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Research Article
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The Effect of Curcumin (Active Substance of Turmeric)on the Acetic Acid-Induced Visceral Nociception in Rats |
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Hossein Tajik,
Esmaeal Tamaddonfard
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Nasrin Hamzeh-Gooshchi
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ABSTRACT
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In the present study, the effect of chronic oral administration of curcumin in the presence or absence of morphine and noloxone was investigated on the visceral nociception induced by acetic acid in rats. Intraperitoneal injection of acetic acid (1 mL, 2%) produced contractions in the abdominal musculature (writhes). The latency time to the beginning of the first writhe was measured and the total number of writhes in the 1 h after acetic acid injection was counted. The latency time to the beginning of the first writhe was significantly (p<0.05) increased and the number of writhes was significantly (p<0.05) decreased by curcumin (20 and 40 mg kg-1 body weight). The same results were obtained after subcutaneous injection of morphine (1 mg kg-1 b.wt.). Naloxone at the dose of 1 mg kg-1 body weight had no effect on pain intensity. Curcumin significantly (p<0.05) enhanced the effect of morphine on the visceral pain responses, however did not reverse the effect of naloxone. Present data suggest that in the acetic acid-induced visceral nociception of rats, curcumin may produce an antinociceptive effect and the endogenous analgesic opioid system is involved in the curcumin-induced antinociception.
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INTRODUCTION
Turmeric, Curcuma longa L. rhizomes, has
been widely used for centuries in the indigenous medicine for the treatment
of inflammatory conditions (Ammon and Wahl, 1991). Curcumin, the major
component of turmeric, has wide range of biological and pharmacological
activities including anti-inflammatory, anti-oxidant, anti-cancer, anti-microbial,
anti-fungal, anti-viral and anti-coagulant activities (Araujo and Leon,
2001; Maheshwari et al., 2006).
On the antinociceptive effect of curcumin it was reported
that curcumin-produced antinociception using tail immersion and hot plate
assays of pain in a diabetic mouse model of neuropathic pain (Sharma et
al., 2006). In addition, Tajik et al. (2007) reported an antinociceptive
effect of curcumin in the formalin test of rats. JCICM-6 is an extract
of an anti-arthritic herbal formula and Curcuma longa is one of
its components. It was found that JCICM-6 produced antinociception in
both tail flick of rats and writhing reflex of mice (Zhou et al.,
2006).
The intraperitoneal administration of agents such as
acetic acid that irritate serous membranes provokes a very stereotyped
behavior in the mouse and the rat which characterized by abdominal contractions,
movements of body as a whole, twisting of dorso-abdominal muscles and
a reduction in motor activity. The test is sometimes called the abdominal
contortion test, the abdominal constriction response, or the stretching
test, but more recently it is known as the writhing test (Le Bars et
al., 2001).
To our knowledge, studies examining the effect of curcumin
on the visceral pain are lacking. Therefore, the present study was designed
to investigate the effect of curcumin on the acetic acid-induced visceral
nociception in rats. In addition, to identify the mechanism that possibly
mediating the effect of curcumin on pain, we assessed the contribution
of the endogenous analgesic opioid system using morphine (an opioid agonist)
and naloxone (an opioid antagonist) with curcumin.
MATERIALS AND METHODS
Animals:
Healthy adult male albino Wistar rats weighing 220-250
g were obtained from the Laboratory Animals Care and Use Center of Urmia
University. Rats were maintained in polypropylene cages with four rats
in each cage with food and water available ad libitum, in a laboratory
with controlled ambient temperature (20-23°C) and under a 12 h light-dark
cycle (lights on 07:00 h; lights on 19:00 h). Eight rats were used in
each treatment. The experimental protocol was approved by the Laboratory
Animals Care and Use Center of Urmia University.
Drugs and treatments:
Drugs used in the present study were curcumin (Merck,
Darmstadt, Germany), morphine sulphate and naloxone hydrochloride (Temad,
Tehran, Iran). Curcumin suspension was freshly prepared in 0.15 M NaCl
(normal saline) and was administered orally at the doses of 10, 20 and
40 mg kg-1 b.wt. once daily for eight days. Oral administration
of curcumin was made in a constant volume of 0.2 mL rat-1 over
a period of 1-2 min. Morphine and naloxone were dissolved in normal saline
and were injected subcutaneously at the same dose of 1 mg kg-1
body weight 30 min before induction of pain. In combined treatments, morphine
and naloxone were injected 30 min after the latest oral administration
of curcumin. It was reported that the acute oral administration of curcumin
at the dose of 50 mg kg-1 had no effect on the formalin pain
(Tajik et al., 2007), therefore, in the present study, the acute
effect of curcumin at the doses of 10, 20 and 40 mg kg-1 b.wt.,
on the visceral pain was not performed.
Writhing test:
Each rat was placed inside a plexiglass observation chamber
(40x30x20 cm) for an acclimation period of 30 min. At the end of this
period, drug treatment was performed according to the time schedule for
each treatment and then 1 mL of 2% acetic acid was intraperitoneally injected
using a 25-gauge injection needle. Immediately after injection of acetic
acid, the latency time to the beginning of the first contraction of the
abdominal musculature (writhe) was measured and the number of writhes
was counted during a 60 min observation period. A writhe was defined as
a wave of the contraction of the abdominal musculature followed by extension
of the hind limbs (Fukui et al., 2006). Control rats which received
appropriate amount of normal saline did not show any spontaneously occurring
body writhes.
Statistical analysis:
Data were expressed as mean±SEM. Differences among
treated groups were statistically evaluated using the one way analysis
of variance (ANOVA) followed by Duncan`s test. Differences were considered
significant at p<0.05.
RESULTS AND DISCUSSION
After intraperitoneal injection of acetic acid, the latency time
to the beginning of the first writhe and the number of writhes were obtained
5.1±1 min and 36.5±2.9, respectively. Curcumin at the dose
of 10 mg kg-1 b.wt. did not affect the latency time and number
of writhes, whereas at the doses of 20 and 40 mg kg-1 b.wt.,
curcumin significantly (p<0.05) increased the latency time to the beginning
of the first writhe. The number of writhes was significantly (p<0.05)
decreased by curcumin at the doses of 20 and 40 mg kg-1. The
effect of curcumin (40 mg kg-1) on the pain response was greater
than that of curcumin (20 mg kg-1) (Table 1).
The latency time to the beginning of the first writhe was increased and
the number of writhes was decreased after subcutaneous injection of morphine
(1 mg kg-1 b.wt.). However, noloxone alone had no effect. Curcumin,
with no effect on the action of naloxone, significantly (p<0.05) enhanced
the effect of morphine on the latency time to the beginning of the first
writhe. The decrease in the number of writhes induced by morphine was
also significantly (p<0.05) enhanced by morphine (Table
2).
In the present study, it was found that intraperitoneal
injection of acetic acid produced contraction in the abdominal wall musculature.
The acetic acid-induced writhing is a standard test for visceral pain,
sensitive to opiates as well as non-opiates analgesics (Steranka et
al., 1987). The associated antinociceptive response is believed to
involve the release of endogenous substances, such as bradykinin and prostanoids
among others that stimulate nociceptive endings (Berkerkopf and Weichman,
1988).
Table1: |
Effect of chronic
oral administration of curcumin on the visceral nociception induced
by acetic acid in rats |
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a: Measured
after acetic acid administration (1 mL, 2%), b: Counted
in an 1 h observation period after acetic acid administration. Values
are mean±SEM, n = 6 in each group, *: p<0.05 vs. normal
saline group,†: p<0.05 vs. curcumin (20 mg kg-1),
one way ANOVA followed by Duncan`s Test, p.o.: Per oral |
Table 2: |
Effect of chronic
oral administration of curcumin on the visceral nociceptive changes
induced by morphine and naloxone in the writhing test of rats |
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a: Measured
after acetic acid administration (1 mL, 2%), b: Counted
in an 1 h observation period after acetic acid administration. Values
are mean±SEM, n = 6 in each group, *: p<0.05 vs. normal
saline group, †: p<0.05 vs. curcumin and morphine groups,
one way ANOVA followed by Duncan`s Test, p.o.: Per oral, s.c.: Subcutaneous |
In this study, chronic oral administration of curcumin
suppressed visceral nociception induced by acetic acid. It seems that
anti-inflammatory property of curcumin may contribute to its antinociceptive
effect. In the formalin test of rats, it has been shown that acute oral
administration of curcumin at the high doses (100 and 200 mg kg-1
b.wt.) suppresses the second phase of pain (Tajik et al., 2007).
The second phase of formalin-induced pain is well known as an inflammatory
pain (Tjolsen et al., 1992). In addition, it has been reported
that curcumin has ability to inhibit the activation of inflammatory mediators
such as cyclooxygenase-2, lipooxygenase, inducible nitric oxide synthase
and nuclear factor kappa B (Bengmark, 2006). On the other hand, it has
been found that after intraperitoneal injection of acetic acid, inflammatory
reactions develop in the peritoneum (Clementi et al., 1999).
In current study, morphine but not naloxone suppressed
the acetic acid-induced visceral pain. This finding is in accordance with
previous reports that intraperitoneal injection of morphine reduces the
number of acetic acid induced abdominal contractions in mice and pretreatment
with naloxone has been shown to inhibit the suppressive effect of morphine
(Reichert et al., 2001).
In this study, curcumin, without any effect on the naloxone
action, potentiated the morphine-induced antinociception. This indicates
that the antinociceptive effect of curcumin may be associated on the activation
of the opioid system. The sensation of pain is well known to be modified
by endogenous opioid system. Morphine (an opioid agonist) and naloxone
(an opioid antagonist) are used to explore the involvement of the endogenous
opioid analgesic system activated by novel analgesics (Ananthan, 2006).
In conclusion, it seems that several mechanisms are involved
in the antinociceptive effect of curcumin. Further studies are needed
to identify the antinocieptive activity of curcumin in pain mechanisms.
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