THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE
Volume 11, Number 1, 2005, pp. 135–142
© Mary Ann Liebert, Inc.
Electroacupuncture Attenuates Inflammation in a Rat Model
RUI-XIN ZHANG, M.D., Ph.D.,1LIXING LAO, Ph.D., L.Ac.,2XIAOYA WANG, M.D.,1
ARTHUR FAN, Ph.D., L.Ac.,1LINBO WANG, B.S.,1KE REN, M.D.,Ph.D.,2
and BRIAN M. BERMAN, M.D.,1
Background: Acupuncture has traditionally been used in China and is being increasingly applied in West-
ern countries to treat a variety of conditions, including inflammatory disease. However, clinical trials investi-
gating the effectiveness of the anti-inflammatory effects of acupuncture have yielded inconsistent results, and
the underlying mechanisms of acupuncture-produced anti-inflammation are unclear.
Objective: To evaluate the effectiveness of electroacupuncture (EA) on inflammation in a rat model.
Materials and methods: Four experiments were conducted on male Sprague-Dawley rats (n ? 8–9 per
group). Inflammation was induced by injecting complete Freund’s adjuvant (CFA) subcutaneously into the plan-
tar surface of one hind paw of the rat. Experiment 1: To determine the effect of EA (10 and 100 Hz) versus
sham treatment on inflammation. Experiment 2: To investigate the involvement of the adrenal glands on the
effect of EA treatment using adrenalectomized (ADX) rats. Experiment 3: To determine the effects of EA on
plasma levels of corticosterone. Experiment 4: To determine the effects of EA treatment versus immobilization
on such stress indicators as heart rate and blood pressure.
Results: At 10 Hz EA significantly reduced CFA-induced hind paw edema. The effect was partially blocked
in the ADX rats. EA significantly increased plasma levels of corticosterone but produced no noticeable signs
Conclusion: At 10 Hz but not 100 Hz, EA suppresses inflammation by activating the hypothalamus-pitu-
itary-adrenal axis (HPA) and the nervous system.
Callahan, 2001; Pincus et al., 1993; Sangha, 2000; Wenzel,
2003). The treatment of such diseases with conventional
medicine, such as nonsteroidal anti-inflammatory drugs
(NSAIDs), opioids, and the recently developed cyclooxy-
genase-2 (COX-2) inhibitors (Buffum and Buffum, 2000;
Pomp, 2002; Scheiman, 2001; Stiel, 2000), are often asso-
ciated with adverse effects. As many as 42% of patients use
complementary and alternative medicine (CAM), including
acupuncture, to fulfill their needs in lieu of or as an adjunct
to conventional medicine (Eisenberg et al., 1998). Acupunc-
ture, a therapeutic modality from Traditional Chinese Med-
hronic inflammatory diseases affect a large population
of patients (Andres and Friedman, 1999; Palm and
icine (TCM), has been used in China and other Asian coun-
tries for thousands of years to treat a variety of conditions,
including inflammatory disease (Cheng, 1999; O’Connor
and Bensky, 1981). However, previous clinical trials have
reported inconsistent results on the anti-inflammation ef-
fectiveness of acupuncture (Bhatt-Sanders, 1985; Zijlstra et
al., 2003). For example, some clinical trials reported that
acupuncture was effective in the treatment of rheumatoid
arthritis (Liu et al., 1993; Man and Baragar, 1974), while
others reported negative results (David et al., 1999). Simi-
larly, contradictory and conflicting results were reported on
the effects of acupuncture in the treatment of asthma (Bier-
nacki and Peake, 1998; Joos et al., 2000; Medici et al., 2002).
Additionally, the underlying mechanisms of acupuncture are
1Center for Integrative Medicine, School of Medicine, University of Maryland, Baltimore, MD.
2Department of Biomedical Sciences, Dental School, University of Maryland, Baltimore, MD.
The hypothalamus–pituitary–adrenal (HPA) axis is
known to be involved in the anti-inflammatory process in
which glucocorticoid (GC) is secreted from the adrenal
glands as the end product. GC suppresses the inflamma-
tion/immune response to recover homeostasis (Ahluwalia,
1998; Pelaia et al., 2003). Our previous study demonstrated
that EA at both 10 and 100 Hz produced antihyperalgesic
effect in a persistent inflammatory pain animal model (Lao
et. al. 2004). The present study was designed to evaluate the
anti-inflammatory effect of acupuncture and explore the
mechanisms involving GC (known as corticosterone in rats)
in a complete Freund’s adjuvant (CFA)-induced persistent
hind paw inflammation rat model. We hypothesize that EA
alleviates inflammation with involvement of HPA. Our spe-
cific aims are: (1) whether 10 Hz or/and 100 Hz EA sup-
presses CFA-induced paw edema, (2) whether the anti-in-
flammatory effect of EA, if any, is associated with adrenal
coricosterone, and (3) whether the effect of EA is attribut-
able to stress-induced HPA activation.
MATERIALS AND METHODS
Male Sprague-Dawley rats weighing 280–350 g (Harlan,
Indianapolis, IN) were kept under controlled environmental
conditions (22°C ? 0.5°C, relative humidity 40%–60%, 12-
hour alternate light–dark cycles, food and water ad libitum).
The animal protocols were approved by the Institutional An-
imal Care and Use Committee (IACUC) at the University
of Maryland School of Medicine. The ethical guidelines for
the treatment of animals of the International Association for
the Study of Pain were followed in these experiments (Zim-
Bilateral adrenalectomy (ADX) surgery was performed
via the dorsal approach (Wilson et al., 2000) under anes-
thesia with sodium pentobarbital (50 mg/kg, intraperi-
toneally). The removed tissues were dissected to confirm
that both the adrenal cortex and adrenal medulla were re-
moved completely. All ADX rats were given 0.9% saline ad
libitum to compensate for sodium loss after the operation.
The sham ADX rats underwent the same surgical procedure,
except that adrenal glands were not removed. The rats were
allowed to recover for seven days before experimentation.
Inflammation was induced by injecting CFA (Sigma, St.
Louis, MO; suspended in an 1:1 oil/saline emulsion, 0.5
mg/mL heat-killed Mycobacterium tuberculosis) subcuta-
neously into the plantar surface of one hind paw of the rat
using a 25-gauge hypodermal needle (Iadarola et al., 1988;
Stein et al., 1988). The inflammation appeared within 2
hours after the injection, peaked between 6–24 hours, and
lasted approximately 2 weeks. The edema (hind paw thick-
ness) was measured with a caliper prior to and 2.5 hours, 5
hours, 1, 3, 5, and 7 days post-CFA injection. The investi-
gator who conducted the measurement was blinded to the
In each of the four experiments, the rats were randomly
divided into treatment or control groups. In the first set of
experiments, three dosages of CFA (0.06 mL, 0.08 mL,
0.1 mL) were injected respectively into one hind paw of rats
in three different groups (n ? 8–9), after which the rats were
treated with EA or sham treatment to determine the effect
of EA on edema. In the second set of experiments (n ? 8–9),
ADX rats and sham ADX rats were injected with 0.08 mL
CFA, the optimal dosage determined in the first set of the
experiments, and then treated with EA or sham treatment.
A separate group of ADX rats was injected with 0.04 mL
CFA and treated with EA or sham treatment. In the third set
of experiments (n ? 8–9), plasma levels of corticosterone
in EA and sham treatment treated rats were measured 5
hours post-CFA with enzyme-linked immunosorbent assay
(ELISA). In the fourth set of experiments, rats were divided
into EA treatment (with no immobilization) (n ? 6) and im-
mobilization (n ? 6) groups. Immobilization was achieved
by restraining the animals in a Plexiglas Broome-style ro-
dent restrainer (Kent Scientific, Litchfield, CT) for 20 min-
utes. Heart rate (HR) and systolic blood pressure (SBP) were
measured 20 minutes prior to CFA injection, 2 hours post-
CFA, and 2.5 hours post-CFA during EA treatment or im-
mobilization (Cox et al., 1985). SBP and HR were measured
in conscious rats by indirect tail plethysmography using the
BP-HR Monitor (model MK-1030, MUROMACHI KIKAI
Co. Ltd, Japan).
Acupuncture treatment procedures
To maximize the anti-inflammatory effect and to treat an-
imals prophylactically, EA treatment was given twice, for
20 minutes each, once immediately after administration of
CFA and again 2 hours post-CFA (Lao et al., 2004). EA pa-
rameters of 10 and 100 Hz at 3 mA and 0.1 ms pulse width,
which showed significant antihyperalgesic effects on the rat
inflammation model in our previous studies (Lao et al., 2001,
2004), were used in the present study. The equivalent of the
human acupoint Huantiao (GB30) was chosen for bilateral
needling based on TCM meridian theory (O’Connor and
Bensky, 1981) and on its successful use in our previous stud-
ies, as well as on studies by others (Lao et al. 2001, 2004;
Xu et al., 1993). In humans, GB30 is located at the junction
of the lateral one third and medial two thirds of the distance
between the greater trochanter and the hiatus of the sacrum;
underneath are the sciatic nerve, inferior gluteal nerve and
gluteal muscles (Cheng, 1999). GB30 was located on the
rat’s hind limbs using the comparable anatomical landmarks.
After cleaning the skin with alcohol swabs, a disposable
acupuncture needle 32-gauge, 0.5-inch in length) was in-
ZHANG ET AL.
serted on a slant approximately 0.5-inch deep into GB30 on
each of the animal’s hind limbs, and a pair of electrodes was
attached to the ends of the needles. The needles and the elec-
trodes were stabilized with adhesive tape. EA stimulation
was delivered by an electrical stimulator (A300 Pulsemas-
ter, World Precision Instruments, Sarasota, FL) via an iso-
lator (A360D Stimulus Isolator, World Precision Instru-
ments), which converts electrical voltage into electrical
current. While EA frequency was held constant, intensity
was adjusted slowly (over a period of approximately 2 min-
utes) to the designated level of 3 mA, which is the maxi-
mum EA current intensity that the conscious animal can tol-
erate. Mild muscle twitching was observed. During EA
treatment, each rat was placed under an inverted clear plas-
tic chamber (approximately 5 ? 8 ? 11 inch) but was nei-
ther restrained nor given any anesthetic. The animals re-
mained awake and still during treatment and showed no
observable signs of distress. For sham treatment control,
acupuncture needles were inserted bilaterally into GB30, but
no electrical stimulation or manual needle manipulation was
applied. This sham procedure produced no antihyperalgesic
effect on this animal model in our previous study (Lao et
al., 2004). This is consistent with the concept of traditional
TCM acupuncture practice that needling techniques and ma-
nipulation are important for producing desired therapeutic
effect (Cheng, 1999; O’Connor and Bensky, 1981). Because
it is most comparable to the “real” treatment procedure but
produces little therapeutic effect, we used it as a sham con-
trol in this study.
Plasma preparation and ELISA
After inducing inflammation with CFA and administer-
ing EA, we placed the rats under deep anesthesia with
Hindpaw Thickness (mm)
Baseline 2.5 hr
0.08 mL CFA ? sham EA
0.08 mL CFA ? 10 Hz3 mA
1 d3 d 5 d 7 d
Baseline 2.5 hr5 hr 1 d3 d5 d 7 d
0.06 mL CFA
0.08 mL CFA
0.1 mL CFA
0.1 mL CFA ? sham EA
0.1 mL CFA ? 10 Hz 3 mA
0.6 mL CFA ? sham EA
0.6 mLCFA ? 10 Hz 3 mA
mL) induced hind paw edema (A, n ? 8–9 each group). After CFA injection, 10–Hz, 3-mA, 0.1-ms pulse EA significantly inhibited
0.06 mL CFA-induced inflammation at 5 hours and 1 day (B, n ? 8 each group) and 0.08 mL of CFA-induced inflammation at 5 hours
and 3 days (C, n ? 8–9 each group) but did not inhibit 0.1 mL of CFA-induced inflammation at any time point (D, n ? 8–9 each group).
Inflammation was determined by increased paw thickness (mm); *p ? 0.05 compared to sham treatment; ***p ? 0.001, ****p ? 0.0001
compared to 0.08 mL CFA group.
Effects of 10-Hz electroacupuncture (EA) on hind paw edema. Complete Freund’s adjuvant (CFA) dose-dependently (0.06–0.1
sodium pentobarbital (100 mg/kg, intraperitoneally) at 5
hours post-CFA. Trunk blood (2 mL) was collected tran-
scardially and then centrifuged (1310g) for 15 minutes at
4°C. The plasma was collected and stored at ?80°C until
assayed. The corticosterone levels were measured with a
commercially available ELISA kit (ALPCO Diagnostics,
Windham, NH) using the procedure recommended by the
manufacturer. The sensitivity of the kit is 0.23 ng/mL. The
antibody in the kit specifically reacts with corticosterone and
has less than 0.01% cross-reactivity with other adrenal hor-
mones (e.g., aldosterone and cortisone). Corticosterone con-
centrations (ng/mL) were determined by comparing samples
to the standard curve generated with the kit.
The results are presented as mean ? standard error of the
mean (SEM) and compared among groups using two-way
(experiments 1 and 2) or one-way (experiments 3 and 4)
analysis of variance (ANOVA) followed by the Dunnett’s
post hoc test. Stress indicator data were collected in three
consecutive readings 1 minute apart and averaged for each
rat. Group averages were calculated at each time point
(Talpur et al., 2002). p ? 0.05 was considered significant in
EA alleviates inflammation
Figure 1 shows the dose-response curve after CFA injec-
tion. Baseline paw thickness was approximately 5.5 mm,
with no significant differences among the three groups. Al-
though all injected paws developed paw edema over a sim-
ilar time course and peaked 1 day post-CFA injection, the
degree of edema was significantly different in the three
groups (n ? 8–9, p ? 0.01). Peak edema of the group re-
ceiving 0.06 mL CFA was 9.06 ? 0.15 mm, that of the 0.08
mL group was 9.63 ? 0.12, and that of the 0.1 mL group
was 9.90 ? 0.10, thus showing a positive correlation between
the amount of CFA and the extent of edema (Fig. 1A). EA
at 10 Hz significantly reduced 0.06 mL CFA-induced hind
paw edema at 5 hours and 1 day (p ? 0.05, Fig. 1B) and 0.08
mL induced edema at 5 hours and 3 days (p ? 0.05, Fig. 1C)
compared to sham treatment control. EA produced no ob-
servable edema reduction on 0.1 mL CFA-induced hind paw
inflammation (Fig. 1D). One hundred hertz (100 Hz) EA
showed no effect on paw edema (Fig. 2). Therefore, only 10
Hz EA was used in the subsequent experiments.
involves the adrenal gland
After an injection of 0.08 mL CFA, the paw edema in-
duced in sham ADX rats was similar to that in the intact rats
given no surgery. However, the paw edema was more se-
vere in ADX rats than in sham ADX rats at all time points
from 2.5 hours to 7 days post-CFA (p ? 0.05, Fig. 3A).
Compared to sham treatment, 10 Hz EA significantly alle-
viated hind paw edema in sham ADX rats at 5 hours and 3
days post-CFA but not in ADX rats (Fig. 3A). Because ADX
exaggerate the response to the inflammatory stimulus, 0.04
mL of CFA was injected into the hind paws in ADX rats.
After this injection, paw edema in the ADX rats was simi-
lar to that of intact rats given 0.08 mL of CFA. The same
ZHANG ET AL.
0.06 mL CFA ? sham EA
0.06 mL CFA ? 100 Hz 3 mA
Hindpaw Thickness (mm)
0.08 mL CFA ? sham EA
0.08 mL CFA ? 100 Hz 3 mA
Baseline 2.5 hr5 hr 1 d3 d 5 d 7 d
0.1 mL CFA ? sham EA
0.1 mL CFA ? 100 Hz 3 mA
no effects on complete Freund’s adjuvant (CFA) (A, 0.06 mL; B,
0.08 mL; and C, 0.1 mL) induced hind paw edema (n ? 8–9 each
One Hundred (100 Hz) electroacupuncture (EA) showed
Heart Rate (per min)
Systolic Blood Pressure (mmHg)
Hindpaw Thickness (mm)
Baseline 2.5 hr 5 hr1 d 3 d 5 d7 d
Sham ADX 0.08 mL CFA ? sham EA
Sham ADX 0.08 mL CFA ? 10 Hz EA
ADX 0.08 mL CFA ? sham EA
ADX 0.08 mL CFA ? 10 Hz EA
ADX 0.04 mL CFA ? sham EA
ADX 0.04 mL CFA ? 10 Hz EA
paw edema between ADX and sham rats made the anti-in-
flammatory effect of EA comparable in these two groups.
Compared to sham treatment, 10 Hz EA significantly re-
duced 0.04 mL CFA-induced hind paw edema in ADX rats
at 3–5 days but not at 5 hours post-CFA injection (Fig. 3B).
In the ELISA experiment, 10 Hz EA significantly increased
the plasma levels of corticosterone at 5 hours post-CFA
(184.09 ? 23.41 ng/mL) compared to the sham treatment
control (126.37 ? 12.85 ng/mL, p ? 0.05).
EA has little effect on the stress indicators—
heart rate and blood pressure
HR and SBP baselines were similar in the immobilization
control group (389.43 ? 10.21 per minute and 109.63 ? 6.94
mm Hg) and the EA treatment group (398.73 ? 9.54 per
minute and 115.27 ? 5.64 mm Hg). At 2 hours post-CFA, HR
and SBP were not significantly changed from the baseline by
CFA injection alone in either the immobilization group
(403.14 ? 7.47 per minute, 114.24 ? 5.51 mm Hg) or the EA
treatment group (400.40 ? 10.17 per minute 123.21 ? 6.89
mm Hg). However, HR and SBP (449.62 ? 13.6 per minute
and 125.01 ? 5.30 mm Hg) were significantly elevated from
the baseline in animals immobilized for 20 minutes (p ? 0.05),
although not in those treated with 20 minutes of EA (410.68 ?
15.05 per minute, 121.17 ? 3.76 mm Hg) (Fig. 4). HR in the
immobilization group was significantly higher than in the EA
group (p ? 0.05).
This study demonstrated that 10 Hz, but not 100 Hz EA,
significantly alleviated CFA-induced hind paw inflamma-
tion. This finding is consistent with our previous report that
(EA)-induced anti-inflammation in the complete Freund’s adjuvant
(CFA) inflammation rat model. EA did not show any anti-inflam-
matory effects on the ADX group injected with 0.08 mL of CFA
(A, n ? 8–9 each group). However, when 0.04 mL of CFA was in-
jected, ADX blocked EA-induced anti-inflammation at the early
phase, 5 hours post-CFA, but not the late phase of 3–5 days (B, n ?
8 each group). *p ? 0.05 compared to sham treatment in ADX rats;
#p ? 0.05 and ##p ? 0.01 between ADX rats and sham ADX rats.
Adrenalectomy (ADX) effects on electroacupuncture
treatment on heart rate (upper panel, n ? 6) and systolic blood
pressure (lower panel, n ? 6). Complete Freund’s adjuvant (CFA)
inflammation and EA treatment did not significantly change heart
rate or systolic blood pressure. In contrast, immobilization signif-
icantly increased heart rate and systolic blood pressure; *p ? 0.05
compared to baseline; #p ? 0.05 compared to EA group.
Effects of immobilization and electroacupuncture (EA)
10 Hz EA inhibits both hyperalgesia and edema in rats with
hind paw inflammation (Lao et al., 2001). It is also consis-
tent with studies by other investigators showing that EA ef-
fectively prevented the onset of neurogenic edema induced
by capsaicin (Ceccherelli et al., 1999, 2002) and reduces in-
flammation-induced plasma extravasation (Zhao and Zhu,
1992). However, EA showed no effect on the severe in-
flammation induced in intact rats by 0.1 mL of CFA or in
ADX rats by 0.08 mL of CFA. The CFA-induced inflam-
mation animal model has been widely used to investigate
the mechanisms of inflammatory diseases such as arthritis.
It has also been claimed that although EA may be effective
for inflammatory disorders it is not potent enough to match
the robust effects of such pharmaceutical agents as corti-
costeroid. Based on the results of the present study, we spec-
ulate that EA may be clinically useful for treating mild to
moderately inflammatory disorders and may also be used as
adjunct therapy to conventional medicine for severe in-
flammation. Moreover, the different time courses of the ef-
fective EA between the 0.06 and 0.08 mL of CFA suggest
that EA may have different therapeutic effects on different
degrees of inflammatory diseases.
It should be noted that in contrast to the lower frequency
10 Hz EA, 100-Hz EA showed no effect on rat paw edema
in the present study. Differences in the analgesic effects of
high- and low-frequency EA have been reported in unin-
jured animals (Han, 2003), as have high- and low-frequency
differences in antihyperalgesic effects in an inflammatory
pain animal model (Lao et al., 2004). Han (2003) observed
that lower frequency EA induced endorphin while high EA
frequency induced dynorphin. Our previous study using this
CFA inflammatory animal model showed that 100 Hz EA
suppressed hyperalgesia only in the early phase (2.5–24
hours post-CFA) of inflammation, while 10 Hz EA not only
attenuated hyperalgesia in the early phase but also facili-
tated recovery in the late (5–7 day) phases (Lao et al., 2001,
2004). Thus, the lack of anti-inflammatory effect by 100-
Hz EA may be the result of the 100-Hz EA involve differ-
ent mechanisms (Han, 2003).
The anti-inflammatory effects of 10-Hz EA were abol-
ished in ADX rats at 5 hours but not at 3–5 days post-CFA
injection, suggesting that both HPA axis particularly the
adrenal gland and non-HPA mechanisms are associated with
EA anti-inflammation. Adrenal gland involvement in EA-
produced anti-inflammation is further evidenced by the find-
ing that EA significantly increased plasma corticosterone
levels in non-ADX rats. This suggests that EA’s anti-in-
flammatory effect is associated with corticosterone released
from the adrenal gland. Consistently, a number of studies
demonstrated that acupuncture increases cortisol (Bossut et
al., 1983; Cheng et al., 1980; Lee et al., 1982) and corti-
costerone levels (Liao et al., 1979) in normal conditions. A
possible mechanism of EA is that it activates the HPA axis,
which releases corticosterone into the blood. The plasma
corticosterone then in turn suppresses inflammation by shut-
ting off the production of proinflammatory mediator cy-
tokines peripherally at the sites of injury (Collart et al., 1990;
Katoh and Ito, 1995; Kwon et al., 1994; Ray et al., 1995;
Schobitz et al., 1994; Watkins et al., 1995). However, fur-
ther investigation of the nervous system mechanisms and
the involvement of cytokines in the anti-inflammatory ef-
fect of acupuncture is warranted.
The role of HPA in stress has been well studied (Saw-
chenko et al., 2000), which raises the question of whether
the therapeutic action of EA is the result of a nonspecific
stress effect that activates the HPA axis. It has been reported
that high current intensity (6–15 V, 6–8 times the intensity
causing initial muscle twitching) may produce stress-in-
duced analgesia (SIA) in uninjured, restrained animal mod-
els (Pomeranz 1986; Terman et al., 1984). HR and blood
pressure are known indicators of such physical stress as im-
mobilization (Sawchenko et al., 2000). Our data demon-
strated that EA treatment had no significant effect on these
stress indicators. This suggests that the effect of acupunc-
ture on inflammation is likely attributable to a therapeutic
mechanism rather than to nonspecific stress.
In conclusion, our data indicate that EA therapeutically
alleviates peripheral inflammation, which is associated with
activation of the HPA system, and possible the central ner-
vous system as well.
We would like to thank Lyn Lowry, Ph.D., for her edi-
torial support. This work was funded by National Institutes
of Health grant AT00084.
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