal and intraperitoneal gabapentin did not inducesignificant changes of hemodynamics over the 60 min compared to the baseline
value. Intracerebroventricular gabapentin increased systolic and diastolic blood pres-
sure, but there is no statistically difference in blood pressure change according to
Department of Anesthesiology and Pain Medicine,
Chonnam National University, Medical School, 8 Hakdong, Donggu, Gwangju 501-757, Korea
Key Words : Gabapentin; Hemodynamics; Injections, Spinal; Injections, Intraventricular; Injections,
Tel : +82.62-220-6893, Fax : +82.62-232-6294. INTRODUCTION MATERIALS AND METHODS
Gabapentin, a structural analogue to gamma-aminobu-
All experiments were reviewed and approved by the Insti-
tyric acid (GABA), is orginally developed as an anticonvul-
tutional Animal Care Committee, Research Institute of Med-
sant (1). It has been shown to reverse allodynia and hyperal-
ical Science, Chonnam National University.
gesia of many pain models in animal studies. Intrathecal
Male Sprague-Dawley rats weighing 300-325 g were used.
gabapentin attenuates tactile-evoked allodynia in the Chung
Rats were housed in groups of 4-6 with free access to food
model of neuropathy (2) and thermal hyperalgesia in a rat
model of painful peripheral neuropathy (3). Partridge et al.
For IT administration of the drug, rats were implanted
demonstrates its efficacy on substance-P induced thermal
with polyethylene (PE)-10 catheter (10). Briefly, under enflu-
hyperalgesia (4). In studies on facilitated pain in rats follow-
rane (3-4%)/O2 anesthesia, the head of rats was placed in a
ing the formalin test, gabapentin suppress the pain behavior
stereotactic head holder. A skin incision was made along the
observed during the second phase (5, 6). Furthermore, its
dorsum of the skull, and dura mater was exposed by blunt
effectiveness for the treatment of neuropathic pain such as
dissection. The dura was incised, and a polyethylene (PE-10)
postherpetic neuralgia (7) and complex regional pain syn-
catheter was advanced caudally to end at lumbar enlargement.
drome (8) has been reported in human studies.
The external catheter was tunneled under the skin and exit-
Although some adverse effects have been noted, they were
usually slight and disappeared within 2 weeks without inter-
The ICV route for drug injection was constructed through
ruption of the treatment, and the most serious adverse effect
skull (11). Placing the rat in a stereotactic holder under enflu-
rane (3-4%)/O2 anesthesia, a burr hole was made at 0.5 mm
Owing to these advantages and effectiveness, gabapentin
caudally from the coronal suture and 1.0 mm laterally from
has been widely used in the management of a variety of neu-
the sagittal suture. Through this hole, a stainless steel, thin-
ropathic pain, but there are lack of data or information about
walled guide cannula was placed into the ventricle to a depth
its effect on hemodynamics and no known cardiovascular side
of 3 mm from dura mater and affixed to the skull with stain-
less steel screws and cranioplastic cement.
Therefore, the purpose of this study was to examine the
After surgery, rats were kept in individual cages. Animals
changes of hemodynamics following administration of intra-
showing neurologic dysfunction postoperatively were sacri-
thecal (IT), intracerebroventricular (ICV), and intraperitoneal
ficed immediately by excessive enflurane inhalation. Only
rats that displayed no postsurgical motor or sensory deficitswere assessed. Experiments were performed at least 4-5 days
ics were measured at the same time intervals.
For IP administration, the drug was injected into the peri-
All data are presented as means±SEM. Baseline blood
pressure and heart rate were compared by using one-way
In order to measure hemodynamic changes, a PE-50 catheter
ANOVA. Stastistical analysis of hemodynamic changes was
was inserted into the tail artery under enflurane (3-4%)/O2
done using two-way repeated-measures ANOVA. A p value
anesthesia and then the rats were restrained in a restraint
<0.05 was considered statistically significant.
cylinder. The catheter was flushed with 0.5 mL heparinizedsaline. The arterial line was connected to a pressure trans-ducer of monitor (Datex-Ohmeda AS/3, Finland) for con-
tinuous recording of blood pressure and heart rate.
Rats were divided into three groups of IT (n=20), ICV
The baseline systolic blood pressure, diastolic blood pres-
(n=22), and IP (n=20) according to the route of drug adminis-
sure, and heart rate were 127.8±1.5 mmHg, 92.6±9.4
tration. Each group was divided into four subgroups accord-
mmHg, and 416.4±2.9 beats/min, respectively. The base-
line blood pressure and heart rate in the several treatment
The doses of gabapentin for IT and ICV were 10, 30, 100,
groups did not differ. No changes of hemodynamics com-
and 300 g, respectively, and those for IP were 10, 30, 100,
pared with baseline value were seen over the 60 min-period
and 300 mg/kg, respectively. Gabapentin was dissolved in
following administration of IT and IP gabapentin (Fig. 1, 3).
physiologic saline. A gear-driven microinjector was used to
However, systolic and diastolic blood pressure were gradu-
deliver the drug in IT and ICV groups, and the drug was
ally increased compared with baseline blood pressure after
given in 10 L of saline. IT administration was followed by
administration of gabapentin in all ICV subgroups (Fig. 2).
an additional 10 L of saline to flush the catheter. In the IP
And the change of heart rate was not statistically significant.
group, the drug was injected into the peritoneal cavity with
Although the blood pressure was significantly increased after
a volume of 3 mL/kg through the slit of the restraint cylin-
ICV injection, the extent of change was not different among
der. Blood pressure and heart rate were measured at 5, 10,
15, 20, 30, 40, 50, and 60 min after IT and ICV adminis-tration. After 30 min following IP injection, hemodynam-
Fig. 1. Time effect curve of intrathecal gabapentin for systolic
blood pressure (SBP) and diastolic blood pressure (DBP) and
heart rate (HR). Gabapenin was administered at time 0. Each
line represents the mean±SEM of 5-7 rats.
Fig. 2. Time effect curve of intracerebroventricular gabapentin for systolic blood pressure (SBP) and diastolic blood pressure (DBP) andheart rate (HR). Gabapenin was administered at time 0. Each line represents the mean±SEM of 5-7 rats. *Statistically significant com-pared with baseline value. DISCUSSION
response of rat paw formalin test, thermal injury model, ratmodel of peripheral neuropathy and surgically induced neu-
Gabapentin, administered via IT, IP, but ICV routes, did
not affect the blood pressure or heart rate in the present study.
Although there are many proposals for the mechanism of
These findings indicate that gabapentin may be given safely
action of gabapentin, it has not been fully elucidated. Non-
via IT and IP routes without the change of hemodynamics.
strychnine site of NMDA receptor and the 2 subunit of
Numerous animal and human studies have shown that
voltage-sensitive calcium channels have been suggested as
gabapentin is effective in a wide variety of pain syndromes.
the binding site of gabapentin (4, 5, 13). Clinically, the most
In human studies, it consistently provided relief of pain asso-
common side effects of gabapentin are dizziness, somnolence,
ciated with various conditions including postherpetic neu-
headache, and diarrhea (12). Side effects increase linearly with
ralgia (7), diabetic peripheral neuropathy (12), and complex
the increase of the daily dose, but the relative safety is sup-
regional pain syndrome (8). Its efficacy on allodynia and
ported in many studies including a case report of overdose
hyperalgesia was also demonstrated in numerous animal
of 48.9 g with lack of serious toxicity (14, 15). In addition,
studies (2-6). In these studies, gabapentin reduced the pain
there has been no documentation of side effects on cardio-
Fig. 3. Time effect curve of intraperitoneal gabapentin for sys-
tolic blood pressure (SBP) and diastolic blood pressure (DBP)
and heart rate (HR). Gabapenin was administered at time -30
min. Each line represents the mean±SEM of 5-7 rats.
tionship are uncertain and further studies for the side effects
Although the current study was undertaken on animals,
of ICV gabapentin including cardiovascular effects are re-
it showed that neither systemic nor intrathecal gabapentin
quired. The above mentioned findings jointly suggest that
affected the hemodynamics. These results are consistent with
gabapentin does not affect cardiovascular responses when it
the previous findings (5, 6). Furthermore, intraduodenal
is used via IT or IP but ICV route. Thus, if another prepara-
gabapentin (100 mg/kg) produced no significant effects on
tion of IT or IP route is developed in the future, albeit only
the mean arterial blood pressure and heart rate (16), although
oral agents are clinically available now, it can be prescribed
animals in that study were pretreated with guanethidine and
safely without cardiovascular side effects. But the result of
anesthetized owing to the invasiveness of the study. And 100
increased blood pressure caused by ICV gabapentin suggests
mg/kg gabapentin did not change the mean blood pressure
that it should be used cautiously, especially in patients with
within 60 min after intravenous administration in another
In conclusion, ICV gabapentin increased systolic and
In our study, IT or IP administration of gabapentin did
diastolic blood pressure, but IT and ICV gabapentin did
not affect blood pressure and heart rate. However, systolic
and diastolic blood pressure were increased after ICV admin-istration. Considering the minimal hemodynamic effect ofIT gabapentin, increased blood pressure in ICV gabapentin
was an unexpected result. Furthermore, dose-dependency wasnot observed in the ICV group. This different result might
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