Journal of Ethnopharmacology 112 (2007) 380–385

Antinociceptive activity of Syzygium jambos leaves extract on rats

D. Ávila-Peña a,∗ , N. Peña a , L. Quintero b , H. Suárez-Roca b
a Laboratorio de Productos Naturales, Faculty of Science, University of Zulia, PO Box 526, Maracaibo 4001-A, Venezuela
b Section of Neuropharmacology and Neuroscience, Instituto de Investigaciones Clı́nicas, Faculty of Medicine,

University of Zulia, PO Box 23, Maracaibo 4001-A, Venezuela

Received 29 May 2006; received in revised form 22 March 2007; accepted 26 March 2007
Available online 30 March 2007

Abstract
Syzygium jambos (L.) Alston (Myrtaceae) (syn Eugenia jambos) is a widespread medicinal plant traditionally used in sub-Saharan Africa to treat
several diseases. The analgesic potential of leaf hydro-alcoholic extracts was assessed in rats. Hot plate and formalin tests were used to estimate
cutaneous nociception whereas measurements of forelimb grip force were done to assess muscular nociception under normal and inflammatory
conditions. In the hot plate test, Syzygium jambos extract produced a significant increase in the withdrawal response latencies in a dose-dependant
manner (10–300 mg/kg i.p.) and with a maximal effect (analgesic efficacy) similar to that of morphine. The extract (100–300 mg/kg i.p.) significantly
reduced pain scores in all the phases of the formalin test with an analgesic efficacy higher than that shown by diclofenac. Although the extract
(300 mg/kg) did not alter grip force in intact rats, it reversed the reduction in grip force induced by bilateral injection carrageenan in the forelimb
triceps. This analgesic effect of the extract on muscle hyperalgesia was not antagonized, but enhanced, by naloxone. Thus, the Syzygium jambos
extract has remarkable analgesic effects on both cutaneous and deep muscle pain that is not mediated by opioid receptors.
© 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Syzygium jambos; Myrtaceae; Antinociceptive activity

1. Introduction Slowing et al. (1994a,b, 1996) reported an anti-inflammatory

The genus Syzygium is one of 75 genera (about 3000 species)
belonging to the family Myrtaceae which are native in the trop-
ics, particularly in tropical America and Australia (Hutchinson,
1960). This genus has been reported for their different uses in
medicine. Syzygium cumini, Syzygium aromaticum, Syzygium
jambolanum and Syzygium jambos are the most pharmacolog-
ically studied species, and have been recommended to treat
haemorrhage, dysentery and gastrointestinal disorders (Moreira,
1978; Cruz, 1979), diabetes (Kelkar and Kaklij, 1996; Stanely
Mainzen et al., 1998), inflammation (Chaudhuri et al., 1990;
Kim et al., 1998; Muruganandan et al., 2001). They have also
been used as sedative and anticonvulsant (De Lima et al., 1998),
as antihypertensive (Bhargava et al., 1968), against herpesvirus
(Kurokawa et al., 1998), as inhibitor of histamine release (Kim
et al., 1998), and antimicrobial (Djadjo Djipa et al., 2000).
∗ Corresponding author. Tel.: +58 261 798 77 04; fax: +58 261 798 77 04.
E-mail addresses: dinavila@cantv.net (D. Ávila-Peña),
hsuarezroca@yahoo.com (H. Suárez-Roca).
activity for Syzygium jambos leaves extract and its isolated
flavonoid glycosides. The anti-inflammatory activity is closely
related to analgesic activity. In fact, leaves infusions of Syzy-
gium jambos, which grows in some locations of the Venezuelan
Andes Mountains and is known under the name of Pomarrosa,
are used in folk medicine as febrifuge and remedy for the relief
of inflammatory pain, especially in sore throats. Thus, we have
now evaluated the potential analgesic activity of Syzygium jam-
bos leaf hydro-alcoholic extract on cutaneous and muscle pain
rat models under normal and inflammatory conditions.
2. Materials and methods
The species were collected in Betijoque, Trujillo State
(Venezuela) in January 2002, based on ethnopharmacological
information. The botanical identity of plants was authenticated
in the Biology Department of the University of Zulia. Voucher
specimens are preserved in the Science Herbarium of the Uni-
versity, under No. MP-3888. Dried and powered aerial parts
(2.6 kg) were extracted with petroleum ether by means of soxh-
let, followed by an exhaustive extraction with MeOH at room

0378-8741/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2007.03.027
 D. Ávila-Peña et al. / Journal of Ethnopharmacology 112 (2007) 380–385
temperature. After evaporation a dark residue was obtained with
a yield of 14.5% (w/w), which was washed with water–ethanol
(1:1). The resultant hydro-alcoholic extract was dried under
reduced temperature and pressure using a rotary evaporator to
yield 284 g.
2.1. Animals
Male Sprague–Dawley rats (250–300 g) (Centro Tecnológico
IVIC, Caracas, Venezuela), were used for experiments (five
rats/group for each test). The rats were maintained under stan-
dard animal housing conditions and had access to standard
laboratory food and water ad libitum. The experimental pro-
tocol was approved by the Technical Committee of Faculty of
Science.
2.2. Assessment of thermal cutaneous nociception
To evaluate cutaneous thermal nociception, we used hot plate
test at 52.5 ± 0.5 ◦ C (IITC, Inc., California, USA) as previously
described by Woolfe and Mcdonald (1944). Thermal nocicep-
tion was estimated by measuring withdrawal response latency,
that is, time elapse from the placement of the animal on the
hot plate surface until animal jumps or licks any of its hind
paws. A pre-treatment measurement was performed to determine
baseline nociception. Then rats were treated i.p. with either iso-
tonic saline solution (0.9% NaCl) as control vehicle or different
doses of Syzygium jambos hydro-alcoholic extract (10, 100 and
300 mg/kg); response latencies were measured 15, 30, 60, 90
and 120 min later. The opioid analgesic morphine chlorhydrate
(7.5 mg/kg, i.p.) was used as a positive control for the test.
2.3. Assessment of inflammatory cutaneous nociception
To evaluate inflammatory pain, we used the formalin test
as described by Dubuisson and Stephen (1977). Nociceptive
response was induced by subcutaneous injection of formalin
(100 ␮l, 1%) into the plantar region of the right hind paw. Pain
behavior was recorded at 180-s intervals, using a rating scale
as described by Dubuisson and Stephen (1977). An observer
unaware of rat’s treatment did a computer-assisted scoring of
the nociceptive behavior. Rats were treated i.p. with either iso-
tonic saline solution (0.9% NaCl) as control vehicle or different
doses of Syzygium jambos hydro-alcoholic extract (10, 100 and
300 mg/kg), 30 min before the formalin injection in the hind
paw. In a group of rats, the non-steroidal anti-inflammatory drug
sodium diclofenac (30 mg/kg, i.p.) was used as a positive control
for the test.
2.4. Antagonism of Syzygium jambos extracts effects
To determinate the involvement of opioid receptors, we evalu-
ated the effect of the opioid antagonist naloxone on the analgesic
activity of Syzygium jambos extracts on thermal nociception.
Immediately after obtaining basal response latencies in the hot
plate test, either vehicle or naloxone hydrochloride (0.1 mg/kg
s.c.; RBI-Sigma, Natick, MA, USA) was administered. The hot
381
plate response latencies were sequentially measured 15, 30,
60, 90 and 120 min later. Syzygium jambos extract (300 mg/kg,
i.p.) was given immediately after the second measurement of
response latency, that is, 15 min after the injection of vehicle or
naloxone. To verify that dose of naloxone was sufficient to antag-
onize opioid-mediated analgesia, in a set of rats, we administered
morphine chlorhydrate (7.5 mg/kg) 15 min after the injection of
either vehicle or naloxone. To determine the effect of the block-
ade of opioid receptors per se on thermal nociception, in a set
of rats, we administered naloxone 15 min after the injection of
vehicle.
2.5. Assessment of muscle nociception
Muscle nociception was evaluated using force grip test as
described by Kehl et al. (2000). At the beginning of the exper-
iment, baseline forelimb grip force was obtained. Then the
animals were injected i.p. with either vehicle (0.33 ␮l NaCl,
0.9%), sodium diclofenac (30 mg/kg) as positive control, or
Syzygium jambos extract (300 mg/kg) and after 30 min another
force grip measurement was done. Then, muscle inflammation
was induced by the bilateral injection of carrageenan (2.5%
p/v; 100 ␮l per triceps) in the forelimb triceps muscles of rats
briefly anesthetized with ether. After 24 h, vehicle, Syzygium
jambos extract or sodium diclofenac were again administered
and 30 min later grip force was estimated.
In a separate set of experiments, we evaluated the role of
opioid receptors in the analgesic activity of Syzygium jambos
extract on muscle nociception. Grip force values were obtained
before (baseline) and 30 min after the injection of either mor-
phine chlorhydrate (7.5 mg/kg, i.p.), 0.9 % NaCl (vehicle, i.p.),
or opioid receptor antagonist naloxone (1 mg/kg, s.c.).
2.6. Statistical analysis
All the data were expressed as mean ± standard error of the
mean. Since collected data were normally distributed according
to the Kolmogorov and Smirnov Normality Test, we used para-
metric statistics. The effect of the Syzygium jambos extract on the
pain tests was evaluated by performing either a one- or two-way
ANOVA, followed by two-tailed Bonferroni test. Significance
was assumed at α = 0.05.
3. Results and discussion
Syzygium jambos extract produced a marked and significant
dose-dependant elevation of the hot plate response latencies at
the doses of 100 and 300 mg/kg (Fig. 1B). The onset of analgesic
effect was observed at 15 min and lasted for almost 2 h after
the injection, indicating that the extract produces a long-lasting
analgesia for thermal pain. The extract showed an effect onset
time and analgesia efficacy comparable to that of morphine, a
potent opioid analgesic (Shavit et al., 1986; Moore et al., 2006)
(Fig. 1A).
On the other hand, the rats submitted to the formalin test dis-
played two excitatory phases and one inhibitory interphase of the
nociceptive behavior (Figs. 2 and 3). The first phase occurred by
382 D. Ávila-Peña et al. / Journal of Ethnopharmacology 112 (2007) 380–385
Fig. 1. Analgesic effect of morphine (positive control) and the hydro-alcoholic
extract of Syzygium jambos. Ordinate represents latency time (in seconds) for
nociceptive withdrawal response of the animal. Abscissa shows time (in minutes)
since administration of the agent. E10, E100, and E300 stand for 10, 100, and
300 mg/kg of extract, respectively. * represents a significant difference respect
to corresponding vehicle. Two-way ANOVA followed by Bonferroni test: (A)
for treatment, F1,60 = 46.13, p < 0.0001; for time, F5,60 = 0.74, p < 0.5979; for
interaction, F5,60 = 0.87, p < 0.5040 and (B) for treatment, F15,120 = 24.52,
p < 0.0001; for time, F3,120 = 4.68, p < 0.0006; for interaction, F5,120 = 1.69,
p < 0.0619.
direct stimulation of sensorial fibers type C by formalin action,
inhibitory interphase is mediated by descendent fibers, and the
second excitatory phase is mediated by both a peripheral inflam-
matory process sensible to anti-inflammatory drugs and spinal
central sensitization (Jolsen et al., 1992). The rats pre-treated
with 100 and 300 mg/kg Syzygium jambos extracts obtained sig-
nificantly lower pain scores in the two excitatory phases and
the inhibitory interphase, as compared to vehicle treated rats
(Figs. 2B and 3B). This analgesic effect was dose-dependent and
lasted for all the observation period (30 min). In rats pre-treated
with diclofenac, a known non-steroidal anti-inflammatory, non-
selective cyclo-oxygenase inhibitor (Tegeder et al., 2000; Grace
et al., 2001), pain scores were lower than vehicle-pre-treated
only during the inhibitory interphase but not during the first
and second excitatory phases (Figs. 2A and 3A). These find-
ings of our study indicate that the Syzygium jambos extract had
an analgesic efficacy for inflammatory pain higher than that of
diclofenac.
To evaluate if the Syzygium jambos extract possesses anal-
gesic action on deep pain, we evaluated the effect of the extract
on the grip force. This procedure allows estimating muscle
nociception under normal conditions and hyperalgesic states
present during inflammation. We induced muscle inflamma-
tion by the injection of carrageenan, a phlogistic agent that
caused severe inflammation and pain in the triceps of the ani-
Fig. 2. Effect of 30 mg/kg, i.p. sodium diclofenac (diclofenac) and Syzygium
jambos extract on inflammatory cutaneous nociception estimated with the for-
malin test. Ordinate shows pain intensity expressed as pain scores generated by
Dubuisson rating scale. Abscissa displays observation intervals (3 min each)
following intraplantar injection of formalin (0.1 cm3 , 1%) in the right hind
paw of the rats. Veh, E10, E100, and E300 stand for vehicle and 10, 100, and
300 mg/kg of extract, respectively. * represents a significant difference respect
to control vehicle (0.9% NaCl). Two-way ANOVA followed by Bonferroni
test: (A) for treatment, F1,100 = 24.25, p < 0.0001; for interval, F9,100 = 13.84,
p < 0.0001; for interaction, F9,100 = 1.14, p < 0.3405 and (B) for treatment,
F3,200 = 68.14, p < 0.0001; for interval, F9,200 = 20.17, p < 0.0001; for inter-
action, F27,200 = 4.34, p < 0.0001.
mal. Fig. 4 shows that the injection of the vehicle, diclofenac,
and the Syzygium jambos extract did not produce any signifi-
cant change on the rat’s grip force. After 24 h of the injection
of carrageenan, the rats became more sensitive to the pain as
expressed by a significant drop in the grip force values. This
drop in grip force was blocked by sodium diclofenac while the
extract (300 mg/kg) reversed the effect, increasing significantly
grip force (Fig. 4). This finding of the present study suggests that
the Syzygium jambos extract did not alter physiological muscle
nociception, but it potently reduced muscle hyperalgesia, that
is, the exaggerated nociception seen under inflammation of the
muscle.
Since the analgesic efficacy of Syzygium jambos extract was
comparable to that of morphine and higher than that display by
diclofenac, we assessed the involvement of opioid receptors by
using the selective antagonist naloxone. Fig. 5A and B show
that naloxone alone produced cutaneous thermal hyperalgesia
(a decrease in hot plate response latency), suggesting a tonic
 D. Ávila-Peña et al. / Journal of Ethnopharmacology 112 (2007) 380–385 383

Fig. 4. Effect of Syzygium jambos extract on muscle nociception under normal

and inflammatory conditions, estimated by changes in grip forces. Ordinate rep-
resents changes in grip forces measured before (baseline) and 30 min after the
i.p. administration of either vehicle, 7.5 mg/kg sodium diclofenac or 300 mg/kg
Syzygium jambos extract (E300). Then, inflammatory conditions were induced
by the injection of carrageenan (2.5% p/v; 100 ␮l) into both triceps of the ani-
mals; 24 h later, vehicle, diclofenac or extract were administered 30 min before
the last grip force estimation. * represents significant difference compared to
the respective vehicle (one-way ANOVA followed Bonferroni: for inflammatory
conditions, F2,15 = 6.130, p = 0.0113).

Fig. 3. Effect of sodium diclofenac and Syzygium jambos extract on the forma-
lin test phases. Ordinate shows intensity pain (estimated as pain scores) in rats
treated with agents. Abscissa represents the different phases of pain produced
by the intraplantar injection of formalin: phase 1 (0–6 min after the injection);
interphase (6–15 min after the injection); phase 2 (15–30 min after the injec-
tion). Veh, E10, E100, and E300 stand for vehicle and 10, 100, and 300 mg/kg
of extract, respectively. * represents a significant difference respect to the cor-
responding vehicle group. Two-way ANOVA followed by Bonferroni test: (A)
for treatment, F1,30 = 9.47, p = 0.0044; for phases, F2,30 = 11.73, p = 0.0002;
for interaction, F2,30 = 1.69, p < 0.2009 and (B) for treatment, F3,60 = 28,37,
p = 0.0001; for phases, F2,60 = 16,84, p = 0.0001; for interaction, F6,60 = 5.09,
p < 0.0003.

inhibitory modulation of pain by an endogenous opioid system.

Surprisingly, naloxone increased, instead of reducing, the anal-
gesic effect of the extract, indicating that the analgesic effect
of Syzygium jambos extract on thermal cutaneous pain was not
mediated by opioid receptors. Similarly, the analgesic effect of
the extract on muscle hyperalgesia was increased by naloxone
since grip force was higher in carrageenan-injected rats treated
with both naloxone and the extract than with the extract alone
(Fig. 6). Thus, the remarkable analgesic effects of Syzygium jam- Fig. 5. Effect of naloxone on the analgesic effect of Syzygium jambos extract.
bos extract had on both cutaneous and deep muscle pain was not Ordinate shows latency time for rat the nociceptive response. Abscissa represents
mediated by opioid receptors (Choi et al., 2003). It is impor- the time elapsed since administration of naloxone or vehicle. Veh = vehicle (0.9
tant to note that the extract-induced analgesia detected in tests % NaCl), Nal = naloxone 0.1 mg/kg s.c., E300 = 300 mg/kg i.p. of extract. * rep-
resents a significant difference respect to respective control. Two-way ANOVA
designed for cutaneous pain (hot plate and formalin test) can-
followed by Bonferroni test: (A) for treatment, F1,70 = 13.32, p < 0.0005; for
not be attributed to motor impairment since the extract did not time, F6,70 = 0.23, p = 0.9668; for interaction, F6,70 = 0.3810, p = 0.8888 and
significantly diminish grip force in the intact muscle conditions (B) for treatment, F1,70 = 10.76, p < 0.0016; for time, F6,70 = 3.817, p = 0.0024;
(Figs. 4 and 6). for interaction, F6,70 = 1.083, p = 0.3813.
384 D. Ávila-Peña et al. / Journal of Ethnopharmacology 112 (2007) 380–385
Fig. 6. Effect of Syzygium jambos extract on muscle nociception: antagonis-
tic action of naloxone. Vehicle (0.9% NaCl), morphine, as a positive control
(A), and extract (B) were administered via i.p.; Veh = vehicle, Mor = morphine,
Nal = naloxone, E300 = 300 mg/kg of Syzygium jambos extract. Ordinate shows
change in grip force from baseline values taken before pharmacological treat-
ment, as a nociceptive response of the animal. Carrageenan was injected i.m.
(2.5% p/v; 100 ␮l) into both triceps. * represents a significant difference com-
pared to Veh-Veh group. ** represents significant difference compared to
Veh-E300 group (two-way ANOVA followed by Bonferroni test: B, for inflam-
matory conditions, F7,40 = 3.436, p = 0.0057).
We do not know the mechanisms that mediate the potent
analgesic effect by this plant extract. The flavonoids pre-
viously isolated from Syzygium jambos leaves (Slowing
et al., 1994a,b, 1996), myricetin- and quercetin-3-O-␤-d-
xilopyranosyl-(1-2)-␣-l-rhamnopyranosides were more effec-
tive as anti-inflammatory agents than phenylbutazone and
indomethacin, showing more than 60% inhibition at the dose
of 10 mg/kg. Some flavonoids exert antipyretic effects but their
analgesic profile seems to be weak (Agarwal, 1982; Alcaraz
and Jiménez, 1988,) while others have a clear analgesic action
(Picq et al., 1991; Meotti et al., 2006; Takano-Ishikawa et al.,
2006). As a matter of fact, quercetin produces a significant
dose-dependent analgesic effect in mice, which involves pri-
marily the modulation of adrenergic pathways (Kaur et al.,
2005). Interestingly, Syzygium jambos leaves contain quercetin-
glycosides which could be responsible for the action analgesic of
the plant.
4. Conclusions
Syzygium jambos extract (100 and 300 mg/kg i.p.) produced
a long-lasting analgesia for thermal cutaneous pain that had an
onset time and efficacy comparable to that of morphine, a potent
opioid analgesic. Syzygium jambos extract also had an analgesic
effect on inflammatory cutaneous pain with an efficacy higher
than that of diclofenac, a known anti-inflammatory drug. On
the other hand, the extract did not alter muscle nociception in
normal conditions but it markedly reduced muscle hyperalgesia
seen under inflammation of the muscle. These analgesic effects
of Syzygium jambos extract on both cutaneous and deep muscle
pain were not mediated by opioid receptors since they were
abolished by the selective blockade of opioid receptors with the
antagonist naloxone.
The present study demonstrated the analgesic activity of the
infusion used in Venezuelan folk medicine.
Acknowledgments
The authors wish to thank Dr. Miguel Pietrangeli (Depart-
ment of Biology, University of Zulia) for botanical identification.
This study was supported by FONACIT (Grants S1-97001209
and Lab-97000665).
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