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African Journal of Pharmacy and Pharmacology Vol. 6(23), pp. 1679-1684, 22 June, 2012
Available online at http://www.academicjournals.org/AJPP
DOI: 10.5897/AJPP12.179
ISSN 1996-0816 ©2012 Academic Journals
Full Length Research Paper
Evaluation of analgesic and anti-inflammatory effects of
fresh onion juice in experimental animals
Sima Nasri1, Mahdieh Anoush2* and Narges Khatami1
1Department of Physiology, Payame Noor University of Tehran, Tehran, Iran.
2School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
Accepted 16 May, 2012
Onion is a well known traditional medicinal plant that has been consumed for its putative nutritional
and health benefits for centuries. This study was carried out to determine the possible analgesic and
anti-inflammatory effects of fresh onion juice in experimental animals. Hot plate and formalin tests were
used to study the analgesic effect of fresh onion juice in mice during acute and chronic pain stages
modeling, respectively. The anti-inflammatory effect of fresh onion juice was assessed by applying
carrageenan sub plantar injection to Sprague-Dawley rats. The obtained results illustrated a significant
analgesic property for fresh onion juice in both pain phases compared with positive control group
(Pv≤0.05); the effects were similar to that of morphine (5 mg/kg) as the standard treatment. In
inflammation assessment, fresh onion juice was able to decrease the hind paw thickness significantly
in comparison with control group (Pv≤0.001). In the mean time, it also demonstrated better results than
the standard treatment, diclofenac with a 10 mg/kg dosage, (Pv≤0.05). It can be concluded that fresh
juice of onion is capable of inhibiting both acute and chronic pain as well as inflammation, with a more
strong effect towards inflammation.
Key words: Allium cepa, analgesic, anti-inflammatory, hot plate test, formalin test, carrageenan test.
INTRODUCTION
Onion (Allium cepa) is among the oldest cultivated plants,
and it is used both as a food and for medicinal application
(Lanzotti, 2006). A. cepa is a member of the family
Liliaceae, which consist of over 250 genera and 3700
species. The origin of A. cepa may be the region between
the rivers Euphrates and Tigris, which is the former
Mesopotamia and actually Iraq (Hegi, 1939). Nowadays
onion is cultivated all over the world, especially in
moderate climates (Muhlbauer et al., 2003).
Onion bulbs consist of water, carbohydrate, fibre,
protein, fat, vitamins (C, E) and minerals. This plant is a
rich source of several phytonutrients with interesting
*Corresponding author. E-mail: anoushm@zums.ac.ir. Tel: +98
241 4273637. Fax: +98 241 4273639.
Abbreviations: LT, Latency time; IP, intra-peritoneal; FOJ,
fresh onion juice.
pharmacological properties such as thiosulphinate,
volatile sulfur compounds and more polar compounds of
phenolic or steroidal origin like flavonoids (Lanzotti,
2006). Therefore, onion is among those useful plants for
treatment or prevention of a number of diseases,
including cancers (Shenoy and Choughuley, 1992;
Shutenko et al., 1999), coronary heart diseases (Lanzotti,
2006), diabetes (Sheela et al., 1995) and cataract
(Sanderson et al., 1999). Besides, many scientific
researchers showed that onion extract has significant
antioxidant activity because of its high amount of
flavonoids such as quercetin. (Nuutila et al., 2003; El-
Sayed and Rizk, 2009).
A study in the year 2003 showed that hydrophilic
ethanolic extract of onion inhibited osteoclast activity and
increased the bone formation process (Muhlbauer et al.,
2003(. In addition, it has been shown recently that the
oral intake of fresh onion juice had both spermatogenesis
and anti-protozoal effects in Toxoplasma gondii infected
rats (Khaki et al., 2011; Gharadaghi et al., 2012). Also,
1680 Afr. J. Pharm. Pharmacol.
there was an evidence of possible anti-inflammatory
effect for onion extract (Alpsoy et al., 2011). Inflammation
is as a result of increase in the number of leukocytes and
some other complex mediator molecules. One of the
most important ubiquitous substances that indicate and
modulate cell and tissue responses involved in
inflammation are prostaglandins (Gupta et al., 2006).
Among the most widely used medications for analgesia
and inflammation are the non-steroidal anti-inflammatory
drugs (NSAIDS) and their worldwide use demonstrated
their efficacy in reducing pain and inflammation (Laine,
2001). The NSAIDs consist of traditional non-selective
NSAIDs which inhibit both COX-1 and COX-2 and
selective COX-2 inhibitors (Ulrich et al., 2006). Although
they are effective at relieving pain and inflammation, both
types of NSAIDs are associated with serious adverse
events specially when used chronically (Herndon et al.,
2011). The traditional NSAIDs are associated with an
increased risk of gastrointestinal ulcers, including
gastrointestinal hemorrhage, perforation and obstruction
(Dhikav et al., 2003). The selective COX-2 inhibitors have
an improved gastrointestinal tolerability profile; however,
serious cardiovascular effects emerged from clinical
studies in recent years (Ong et al., 2007). Thus, many
researchers have dedicated their efforts to search for
safer drugs as well as natural products with less adverse
effects.
In this study, the analgesic effect of fresh onion juice in
both chronic and acute pain induction model with hot
plate and formalin test respectively in mice, as well as its
anti-inflammatory effect using carrageenan induced paw
edema in rats were investigated.
MATERIALS AND METHODS
Experimental animals
Male albino mice (25 to 30 g) and male Sprague-Dawley rats (220
to 250 g) were used in this study. Animals were obtained from
Tehran University of Medical Sciences and housed in the animal
holding unit of the School of Pharmacy at Zanjan University of
Medical Sciences with a 12 h light-darkness cycle, air-conditioning
(22 ± 2°C 45 to 55% humidity) in plexi-glass cages and free access
to food and water. All animals received human care according to
the guidelines published by the National Institutes of Health (NIH,
2000). The ethic regulations were followed in accordance with
national and institutional guidelines for the protection of animal
welfare during experiments. This study was approved by The Ethics
Committee of Payame Noor University. All animals were given three
days time to get acclimatized with laboratory conditions before
experiments begin.
Chemicals
Carrageenan lambda type I and formalin 35% solution were
purchased from Sigma-Aldrich Co. (Hamburge, Germany). Sodium
chloride solution 0.09% was obtained from Soha Helal
Pharmaceutical Hygienic (Tehran, Iran), while morphine and
diclofenac ampoules were bought from Darou Pakhsh
Pharmaceuticals Mfg. Co. (Tehran, Iran) and Tolid Darou Co.
(Tehran, Iran) respectively.
Preparation of fresh onion juice
Fresh white onions (A. cepa.) was purchased from a retail store
(Zanjan, Iran) and identified by botanists in the herbarium of School
of Pharmacy, Zanjan University of Medical Sciences. On the day of
experiments the onions were pealed, weighed and crushed well in
an electrical mill. Then the crushed product was filtered using sterile
filter papers with 40 micrometers mesh size. The transparent liquid
obtained was used freshly within 2 h after preparation to investigate
the possible analgesic and anti-inflammatory effects.
Carrageenan-induced paw edema in rats
Male Sprague-Dawley (S.D) rats (n=36) were divided into six
groups with six rats in each. Paw edema was induced by sub-
plantar injection of 50 µl 1% (w/v) solution of sterile carrageenan in
saline to the right hind paw (Zhang et al., 2011). Three groups of
animals received different doses of fresh onion juice (5, 7.5 and 10
ml/kg) intraperitoneally (I.P) half an hour before carrageenan
injection. Animals in the negative control group received normal
saline, while animals in the positive control group were
administered 10 mg/kg of diclofenac (Darou Pakhsh, Iran), the
standard anti-inflammatory drug and another group given 5 mg/kg
of morphine (Tolid Darou, Iran) intraperitoneally. Paw edema was
measured according to Olajide et al. (1999); before and at 1, 2, 3
and 4 h after induction of inflammation using a caliper vernier (scale
0.1 mm).
Hot plate method
The hot plate test described by Eddy and Leimback (1953) was
used to assess the analgesic effects of fresh onion juice (Kumar et
al., 2009). The animals were divided into six groups with eight mice
in each. Three groups were treated with different doses of fresh
onion juice (5, 7.5 and 10 ml/kg) via I.P injection; one group
received normal saline (7.5 ml/kg) as negative control group,
another group, received morphine (5 mg/kg) as positive control and
the final group of mice received naloxone (4 mg/kg) 10 min before
fresh onion juice. Moreover, 15 min after the administration of fresh
onion juice; the animals were placed on a hot plate with 50 ± 0.5°C.
A cut-off time period (40 s) was considered as maximal latency at
which the animal was picked up from the hot plate by the examiner
to avoid injury to mice tissues. Licking or picking up the hind paw
was recorded as the reaction time and measured at time points of
0, 15, 30, 45 and 60 min (Kumar et al., 2009). Morphine (5 mg/kg)
was used as a reference drug (Abbas et al., 2011).
Formalin test and the pain score
In order to perform this test, 32 male S.D rats were rendered in 4
groups with 8 rats in each as follows: Negative control group
received 7.5 ml/kg of normal saline, while positive control group
treated with 5 mg/kg morphine as the standard drug intra-
peritoneally 15 min before formalin injection. The test group
received 7.5 ml/kg fresh onion juice (as an optimum dose) and one
group received I.P injection of naloxone (4 mg/kg) 15 min before
formalin injection. Formalin test chamber includes a plexi glass box
with a 45° mirror at the bottom of the box in order to monitor the
position of the animal in the chamber for accurate observation. All
of the animals received formalin as the standard stimulant of both
acute and chronic phase of inflammatory pain (Kim et al., 2007).
Prior to formalin injection, the animals were placed in another cone
shaped chamber for 30 min. After injection of 50 µL formalin (2.5%)
into their right paw, they were transferred to the plexi glass box and
were observed by recording the reflexes every 15 s based on
Nasri at al. 1681
4
4.5
5
5.5
6
6.5
7
7.5
8
8.5
0
60
120
180
240
Time (min)
Hind paw thickness (mm)
(mm)
OFJ (7.5 ml/kg)
Morphine (5 mg/kg)
Diclofenac (10 mg/kg)
Control (normal saline 7.5
ml/kg)
***
***
***
***
**
***
***
***
Figure 1. The effects of fresh onion juice, morphine and diclofenac towards hind paw edema in carrageenan
induced acute inflammation. A vernier caliper was applied to measure the hind paws thickness right before and
at four time points with 60 min intervals. Each measurement was repeated three times and the average was
recorded for that animal. The diagram shoes that FOJ was even more effective than both diclofenac and
morphine. All values represent mean ±S.E.M and are at least from 8 independent animals. **Shows significant
difference (p≤0.01) with control group; ***Shows significant difference (p≤0.001) with control group.
original Dubuisson Dennis method with the score of 0, 1, 2, 3 as
follows (Abbott et al., 1995): zero (0) score mentions that animal
has a complete balance and is walking normally regardless to the
injected foot; score (1) applied for the time points that the animal
has a moderate imbalance while moving because of pushing the
body weight towards the injected foot; score (2) was correlated to
the time points when animal was not only walking with a high
imbalance but also raising the painful injected foot from the box
floor; score (3) is given to the animal licking the painful injected feet
intensely or shaking it. The quantitative data was counted per 5 min
and recorded based on the pain score on each time interval. The
data gathered within 60 min after formalin injection was calculated
as follows:
Pain score: [0T0 + 1T1 + 2T2 + 3T3] / 20
Where T0, T1, T2 and T3 refer to the frequency for 15 s that animals
expressed behaviors related to 0, 1, 2 and 3 scores, respectively.
The first 5 min after injection for all groups was taken as acute
phase 0 to 5 min and 16 to 60 min as chronic phase.
Statistical analysis
In order to perform comparative statistical analysis of the results
between different groups, SPSS 17.0 software was applied. All the
results were expressed as (mean ± SEM) and P values equal or
less than 0.05 (Pv≤0.05) were determined as significant levels of
difference.
RESULTS
Effects of morphine and fresh onion juice on
carrageenan-induced inflammation
As shown in Figure 1, the thickness of hind paw was
measured after a sub-plantar injection of carrageenan
while rats were received diclofenac, morphine, fresh
onion juice and normal saline as positive control,
morphine test, fresh juice test and negative control
groups, respectively. Interestingly, fresh onion juice
illustrated the best response in this test and showed a
significant difference not only with negative control group
(PV ≤0.001), but also with the group which received both
morphine and diclofenac (PV ≤0.05); the later one was
selected as our standard treatment for anti inflammatory
assessments.
Effects of morphine and fresh onion juice on hot
plate acute pain model
Using this method, the sensitivity of mice towards pain
stimulates received via a standard hot plate, was
measured. In order to access the least bias with control
group, the ratio of latency time changes were measured
applying the formula below for each mouse:
(L.Tt - L.T0) / L.T0
L.Tt expresses the latency time for each mouse in the
specific time intervals after receiving treatments, while
L.T0 shows the latency time at the zero point just prior to
receiving any treatment.
According to the dose-response curve results, the 7.5
ml/kg dosage had the best latency time responses.
Therefore, this dose has been used later on, in other
protocols and tests. It can be deducted from Figure 2
1682 Afr. J. Pharm. Pharmacol.
Time (min)
15 30 45 60
Control (7.5 ml/kg)
Naloxone (4 mg/kg) + OFJ (7.5 ml/kg)
Morphine (5 mg/kg)
OFJ (7.5 ml/kg)
Figure 2. The analgesic effects of fresh onion juice in comparison with that of morphine on hot plate test. The
latency time for animals’ response to hot plate stimulus was measured within 15 min intervals during 60 min. The
FOJ’s injection moment was equal to 0 time point. The results were calculated as (L.Tt- L.T0)/ L.T0. naloxone was
used as an antagonist for opioid receptors in order to determine if the extract show its effect via opioid receptors. All
values represent Mean ±S.E.M and are at least from 8 independent animals. **Shows significant difference (p≤0.01)
with control group; ***Shows significant difference (p≤0.001) with control group.
thatmorphine has the best analgesic effect with a
noticeable significant difference (PV≤0.001) which was
almost the same for the fresh juice especially in first 30
min. This result expresses that the fresh juice plays its
best role as an analgesic agent in first 30 min with a high
significant difference according to control group
(PV≤0.05). Although the diagram for morphine illustrates a
sharp increase in the first 30 min followed by a plateau
phase; adding naloxone to the morphine treated ones,
changed the shape of the diagram and makes it similar to
the one for fresh juice.
Effects of morphine and fresh onion juice on
formalin-induced pain
During this method, the pain score was calculated
according to original Dubuisson Dennis method which
has been lately modified (Mokhtari, 2011) during 60 min.
The results obtained from this method indicate that our
treatments were useful in the first 45 min in depriving the
pain score significantly (PV≤ 0.05). According to Figure 3,
no significant difference was observed between morphine
and fresh juice (Pv≥0.05) in controlling both acute and
chronic pain phase which were determined at 0 to 5 min
for acute pain phase, and 16 to 60 for chronic one.
On the other hand, Figure 3 indicates the possible
relationship between the effects of morphine and fresh
juice while we used naloxone together with the fresh
onion juice; as it can be seen there were observed no
significant differences between two groups in all time
intervals. Adding naloxone to morphine received animals
made the diagram more similar to control group, hence
the results for that group was not illustrated in Figure 3.
DISCUSSION
In this study, three different methods have been applied
in order to identify the possible analgesic as well as anti
inflammatory effects of fresh onion juice in mice and rats.
According to the well known models for both hot plate
and carrageenan test, it has been suggested in current
protocols in pharmacology as well as some articles to
apply mice for hot-plate test investigations and rats for
carrageenan induced inflammation (Buadonpri et al.,
2009; Bannon and Malmberg, 2007) Results obtained
from carrageenan test indicates a strong anti-
inflammatory effect with a significant difference not only
with the negative control group (Pv≤0.001), but also with
the positive control one (Pv≤0.05). This finding illustrates
a possible potent COX inhibitory effect of onion juice in its
therapeutic dosage because it was as effective as the
standard treatment (diclofenac) towards inflammation.
The odd finding of this step was the similar anti
inflammatory response for both morphine and diclofenac.
This finding is a subsidiary for the very recent finding of a
research group in Denmark proving a noticeable anti-
inflammatory characteristic for opioids in general, as well
as morphine in particular (Lindegaard et al., 2010) with
an unknown mechanism.
According to some studies, fresh onion juice is capable
Nasri at al. 1683
-0.5
0
0.5
1
1.5
2
2.5
0
1
2
3
4
5
6
7
8
9
10
11
12
Time intervals (every 5 min)
Control (normal salin 7.5ml/kg)
Naloxone (4mg/kg)+OFJ (7.5ml/kg)
OFJ (7.5ml/kg)
Morphine (5 mg/kg)
**
***
*
***
***
***
**
*
*
Pain score
Figure 3. The effects of fresh onion juice, morphine and naloxone plus FOJ on both acute and chronic pain phases
induced by formalin in male mice. Right after formalin injection, the pain scores were calculated during one hour and
because of the biphasic nature of pain, the acute phase was allocated the first 5 min after formalin injection, while
chronic pain arose between 20 to 25 min and lasted for 10 min. This figure illustrates the significant differences
between treated groups and control group which received normal saline. All values represent Mean ±S.E.M and are at
least from 8 independent animals. * Shows significant difference (p≤0.05) with control group; **shows significant
difference (p≤0.01 with control group; ***shows significant difference (p≤0.001) with control group.
of inhibiting arachidonic acid metabolism (Dorsch et al.,
1988) and so it can prevent formation of leukotrienes and
thromboxanes, via inhibiting COX and LOX
(lipoxygenase) pathways responsible for its anti apoptotic
effect (Alpsoy et al., 2011). On the other hand, it was
proven that flavonoids express anti-inflammatory
properties by which they inhibit the proliferation and
activity of lymphocytes (Recio et al., 1995). According to
high content of flavonoids such as quercetin (Lanzotti,
2006) in onion juice and extract, it can be claimed that
this potent anti-inflammatory effect might be because of
quercetin as would need to be investigated in further
studied. Moreover, one paper suggested that onion can
cause analgesia as well as local anesthesia via
mitochondria (Nouette-Gaulain et al., 2011); which
encouraged us towards assessment of the analgesic
capability for fresh onion juice.
The analgesic effect of fresh onion juice was studied
via two different processes. The hot plate test results
indicated that the fresh juice was helpful in reducing
acute pain in comparison with the negative control group
that received mere normal saline (Pv≤0.05). This effect
was not as potent as morphine (the standard treatment),
with a high significant difference (Pv≤0.001) compared
with negative control group. Moreover, in order to
examine if fresh onion juice penetrates the CNS system
and affect the same receptors as for morphine, naloxone
was injected to one group simultaneously with fresh
onion juice. The results indicated that there might not be
any interactions between these two treatments (morphine
and fresh onion juice). Hence, more studies are needed
to determine the possible analgesic pathway by which
fresh onion juice attenuates pain; which led us to set up
another test using formalin in order to compare the acute
and chronic pain and the effects of both treatments on
these two phases of pain.
Formalin test results showed that fresh juice illustrated
significant analgesic effect both in acute and chronic pain
phases which were assumed as the first 5 min after
formalin sub-plantar injection and the time period
between 16 to 50 min, respectively. It has been assumed
that these two stages represent two different type of pain
related to direct nerve stimulation (acute pain) followed
by an inflammatory process (chronic stage). Diverse
studies proved that opioids such as morphine affect both
stages with the highest inhibitory response presumably
via mu receptors in the central nervous system (Abbas et
al., 2011); on the other hand, there are NSAIDs such as
indomethacine with the most inhibition towards the
chronic stage via COX inhibition (Randolph and Peters,
1997).
According to the literature, reduction in pain,
inflammation and the signal transduction pathway(s)
responsible for both phenomena mentioned above,
results in a decline in plasticity at dorsal root of spinal
cord via deprivation in P substance and/or stimulant
amino acids such as glycine and glutamate from nerve
endings (Willis, 2001; Hunter and Singh, 1994; Terayama
1684 Afr. J. Pharm. Pharmacol.
et al., 2000). In addition, there is a substance called
ajoene found both in garlic and onion which has been
proposed to inhibit the pain receptors at dorsal root of
spinal cord, thus resulting in an inhibition of pain signal
transduction (Yassaka et al., 2010).
Conclusion
It can be concluded that the fresh onion juice is capable
of inhibiting pain and inflammation, the later most
especially, and both the exact mechanism(s) for this
effect via receptor purification as well as the main fraction
responsible for, should be studied in the near future.
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