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Anti-Inflammatory and Antinociceptive Effects of Mitragyna speciosa Korth Methanolic Extract

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To determine the anti-inflammatory and antinociceptive activities of Mitragyna speciosa Korth methanol extract in rodents. Materials and Anti-inflammatory activity was evaluated using carrageenan-induced paw edema and cotton pellet-induced granuloma tests in rats. Antinociceptive activity was measured using the writhing test and the hot plate test in mice, and the formalin test in rats. All drugs and extracts were diluted in dH(2)O and administered through the intraperitoneal route. Results were analyzed using one-way ANOVA followed by Dunnett's test for multiple comparisons among groups. Results showed that intraperitoneal administration of the extract at doses of 100 and 200 mg/kg produced significant dose-dependent activity in all of the nociceptive models evaluated (p < 0.05). With the formalin test, the antinociceptive activity in mice was inhibited only at the highest dose of the extract (200 mg/kg). The study also showed that intraperitoneal administration of the methanol extract of M. speciosa (100 and 200 mg/kg) significantly and dose-dependently suppressed the development of carrageenan-induced rat paw edema (p < 0.05). In the chronic test, however, significant reduction in granulomatous tissue formation in rats was observed only at the highest dose of the methanol extract of M. speciosa (200 mg/kg, p < 0.05). The present study suggests the presence of potent antinociceptive and anti-inflammatory principles in the extract, supporting its folkloric use for the treatment of these conditions.
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Original Paper
Med Princ Pract 2009;18:378–384
DOI: 10.1159/000226292
Anti-Inflammatory and Antinociceptive
Effects of Mitragyna speciosa Korth
Methanolic Extract
W.M. Shaik Mossadeq a, c M.R. Sulaiman a T.A. Tengku Mohamad a H.S. Chiong a
Z.A. Zakaria d M.L. Jabit e M.T.H. Baharuldin b D.A. Israf a
Departments of
a Biomedical Sciences and
b Human Anatomy, Faculty of Medicine and Health Sciences, and
c Department of Veterinary Preclinical Sciences, Faculty of Veterinary Medicine, Universiti Putra Malaysia,
Serdang,
d Faculty of Pharmacy, Universiti Teknologi MARA, Shah Alam, and
e Technical Services Centre, MARDI,
Kuala Lumpur, Malaysia
200 mg/kg) significantly and dose-dependently suppressed
the development of carrageenan-induced rat paw edema
(p ! 0.05). In the chronic test, however, significant reduction
in granulomatous tissue formation in rats was observed only
at the highest dose of the methanol extract of M. speciosa
(200 mg/kg, p ! 0.05). Conclusion: The present study sug-
gests the presence of potent antinociceptive and anti-in-
flammatory principles in the extract, supporting its folkloric
use for the treatment of these conditions.
Copyr ight © 2009 S. Karger AG, B asel
Introduction
Mitragyna speciosa Korth, a member of the Rubiaceae
family, is a tropical plant that is widely found in the rain-
forests of Malaysia and in the central and southern re-
gions of Thailand. The leaves of the M. speciosa Korth
tree, known as ‘biak-biak’ or ‘ketom’ in Malaysia and as
‘kratom’ in Thailand, are often chewed, smoked or made
as tea and have been traditionally used by many laborers
to increase work efficiency and tolerance of hard work
[1] .
In Malaysia’s folk medicine, the leaves are used to treat
diarrhea, fever, asthma, as cough suppressant and for
Key Words
Mitragyna speciosa Anti-inflammatory Antinociceptive
Opioid system
Abstract
Objectives: To determine the anti-inflammatory and antino-
ciceptive activities of Mitragyna speciosa Korth methanol ex-
tract in rodents. Materials and Methods: Anti-inflammatory
activity was evaluated using carrageenan- induced paw ede-
ma and cotton pellet-induced granuloma tests in rats. Anti-
nociceptive activity was measured using the writhing test
and the hot plate test in mice, and the formalin test in rats.
All drugs and extracts were diluted in dH
2 O and adminis-
tered through the intraperitoneal route. Results were ana-
lyzed using one-way ANOVA followed by Dunnett’s test
for multiple comparisons among groups. Results: Results
showed that intraperitoneal administration of the extract at
doses of 100 and 200 mg/kg produced significant dose-de-
pendent activity in all of the nociceptive models evaluated
(p ! 0.05). With the formalin test, the antinociceptive activity
in mice was inhibited only at the highest dose of the extract
(200 mg/kg). The study also showed that intraperitoneal ad-
ministration of the methanol extract of M. speciosa (100 a nd
Recei ved: October 29, 2008
Revis ed: February 12, 2009
Prof. Dr. Mohd Roslan Su laiman
De partment of Biomed ical Sciences , Faculty of Medicine and Health Scienc es
Universiti Putra Ma laysia, 4 3400 Serdang, Selangor (Malaysia)
Tel. +60 3 8947 2603, Fax +60 3 8947 2585
E-Mail mrs@medic.upm.edu.my or mrs 4969@gmail.com
© 200 9 S. Karger AG, Basel
1011–7571/09/0185–0378$26.0 0/0
Accessible online at:
www.karger.com/mpp
Pharmacological Effects of Mitragyna
speciosa Korth Extract
Med Princ Pract 2009;18:378–384
379
some users, to prolong sexual intercourse. In addition, it
is also used for deworming, as cure for stomach ailments
and as a substitute for opium or morphine in the treat-
ment of drug addicts [2, 3] . Over 20 alkaloids have been
isolated from M. speciosa leaves, with mitragynine re-
ported to be the major alkaloid that is responsible for the
substance’s opioidergic effect
[4, 5] . Pharmacologically,
M. speciosa has been shown to possess antitussive, anti-
nociceptive, anti-inflammatory and antidiarrheal prop-
erties
[1, 6 –8] . Despite the reported antinociceptive and
anti-inflammatory activities of M. speciosa methanol ex-
tract (MSM), previous studies focused on the activities of
its alkaloids. Therefore, the aim of the present study was
to investigate the medicinal properties of MSM with re-
gard to its anti-inf lammatory and antinociceptive effects,
so as to provide some pharmacological evidences for its
folkloric uses.
Materials and Methods
Plant Material
The fresh mature leaves of M. speciosa were collected from
undisclosed locations in Selangor and Perlis, Ma laysia. The leaves
were identified and authenticated taxonomically by a botanist,
Ms. Radhiah Zakaria, at the Herbarium Laboratory, Faculty of
Forestry, Universiti Putra Malaysia (UPM), Serdang, Selangor,
where a voucher specimen (ALS 001) was deposited for future ref-
erence.
Preparation of the Extract
MSM was prepared as previously described
[9] . Brief ly, the
leaves (1,000 g) were dried at room temperature for 10 days, pul-
verized into a coarse dry powder ( ! 1 mm from our observation)
and extracted wit h 95% methanol in the ratio of 1:
10 (w/v) by cold
maceration for 72 h. The extract was evaporated to a dark brown
semisolid mass (yield 12%, w/w) under reduced pressure and kept
at –20
° C prior to use.
Phytochemical Analysis
Phytochemical screening of the MSM was performed to detec t
the presence of different classes of constituents, such as alkaloids,
flavonoids, saponins , steroids and triterpenoids , using the follow-
ing reagents and chemicals: alkaloids with Mayer and Dragen-
dorff ’s reagents, flavonoids with NaCl and HCl, tannins with 1%
gelatin and 10% NaCl solutions, saponins with frothing test and
finally, steroids and triterpenoids with Liebermann-Burchard
test.
A n i m a l s
Adult male Sprague-Dawley rats (150 –200 g) and ma le Balb C
mice (20–30 g) were used throughout these experiments. The an-
imals were maintained in a room with a 12-hour light-dark cycle
for at least 7 days before the experiment to allow acclimatization.
The animals were provided with food and water ad libitum. All
experiments were performed according to the Ethical Guidelines
for Investigations of Experimental Pain in Conscious Animals
[10] and approved by the Ethics Committee on Animal Experi-
mentation, Faculty of Medicine and Health Sciences, UPM.
W r i t h i n g Te s t
The test was performed according to Zakaria et al.
[11] , with
slight modifications
[12] . Sixty mice which were equally divided
into six groups (n = 10) were intraperitoneally (i.p.) pretreated
with MSM (50, 100, 200 mg/kg), 0.9% NaCl (control), acetylsali-
cylic acid (ASA, 100 mg /kg) or morphine (5 mg/kg ). In an at tempt
to investigate the participation of the opioid system in the antino-
ciceptive activity of this plant, two separate groups of mice con-
sisting of 10 mice per group were pretreated with the nonselective
opioid receptor antagonist naloxone (5 mg/kg, i.p.), which was
injected 10 min before the administration of the extract (200 mg/
kg, i.p.) or morphine (5 mg/kg, i.p.). After 30 min, 0.6% (v/v) solu-
tion of acetic acid was injected i.p. (10 ml/kg). The number of ab-
dominal constrictions together with the stretching of one or both
hind legs occurring between 5 and 30 min after acetic acid injec-
tion was recorded.
F o r m a l i n T e s t
This procedure was essentially simila r to that described previ-
ously by Zakaria et al.
[11] . Sixt y rats were equally divided into six
gr oups (n = 10). In thi s mo del, for mal in (2.5%, 50 l) was injected
via the intraplantar route into the right hind paw of rats 30 min
after the i.p. administration of 0.9% NaCl (10 ml/kg, control),
MSM (50, 100, 200 mg/kg), ASA (100 mg/ kg), or morphine (5 mg/
kg). The amount of time the animal spent licking or biting the
injected paw was measured between 0 and 5 min (phase 1, neuro-
genic) and 15–30 min (phase 2, inflammatory) after the injection
of formalin.
Hot Plate Test
The test was performed as previously described
[11] . In this
mo de l, 6 0 m ic e w er e e qu al ly d iv id ed in to si x g r oup s ( n = 10). T hi r-
ty minutes after pretreatment with either 0.9% NaCl (control),
MSM (50, 100, 200 mg/kg, i.p.), ASA (100 mg/kg), and morphine
(5 mg/kg), the mice were placed on a heated metal plate (Ugo
Basile, model 7280) maintained at 53 8 1 ° C and the response la-
tency for nociceptive behavior, e.g. shaking, licking the paw or
jumping, was recorded. Mice were removed from the hot plate
immediately after the response. Response latencies were mea-
sured at 0-, 30-, 60-, 120-, 180-, and 240-min intervals after sub-
stance administration, with a cutoff time of 20 s to avoid tissue
injury. In order to investigate the participation of the opioid sys-
tem in the analgesic property of this plant, two separate groups of
mice consisting of 10 mice per group were pretreated with the
nonselective opioid receptor antagonist naloxone (5 mg/kg, i.p.),
which was injected 10 min before the administration of the ex-
tract (200 mg/kg, i.p.) or morphine (5 mg/kg, i.p.) and the exper-
iment was repeated.
Carrageenan-Induced Paw Edema Test
The carrageenan-induced rat paw edema was assessed by the
method described by Loro et al.
[13] . Paw edema was measured
with a plethysmometer (model 7140, Ugo Basile, Italy). The basal
volume of the right hind paw was determined before administra-
tion of any drug. Eight animals per group were pretreated with
MSM (50, 100 and 200 mg/kg, i.p.). Thirty minutes later, edema
Shaik Mossadeq et al.
Med Princ Pract 2009;18:378–384
380
was induced with 0.1 ml of 1% (w/v) solution of carrageenan, in-
jected into the subplantar region of the rat hind paw. Control an-
imals received 0.9% NaCl (10 ml/kg), whereas positive control
animals received ASA (100 mg/kg) under the same experimental
conditions. The volumes of the injected paws were measured im-
mediately after injection (0 h) and then every hour until 5 h after
induction of edema. The results are presented as the paw volume
variation in relation to basal values.
C o t t o n P e l l e t - I n d u c e d G r a n u l o m a T e s t
The met hod of Okoli et al.
[14] wa s e mp loy ed , w it h s li gh t mo d-
ifications. Forty rats were equally div ided into five groups (n = 8).
On day 1, the rats were pretreated with MSM (50, 100 and 200
mg/kg, i.p.). Control animals received either 0.9% NaCl or equal
volume of ASA (100 mg/kg). Thirty minutes after pretreatment,
a sterilized cotton pellet (30 8 1 mg) was subcutaneously intro-
duced in the dorsum of rats anesthetized with Avertin (10 ml/kg,
i.p.). The rats were treated with a single injection of ASA, 0.9%
NaCl or MSM (50, 100 and 200 mg/kg) daily for 7 consecutive
days. On day 8, the animals were sacrificed, the pellets dissected
out and granulomas dried at 60
° C overnight to determine the fi-
nal dry weight. The difference between the initial (30 mg) and
final dry mass was considered as t he weight of the granulomatous
tissues produced.
Statistical Analysis
The results were expressed as mean 8 SEM and analyzed us-
ing one-way A NOVA followed by Du nnett’s test for mu ltiple com-
parisons among groups. Values with p ! 0.05 were considered to
be statistically significant.
R e s u l t s
Phytochemical Analysis
A phytochemical screening of MSM indicated the
presence of the following secondary metabolites: alka-
loids and flavonoids in high concentration, saponins in
moderate concentration, while tannins and sterols were
detected in a low concentration. The extract, however,
was devoid of triterpenes.
Effect of MSM on Acetic Acid-Induced Writhing
The results of the acetic acid-induced writhing test
in mice are given in table 1 . At doses of 100 and 200 mg/
kg i.p., MSM inhibited the writhing responses of mice
caused by the intraperitoneal administration of acetic
acid. The maximal inhibition of the writhing response
was 52.3% with the dose of 200 mg/kg, slightly lower
compared to inhibition by ASA (55.5%) at a dose of 100
mg/kg.
Effect of MSM on the Formalin Test
MSM (200 mg/kg) and morphine significantly inhib-
ited both phases of the formalin test showing a pain in-
hibition of 37.4 and 36.0% in the early phase (0–5 min)
and 46.3 and 53.9% in the late phase (15–60 min), respec-
tively. In contrast, ASA inhibited only the second phase
of the formalin response ( table 2 ).
Effect of MSM in the Hot Plate Test
Morphine and MSM (200 mg/kg) caused a significant
increase in the response latency time to thermal stimula-
tion in mice ( table 3 ). This effect started 30 min after
treatment and persisted throughout the 240-min dura-
tion of the experiment.
Tab le 1. Effect of MSM on acetic acid-induced abdominal writh-
ing test in mice
Group Dose,
mg/kg, i.p.
Writhings Inhibi-
tion, %
Control (NaCl 10 ml/kg, i.p.) 134.7812.3
MSM 50.0 105.6812.6 21.6
100.0 81.387.9*39.6
200.0 64.2811.3*52.3
ASA 100.0 59.9810.8*55.5
Morphine
Morphine+naloxone
MSM+naloxone
5
5+5
200+5
25.989.1
53.7810.51
77.283.9
80.7
60.1
42.0
Values are mean 8 SEM (n = 10). * p < 0.05 significantly dif-
ferent f rom c ontrol (ANOVA foll owed by Du nnett ’s tes t). Cont rol
(13 4.7 8 38.75).
Tab le 2. Effect of MSM on formalin-induced pain in mice
Treatment Total time spent licking, s
0–5 min inhibi-
tion, %
15–30 min inhibi-
tion, %
Control
(NaCl 10 ml/kg, i.p.) 64.686.5 – 205.5812.8 –
MSM, mg/kg, i.p.
50.0 57.685.4 10.8 171.3820.3 16.6
100.0 57.685.5 10.8 131.0819.7*36.2
200.0 40.484.6*37.4 109.0814.1*46.3
ASA, mg/kg, i.p.
100.0 54.084.9 16.4 144.9822.4*29.5
Morphine, mg/kg, i.p.
5.0 41.483.51*36.0 94.8815.7*53.9
Values are mean 8 SEM in seconds (n = 10). * p < 0.05 com-
pared to the control group (ANOVA followed by Dunnett’s test).
Pharmacological Effects of Mitragyna
speciosa Korth Extract
Med Princ Pract 2009;18:378–384
381
Effect of MSM in Carrageenan-Induced Paw Edema
Subplantar injection of carrageenan in control ani-
mals produced a local edema that increased progressive-
ly to a maximum intensity 3 h after the injection and then
gradually declined with time ( table 4 ). On the other hand,
MSM at doses of 100 and 200 mg/kg caused significant
(p ! 0.05) inhibition of the development of paw edema
with an activity higher than that of ASA (100 mg/kg),
with maximal percent of inhibition during the first 3 h
after challenge. In addition, pretreatment with ASA only
exhibited a significant inhibitory action on paw edema at
1 and 3 h after carrageenan injection, decreasing edema
formation by 44 and 60%, respectively. Nevertheless, the
group treated with 200 mg/kg MSM showed the best ac-
tivity, reducing edema by 60 and 63%, respectively, 4 and
5 h after carrageenan injection, even when the inhibitory
effects of the other treatments progressively declined.
Effect of MSM on Cotton Pellet-Induced Granuloma
Investigation of the effect of MSM on the proliferative
phase of inflammation revealed that daily administra-
tion of MSM (200 mg/kg) significantly (p ! 0.05) inhib-
ited the growth of granuloma tissue, provoking an in-
hibitory effect (44.9%) greater than that of ASA (25.4%)
when compared to the control group. In comparison, dai-
ly treatments of MSM (50 and 100 mg/kg) showed only
weak to moderate inhibitory effect with 16.9 and 21.6%
inhibition, respectively ( table 5 ).
Discussion
In the present study, the antinociceptive and anti-in-
flammatory effects of the M. speciosa leaves were investi-
gated in various related models in vivo. It was demon-
Tab le 3. Effect of MSM on the hot plate test in mice
Dose,
mg/kg
Latency time, s
0 30 60 120 180 240
Control 4.9280.24 5.3780.54 5.8280.81 5.4980.72 5.2680.71 4.9980.60
MSM 50 5.5780.13 6.3780.52 7.6680.31 7.7980.38*6.4580.43 4.8980.34
100 5.1280.23 6.4980.56 7.9180.62*7.5180.80*6.4180.53 5.1280.51
200 4.5980.17 6.6480.47 6.7080.5*8.4080.50*7.5780.44*6.6880.44*
ASA 100 5.1480.23 6.0080.39 6.0780.63 5.6480.56 6.3780.34 6.3580.59
Morphine 5 5.1780.22 8.0780.60*9.1980.64*9.6480.62*8.5980.46*6.8880.57*
Morphine+naloxone 5+5 4.8980.22 5.3980.36** 6.5580.38** 8.5780.72** 6.4780.52** 5.9280.40**
MSM+naloxone 200+5 4.9880.21 5.5080.42** 5.6180.26** 7.7180.62** 5.8880.41** 4.8880.28**
Values are mean 8 SEM (n = 10). * p < 0.05 compared to the control. ** p < 0.05 compared to the group receiving appropriate drug/
extract at the same dose without naloxone (Dunnett’s test).
Tab le 4. Effect of MSM on carrageenan-induced hind paw edema in rats
Dose,
mg/kg
Edema, ml
1 h 2 h 3 h 4 h 5 h
Control 0.4880.05 0.4780.06 0.5680.05 0.4780.03 0.4880.04
ASA 100 0.2780.06 (44)*0.4380.07 (9) 0.2880.05 (50)*0.3680.05 (23) 0.3980.06 (19)
MSM 50 0.2480.05 (50)*0.4480.04 (6) 0.3980.05 (30) 0.3580.04 (26) 0.4980.05 (NI)
100 0.1580.04 (69)*0.2580.04 (47)*0.2780.05 (52)*0.3180.03 (34) 0.4980.07 (NI)
200 0.1680.04 (67)*0.1580.04 (68)*0.2180.06 (63)*0.1980.06 (60)*0.1880.07 (63)*
Values are mean 8 SEM, while those in parentheses represent percent inhibition of edema (n = 8). NI = No inhibition. * p < 0.05
compared to the control group.
Shaik Mossadeq et al.
Med Princ Pract 2009;18:378–384
382
strated that MSM (100 and 200 mg/kg, i.p.) significantly
inhibited the mice’s writhing response in the acetic acid-
induced abdominal constriction test. It has been postu-
lated that acetic acid, which was used to induce writhing,
acts indirectly by releasing endogenous mediators that
stimulate pain nerve endings. Increased levels of PGE
2
and PGF
2
as well as in lipoxygenase, liberation of sym-
pathetic nervous system mediators in the peritoneal f luid
and the release of cytokines, such as TNF- , interleukin-
1 and interleukin- , by resident peritoneal macrophages
and mast cells have been reported to be responsible for
pa in s en satio n c ause d b y i.p . ad minist ra ti on o f acetic ac id
[15 –17] . The results also showed that ASA, known to in-
hibit cyclo-oxygenase
[18] , causes significant inhibition.
On the basis of this result, it can be assumed that the
mode of action of this activity might involve a peripheral
mechanism probably mediated via inhibition of lipoxy-
genases and/or cyclo-oxygenase activity. However, the
drawback of this model is that other drugs can cause a
similar effect, such as adrenergic antagonist and muscle
relaxants, leading to possible false-positive results
[19] .
Due to this, the formalin and hot plate tests were selected
to continue this investigation, since they are more spe-
cific and it is possible to identify two distinct phases of
nociception.
Formalin-induced nociception is a well-described
model and can be consistently inhibited by typical anal-
gesic and anti-inflammatory drugs, including morphine
and ASA
[12] . In this model, MSM (200 mg/kg) and mor-
phine inhibited the first and the second phase, while ASA
inhibited only the second phase of the formalin test. Con-
sidering the inhibitory property of MSM on the first and
second phases of the formalin test, we might suggest that
the extract contains active principles acting both central-
ly and peripherally, which also implies that the extract
possesses both antinociceptive and anti-inflammatory
activit y. Fu rthermore, the central ana lgesic effect of MSM
is supported by the results observed in the hot plate test,
a specific test used to elucidate central antinociceptive
properties of pain-relieving agents such as opioid-derived
analgesic drugs
[20] . In the hot plate model, morphine
and MSM (200 mg/kg) caused a significant increase in
the response latency time to the thermal stimulus, thus
confirming the central activity of the extract. In addition,
the results also showed that pretreatment with a nonse-
lective opioid receptor antagonist, naloxone, reversed the
antinociceptive effect of MSM as well as morphine in the
hot plate test. These findings clearly suggest that the an-
tinociceptive effect of MSM is mediated by activation of
the opioid system, which is in agreement with the previ-
ous findings
[3, 5] .
Carrageenan-induced rat paw edema is one of the con-
ventional tests used to evaluate the acute phase of the
anti-inflammatory effect of drugs and natural products
[21] . Carrageenan-induced inflammation is biphasic in
nature. The first phase is attributed to the release of his-
tamine and serotonin; the second phase results mainly
from the potentiating effects of bradykinin on mediator
release and also of prostaglandins, producing edema af-
ter the mobilization of leukocytes
[22] .
With respect to the first phase, the release of hista-
mine and other mediators produced increased vascular
permeability surrounding the site of damaged tissue re-
sulting in edema at the site. Therefore, inhibition of in-
creased vascular permeability and subsequent exudation
will, to some extent, implicate the extent of inflamma-
tory reaction produced at the site of injury. In this mod-
el, the subplantar injection of carrageenan in control an-
imals produced local edema, which increased progres-
sively to reach maximal intensity 3 h after the injection,
after which the effect gradua lly declined with time. How-
ever, MSM (100 and 200 mg/kg) inhibited the develop-
ment of paw edema more than ASA, demonstrating
maximum inhibition during the first 3 h after challenge,
and continued to do so even when the inhibitory effects
of the other treatments progressively declined. This sug-
gests that the extract may suppress the early phase of
edema, possibly by inhibiting the synthesis, release or
actions of the various hyperalgesic mediators which are
known to mediate acute inflammation induced by phlo-
gistic agents and thus produce reduced sensitivit y to pain
receptors
[23] . However, the inhibitory activity produced
by the extract at a dose of 200 mg/kg for a period of 4 h
may be attributed to the action of arachidonic acid and
Tab le 5. Effect of MSM on cotton pellet-induced granuloma test
in rats
Treatment Dose,
mg/kg, i.p.
Granuloma
weight, mg
Inhibition,
%
Control 90.580.010
ASA 100 67.580.003*25.4
MSM 50 75.280.005 16.9
100 71.080.004 21.6
200 49.880.003*44.9
Values are mean 8 SEM (n = 8). * p < 0.05 compared to the
control group.
Pharmacological Effects of Mitragyna
speciosa Korth Extract
Med Princ Pract 2009;18:378–384
383
its metabolites, which at this stage produces edema de-
pendent on neutrophil mobilization
[24] . To gain further
insight into the chronic anti-inflammatory effects in-
duced by the extract, the granulomatous tissue induc-
tion model was employed. This procedure induced an
inflammatory process which involves proliferation of
modified macrophages, fibroblasts as well as the multi-
plication of blood vessels producing a highly vascular-
ized and reddened mass known as granulation tissue. In
this model, daily administration of MSM (200 mg/kg)
inhibited the growth of granuloma tissue, provoking an
inhibitory effect greater than that of ASA when com-
pared to the control group. A putative mechanism asso-
ciated with this activity may be due to the inhibition of
the synthesis of many mediators involved in the forma-
tion of fibrovascular tissue, including chemokines, cyto-
kines and eicosanoids
[25–27] . It is also unclear whether
the enhancement of immune response at this stage, if
any, may play a role in the inhibition of macrophage
transformation into epithelioid cells following injury.
This may account for the anti-inflammatory activities
produced by MSM in both the acute and chronic models
of in f l am m at io n e mp lo ye d. Ev en th ou g h t h e e xa c t m ec h -
anism of action is unknown, the anti-inflammatory ac-
tivity of M. speciosa may result from a combination of
inhibition of pro-inflammatory mediator release and
vascular permeability in addition to enhanced immu-
nity, stimulation of tissue repair and healing processes.
Furthermore, phytochemical analysis of MSM has
demonstrated the presence of alkaloids, saponins, flavo-
noids, tannins and sterols. The anti-inflammatory and/
or antinociceptive actions of these compounds have been
reported by many researchers. Moreover, the suppression
of inducible nitric oxide synthase and cyclo-oxygenase-2
enzymes has been shown for alkaloids and flavonoids
[28, 29] . Saponins have also been reported to have anti-
inflammatory activities by inhibition of the enzymes
inducible nitric oxide synthase, cyclo-oxygenase-2 and
lipoxygenase
[30] . Therefore, it seems that the anti-in-
flammatory and antinociceptive effects of MSM could
also be attributed to the presence of alkaloids, saponins,
flavonoids, tannins and sterols in the leaves of M. spe-
ciosa.
Conclusion
This study showed that MSM possesses antinocicep-
tive and anti-inflammatory properties. However, further
investigation is advocated to elucidate the active prin-
ciple(s) and exact mechanism(s) of its action.
A c k n o w l e d g m e n t s
We thank the staff of MARDI for technical assistance during
the preparation of extract and the Faculty of Medicine and Health
Sciences, Universiti Putra Malaysia for providing the necessary
support for the st udy. This resea rch was supported by a Funda men-
tal Res earch Grant Scheme (FRGS/FASA1-2006/(Sains Perubata n)/
UPM/179) from the Ministry of Higher Education Malaysia.
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... Traditionally, the Mitragyna genus has been trusted and used by the local community to treat various diseases such as fevers, malaria, diarrhea, coughs, hypertension, diabetes mellitus, muscle pain, and worm infections [5]. Scientifically, it has also been reported that Mitragyna has a pharmacological effect that has the potential to be a source of raw materials for drugs that have the following effects: antiinflammatory and antinociceptive [6,7]; anti-obesity [8]; analgesic [9][10][11][12]; antipyretic, sedative, stimulant, and depressant [13][14][15][16]; antidopaminergic [17]; effects on memory [18]; antidiarrheal [19,20]; antioxidant [21,22]; and antimicrobial [21]. ...
... In addition to its opioid-like analgesic effect, mitragynine stimulates postsynaptic alpha-2 adrenoreceptors and inhibits cyclooxygenase-2 messenger RNA (mRNA) and protein expression, suggesting non-opioid receptor pain-relieving effects [53,118,122]. The inhibition of COX-2 may affect the formation of PGE2, which can lead to anti-inflammatory effects [6,53,123]. Moreover, mitragynine impairs neuronal pain transmission via the blockade of Ca 2+ channels, which has been proposed as another antinociceptive mechanism of M. speciosa [124]. ...
... In addition, other compounds such as flavonoids and polyphenols [108] in methanol extract have antioxidant and antimicrobial activity, as reported by Parthasarthy et al. (2009) [21]. The same extract also has anti-inflammatory and antinociceptive activity [6]. ...
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Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name "kratom", and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat , cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products. Citation: Ahmad, I.; Prabowo, W.C.; Arifuddin, M.; Fadraersada, J.; Indriyanti, N.; Herman, H.; Purwoko, R.Y.; Nainu, F.; Rahmadi, A.; Paramita, S.; et al.
... Traditionally, the Mitragyna genus has been trusted and used by the local community to treat various diseases such as fevers, malaria, diarrhea, coughs, hypertension, diabetes mellitus, muscle pain, and worm infections [5]. Scientifically, it has also been reported that Mitragyna has a pharmacological effect that has the potential to be a source of raw materials for drugs that have the following effects: antiinflammatory and antinociceptive [6,7]; anti-obesity [8]; analgesic [9][10][11][12]; antipyretic, sedative, stimulant, and depressant [13][14][15][16]; antidopaminergic [17]; effects on memory [18]; antidiarrheal [19,20]; antioxidant [21,22]; and antimicrobial [21]. ...
... In addition to its opioid-like analgesic effect, mitragynine stimulates postsynaptic alpha-2 adrenoreceptors and inhibits cyclooxygenase-2 messenger RNA (mRNA) and protein expression, suggesting non-opioid receptor pain-relieving effects [53,118,122]. The inhibition of COX-2 may affect the formation of PGE2, which can lead to anti-inflammatory effects [6,53,123]. Moreover, mitragynine impairs neuronal pain transmission via the blockade of Ca 2+ channels, which has been proposed as another antinociceptive mechanism of M. speciosa [124]. ...
... In addition, other compounds such as flavonoids and polyphenols [108] in methanol extract have antioxidant and antimicrobial activity, as reported by Parthasarthy et al. (2009) [21]. The same extract also has anti-inflammatory and antinociceptive activity [6]. ...
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Full-text available
Mitragyna is a genus belonging to the Rubiaceae family and is a plant endemic to Asia and Africa. Traditionally, the plants of this genus were used by local people to treat some diseases from generation to generation. Mitragyna speciosa (Korth.) Havil. is a controversial plant from this genus, known under the trading name “kratom”, and contains more than 40 different types of alkaloids. Mitragynine and 7-hydroxymitragynine have agonist morphine-like effects on opioid receptors. Globally, Mitragyna plants have high economic value. However, regulations regarding the circulation and use of these commodities vary in several countries around the world. This review article aims to comprehensively examine Mitragyna plants (mainly M. speciosa) as potential pharmacological agents by looking at various aspects of the plants. A literature search was performed and information collected using electronic databases including Scopus, ScienceDirect, PubMed, directory open access journal (DOAJ), and Google Scholar in early 2020 to mid-2021. This narrative review highlights some aspects of this genus, including historical background and botanical origins, habitat, cultivation, its use in traditional medicine, phytochemistry, pharmacology and toxicity, abuse and addiction, legal issues, and the potential of Mitragyna species as pharmaceutical products.
... Findings suggest that kratom is purchased by those who suffer from chronic pain in order to reduce or supplement prescription opioid use, self-manage opioid withdrawal, and self-treat chronic or acute psychiatric and physical health conditions (3,(11)(12)(13). The reported therapeutic benefits span improvement in psychiatric symptoms to self-treatment of pain or substance use disorder (SUD) symptoms (1,(14)(15)(16)(17). Despite its reported benefits, long-term and chronic (high dose) kratom consumption can induce the development of tolerance and withdrawal symptoms during discontinuation ( [18][19][20][21]. ...
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Background: Kratom (Mitragyna speciosa Korth.) use outside of Southeast Asia has increased over the past decade. Objectives: This investigation clarifies kratom's role in perceived well-being, overall health, and temporal correlation with drug use to understand kratom's role in the self-treatment of substance use disorders (SUDs). Methods: Between July 2019 and July 2020 an anonymous, cross-sectional, online survey was taken by 7,381 people who use kratom (PWUK) recruited through social media and other online resources. This included an assessment of (a) the relationship between self-reported overall health, concomitant use of drugs of misuse, and demographics; (b) the perceived effectiveness of kratom in self-treating diagnosed health conditions or symptoms; (c) the profile of PWUK primarily for drug dependence, pain, and mood or mental health conditions based on demographics. Results: A total of 5,152 valid responses (45.9% females/53.7% males) were collected. Kratom was primarily used for self-treating pain (73.0%) and improving emotional or mental health conditions (42.2%) without clinical supervision. Those with a SUD (synthetic opioids, methadone, benzodiazepines, or heroin) used kratom after discontinuing illicit or other drugs (94.8%). The primary substances taken before or concomitantly with kratom were cannabis, cannabidiol, benzodiazepines, or kava. PWUKs report a dose-dependent benefit for alleviating pain and relieving negative moods. Adverse effects were primarily gastrointestinal, typically at high (>5 g/dose) and frequent (>22 doses/week) dosing. Conclusions: Kratom was primarily used as a harm-reduction agent for SUDs and self-treatment of chronic conditions. Healthcare professionals need better information about kratom, its potential adverse effects, and clinically significant drug interactions.
... Selain itu berkumpulnya parasit dalam jumlah besar di usus atau lambung ternak dapat menyebabkan penyumbatan atau obstruksi sehingga proses pencernaan makanan terganggu [1]. Penyakit 114 dari daun kadama yang telah diteliti sebelumnya yaitu sedatif [8], stimulan, antidepresan [9], anti-inflamasi [10], antidiare, antioksidan dan antimikroba [11]. Kandungan metabolit sekunder dari daun kadamba adalah senyawa golongan alkaloid, saponin, flavonoid, tannin, steroid dan triterpenoid [12]. ...
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Diseases caused by parasites, especially worms in animals on farms, are one of the problems that farmers often face. Worm disease can decrease the productivity of livestock and cause a decrease in the selling value of livestock at the market. The most common worm disease that attacks livestock is Paramphistomum sp. The treatment of this disease uses nutritious plants, which is one of the alternatives chosen to minimize side effects due to the administration of synthetic drugs. Kadamba leaf was chosen in this study because one of the medical plants that have potential compounds as anthelmintics. The aim of this research is to know the anthelmintic activity of kadamba leaf extract to Paramphistomum sp. 210 samples of Paramphistomum sp. were taken from cow rumen at Tanah Merah slaughterhouses. This study was conducted in vitro with seven experimental groups consisting of one positive control (Albendazole), one negative control (NaCl), and five groups of kadamba leaf extract with concentrations of 2,5%, 5%, 7,5%, 10 %, 12,5% with three replications. The results of the study showed the yield of kadamba leaf extract was 13,88%, and the anthelmintic test showed that kadamba leaf extract had anthelmintic activity against Paramphistomum sp. at all concentrations.
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Kratom leaves (Mitragyna speciosa Korth) have been used by people in West Kalimantan, especially Kapuas Hulu District, as local culture, for traditional medicine. This research was conducted to obtain facts and data on utilization and complaints due to the use of kratom leaves in local culture by the people of Kapuas Hulu Regency. Data obtained by interview using a questionnaire and the determination of the respondents is done by snowball. The relationship between period, dose and frequency of kratom leaf consumption and complaints was searched statistically using the chi-quadrate. It was found that 152 respondents who consumed kratom leaves. The main reason respondents consume kratom leaves to overcome fatigue or get stamina (49%) and to treat illness 25%. Generally, 46% of respondents consume kratom leaves for less than 1 year, although 25% of them are more than 5 years. Most of the respondents consumed kratom leaf powder at a dose of ¼ teaspoon (0.5 g) with the highest frequency once a day (27.94%). Chi-square analysis showed that there was no very significant relationship between the period of drinking kratom leaves and complaints, but there was a very significant relationship between the dose of kratom leaf consumption and complaints and between the frequency of drinking kratom leaves and complaints. There were no complaints such as symptoms of narcotics and drug users. Generally, respondents stated that they did not experience complaints 93.42%. About 6.58% of complaints were feeling tired, drowsy and achy.
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Drug addiction is considered a chronic disorder affecting the individual’s life, his/her family and society. Up till now the treatment of drug addiction is considered a problematic issue. Synthetic drugs available for the treatment of drug addiction are few, of limited efficacy and associated with serious side effects. Therefore, there is a continuous search for better therapeutic agents for drug addiction. Natural products represent a promising source for drug addiction treatment. This review summaries drug addiction definition, its mechanism of action, its types, its diagnosis, factors affecting its development and different available approaches for its treatment especially the use of natural products. Six plants were discussed thoroughly in this review, including, Tabernanthe iboga Baill., Mitragyna speciosa Korth., Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep, Hypericum perforatum L., Panax ginseng C.A. Mey., and Withania somnifera (L.) Dunal.
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The demand for natural-based remedies is rising due to their safety and efficiency compared to synthetic-based medicine. In view of this, the unique bioactive properties of Mitragyna speciosa (M. speciosa) have attracted high interest for its potential application in the pharmacological industry. Therefore, this study aimed to optimise the Ultrasound-Assisted Extraction (UAE) method using Response Surface Methodology (RSM) for the production of crude methanolic extract from M. speciosa leaves. Statistical optimisation was performed to evaluate the effect of temperature, extraction time, and volume of solvent. The phenolic and flavonoid contents of crude methanolic extract were analysed through Total Phenolic Content (TPC) and Total Flavonoid Content (TPC), respectively. Furthermore, Gas Chromatography-Mass Spectrometry (GC-MS) was carried out to determine the characteristic of the crude methanolic extract. The optimal conditions at a temperature of 34 °C, extraction time of 25 min, and volume of the solvent of 166 mL resulted in a maximum yield of 49.72% of the crude methanolic extract with TPC and TFC recorded at 137.3±15.7 mg GAE/g and 90.3±15.3 mg RE/g, respectively. The GC-MS analysis identified the presence of 18 phytochemical compounds in the crude extract including glycerine, phytol, and stigmasterol. These identified compounds could exhibit certain therapeutic effects, such as anti-inflammatory, antioxidant, and antibacterial effects. Therefore, the findings in this study support the suggestion that the various available bioactive compounds besides alkaloid contributed to the bioactive properties in M. speciosa, making it an effective traditional herbal medicine to treat various illnesses.
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The present study was conducted to evaluate the analgesic activity of ethanolic extract of Andrographis paniculata (AP) in mice. The analgesic investigations were carried out using the acetic acid-induced abdominal writhing and the hot-plate tests. It was demonstrated that intraperitoneal (i.p.) administration of the extract at a dose of 30, 100, 300, 500 mg/kg, produced significant inhibition of abdominal constriction induced with 0.6% (v/v) acetic acid in dosedependent manner. It also demonstrated that the extract produced significant dose-dependent increase in the time of latency to a discomfort reaction in the hot-plate model. In addition, the analgesic effect of the ethanolic extract of AP was significantly reversed by a non-specific opioid receptor antagonist, naloxone. These results indicate that AP has an analgesic effect that was mediated through opioid receptors.
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Opuntia dillenii (Ker-Gawl) Haw is a cactus that belongs to the family Opuntiae. Lyophilized aqueous extract of the fruits of the plant, used in Canarian traditional medicine for gastrointestinal and bronchial troubles, was evaluated for analgesic and anti-inflammatory properties in rats and mice. The Opuntia dillenii extract (100-400 mg/kg, i.p.) inhibited, in a dose-related manner, carrageenan-induced paw edema in rats. A dose-dependent action was obtained against chemical (writhing test) and thermic (hot plate test) stimuli, respectively, with doses of 50 and 100 mg/kg.
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Kratom is indigenous to Thailand. Market gardeners, peasants and labourers often become addicted to kratom leaf use. In certain respects, kratom addiction resembles addiction to a drug with narcotic properties, except that long term kratom addicts develop a dark skin, particularly on the cheeks. The age of onset is apparently later than in heroin addiction, and females are rare amongst those who use the substance. There were 5 cases of kratom addiction revealing psychotic symptoms; these had been seen by the author in the last yr (1974) in the outpatient department. Initially, 3 cases were suspected of having kratom psychosis of the basis of their history of addiction and their general appearance and on psychiatric examination. The measure chosen by lar to control kratom addiction by banning the cultivation of the tree has not been found to be effective, since it is a local law It is hoped that drug education for the rural youth in areas where kratom can be grown will be a more effective step towards its control.
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1. Kinins were measured by a radioimmunoassay in the inflammatory exudates induced by carrageenin or zymosan in the peritoneal cavity of normal Wistar rats and of kininogen-deficient Brown Norway rats. 2. After administration of carrageenin to normal rats, levels of immunoreactive kinins showed a single peak during the first two hours and then decreased. The presence of kinins preceded and accompanied the exudation of 125I-labelled albumin. Kinins were identified as bradykinin by chromatography. 3. Captopril, an inhibitor of kininase 2, increased the level of kinins and the volume of the exudates after carrageenin treatment. In Brown Norway rats, the volume of the exudates was small and contained little or undetectable amounts of immunoreactive kinins. 4. During zymosan-induced peritonitis, the exudates were devoid of immunoreactive kinins in both species. The volume of the exudates was larger in kininogen-deficient rats than in normal rats. 5. We conclude that in rats, the kinin system is a major factor responsible for the development of the inflammatory reactions induced by carrageenin, but is not involved in the reactions induced by zymosan.
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Mitragynine is thus a drug with a highly unusual but nevertheless well-documented history of being described as both a depressant and a stimulant, while at the same time possessing the chemical structure one might expect of a psychedelic. It can suppress the opiate withdrawal syndrome, but it is not reversed by nalorphine. Discovering the sites of action of this novel substance, thus resolving the apparent contradictions, may improve understanding in several areas of psychopharmacology. Just as new analytic methods were applied to the molecule in the 1960's, researchers now have at their disposal such techniques as receptor binding studies using radiolabeled compounds. Such studies have yet to be performed.
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We investigated the participation of a sympathetic component in the abdominal contortions induced by intraperitoneal injection of 0.6% acetic acid in the mouse. The beta blocker propranolol (4 mg/kg, sc) caused a small significant (19%) blockade of the contortions but strongly potentiated (greater than 80%) the effect of indomethacin (30% at 5 mg/kg, sc). Significant inhibition of writhing was also observed with sympatholytics such as guanethidine (27% at 30 mg/kg, sc) and by a specific dopamine-I antagonist, SCH 23390 (62% at 400 micrograms/kg, sc). Tyramine, which releases sympathomimetic amines, and cocaine, which partially blocks the uptake of amines, potentiated acetic acid writhing. Intraperitoneal administration of noradrenaline (187 micrograms/kg)potentiated acetic acid-induced writhing. These results are consistent with the suggestion of Nakamura and Ferreira (1) that inflammatory nociception has a dual component: one mediated by cyclooxygenase metabolites and another by sympathetic amines, possibly acting through a DA-1 type receptor.