Review

Analgesic Effect of Ethanol Extract of Dillenia ochreata (Miq.) Teijsm. & Binn. Ex

Martelli in Wistar Rats

Heni Yohandini¹, Fahdella Ghaniya², Muharni Muharni¹* , Fitrya Fitrya²

¹Department of Chemistry, Faculty of Mathematics and Natural Sciences, University of Sriwijaya, Indralaya,

Ogan Ilir, South Sumatera, 30662 Indonesia

²Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Sriwijaya, Indralaya,

Ogan Ilir, South Sumatera, 30662 Indonesia

Abstract

Dillenia ochreata is a traditional medicine used to treat wounds and scabies. In wound healing, one of the

treatments is to reduce pain (analgesic). Some compounds of triterpenoid groups have been known to

be active as analgesic compounds. The leaf of D. ochrea was reported to contain secondary metabolites

triterpenoid centulic acid and 3β-glucopyranosyl-lup-20(29)-en-28 oat. This study aimed to evaluate the

analgesic activity and standardization of the ethanol extract of D. ochreata leaf and determine the

mechanism of action. Analgesic activity was determined by a hot plate method and formalin test, and

the mechanism of action was through muscarinic, dopamine, and opiate receptors, standardization of

extract using the method issued by the Indonesian Ministry of Health. The ethanol extract of D. ochreata

leaf at a 400 mg/kg bw dose has higher analgesic activity (24.85%) than the positive control (18.32%).

Statistical analysis showed a significant difference in analgesic activity percentage between the positive

group and those with a 400 mg/kg bw group dose. The 400 mg/kg bw dose also showed a significant

difference (p<0.05) between neurogenic pain (46.92%) and inflammation (61.19%) in the formalin test

caused by opioid receptors. The evaluation of the analgesic mechanism showed the ethanol extract of D.

ochreata leaf works through opioid receptors. The extract meets the requirements of the standard

parameters. The leaf extract of D. ochreata can be developed as an anti-analgesic from natural medicine.

Keywords: Analgesic; Dillenia ochreata; formalin test; hot plate test; receptors.

Graphical Abstract

*

Corresponding author

Email addresses: muharnikimia@unsri.ac.id

DOI: https://doi.org/10.22437/chp.v9i1.43080

Received April 04^th2025; Accepted June 13^rd2025; Available online June 30^st2025

(https://creativecommons.org/licenses/by/4.0 )

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Introduction

determine the analgesic effects of D. ochreata

leaves

in

rats,

determine

the

analgesic

Pain is a sensory and emotional feeling related to

tissue damage, such as inflammation, infection

or muscle spasms. The drugs most widely used

for the treatment of pain are non-steroidal anti-

inflammatory drugs (NSAIDs). The use of NSAIDs

for a long period can cause side effects such as

gastrointestinal, heart and kidney effects [1].

Therefore, a relatively safe medicinal substance,

such as traditional medicinal plants, is needed for

pain (analgesic) treatment. Dillenia ochreata is a

traditional medicine plant that is used for the

treatment of wounds and scabies. In Indonesia,

this plant is known by the local names simpur

and simpor [2]. The phytochemical analysis

reported that D. ochreata leaves contain

triterpenoid, steroid, phenolic, and flavonoid

compounds. D. ochreata leaf ethanol extract is

active in healing burns and incision wounds [3].

A subchronic toxicity test of the ethanol extract

of D. ochreata leaves up to 400 mg/kgBW showed

no toxicity [4]. The leaf of D. ochreata contained

triterpenoid centulic acid and 3β-glucopyranosyl-

lup-20(29) -en-28 oats, which are active as an

antibacterial with MIC value to Escherichia coli

and Staphylococcus aureus 60 μ g/ml and

120 μ g/ml respectively for centulic acid and

15 μg/ml and 60 μg/ml for 3β-glucopyranosyl-lup-

20(29)-en-28 oat [5, 6]. Centulic acid can

potentially treat inflammatory diseases by

suppressing proinflammatory cytokines such as

TNF-α, INFγ, IL-6, and IL-12 [7]. Some compounds

of triterpenoid groups have been known to be

active as analgesic compounds. Two triterpenes,

betulonic acid and cabraleone, isolated from the

leaves of Combretum glutinosum, have been

reported to be active as an analgesic [8]. The

analgesic activity mechanisms of triterpenoid

involve the inhibition of phospholipase enzymes

and the cyclooxygenase and lipooxygenase

pathway that involves modulating the activity of

mechanism of action and the standardization of

extract

Materials and Methods

Chemicals and Eqipments

Materials used in research: the leaves of Dillenia

ochreata, Ethanol 96% (Brataco^®), Na CMC

(Brataco^®), diclofenac sodium (Aarti Drugs^®),

Formalin 2.5%, atropine sulfate (Ethica industry

pharmacy®),

metoclopramide

(Pharma

chemistry®), naloxone hydrochloride (Indo

pharma®), Tool used in this study: rotary

evaporator (IKA^®HB 10), Hot Plate (DLAB®).

Test Animals.

The experiment used 73 Male albino rats from

the Animal Laboratory Centre at Palembang,

South Sumatra, Indonesia.

experiment of the research has been approved

by the ethics committee from Ahmad Dahlan

University with register No. 022210064. The test

animals were acclimatized for seven days, and

the test animals were provided standard food

and drinks.

The protocol

Sample preparation

Dillenia ochreata leaves fresh (1 kg) were collected

from the Ngulak I Village, Sekayu, Musi Banyuasin

district in South Sumatera, Indonesia. The

sample was identified as Dillenia ochreata (Miq)

Teijsm.

&

Binn.ex Martelli at Herbarium

Bogoriense as Research Center for Biology,

Indonesian

Indonesia,

Institute of

with register

Science Cibinong,

number B-

82/IV/D1.01/i/2021.

Extraction

inhibitory

neurotransmitters,

as

well

as

The fresh D. ochreata leaves were dried and

ground in a grinding mill into a powder. The D.

ochreata leaves powder (200 g) was extracted

using the maceration method using ethanol 96%

(1 L) for 72 hours. After that, the Whatman filter

paper was used for filtration. The maceration was

carried out with three repetitions [6]. The filtrate

was concentrated to dryness using a rotary

evaporator and water bath at 60 ⁰C at a speed of

interaction with the central nervous system. This

compound can reduce the production of pain

mediators

such

as

prostaglandins

and

leukotrienes,

and

modulate synaptic

transmission in the brain [9]. Analgesic activity of

the extract was related to its potential to

modulate the release of inflammatory mediators

responsible for pain.

This study aims to

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80 rpm until a concentrated extract was obtained

at a constant weight. Then, the crude extract was

determined as the yield percentage.

mechanism of muscarinic receptors using two

groups (I and II), evaluate the mechanism of

dopamine receptors using two groups (III and IV)

and evaluate the mechanism of opiate receptors

using two groups (V and VI). The treatment in

each group is shown in Table 1. All rats have

conducted a hot plate test for 1 hour before

administration of all receptor antagonists. One

hour later, all groups were treated with the 2 ml

ethanol extract at the dose with the highest

analgesic effect determined by the hot plate test

(400 mg/kg bw), then 2 hours after the ethanol

extract was administered, and all rats conducted

a hot plate test [13].

Hot Plate Test

The test was conducted using the hot plate

method described by Raveendran et al. (2019)

[10]. Wistar rats (25 male, weighing 150-250 g)

were divided into five groups:

negative (1%

NaCMC). Positive (diclofenac sodium 4.5 mg/kg

body weight (BW) and three treatment groups at

doses 100, 200 and 400 mg/kg bw. A preliminary

animal test was conducted to determine the

initial response. The animal is placed on the hot

0

plate at a temperature of 50 C. The response

Standardization of the Extract

time

was

measured,

such

as

jumping,

withdrawing, pawing, and feet licking. After the

preliminary test, the animal was treated with

ethanol extract of D. ochreata with doses of 100,

200, and 400 mg/kg bw while the positive control

group was given diclofenac sodium. Hot plate

tests were conducted sixty minutes after

treatment, and the test was performed every 30

minutes for 5 hours. The analgesic activity was

determined based on response time compared

to the control negative and expressed as latency

time [11].

Standardization of the extract was carried out by

measuring specific parameters (organoleptic

properties, the water and ethanol soluble

extractive content) and non-specific parameter

analysis (water content, total ash content, acid

soluble ash content, metal contamination and

microbial contamination) using the method

issued by Indonesian Ministry of Health [14].

Statistical Analysis

The data were analyzed statistically using the

Shapiro-Wilk normality test. If the data is

normally distributed (p-value > 0.05), continue to

test with the One-way ANOVA test analysis and

Paired samples t-test using the SPSS®.

Formalin Test

The twelve rats were divided into two treatment

groups comprising six male rats. Group 1 was

treated with Na CMC 1%, while group 2 was

treated with ethanol extract, which provided the

greatest analgesic activity in the hot plate test

(400 mg/kg bw). Two hours after treatment, each

rat was injected on the surface of its left hind paw

with 0.05 ml formalin solution (2.5%). Then, the

animals were hot plate tested and observed

response time for such as jumping or withdrawal

of the paws 1 hour was recorded. The initial

phase lasts 0 to 5 minutes, and the final lasts 20

to 60 minutes. The percentage of analgesic

power was calculated [12].

Result and Discussion

Hot plate test. D. ochreata leaf simplicia (200 g),

after

Extraction

with

96%

ethanol

and

concentration, obtained a crude extract of 29.62

g with a yield percentage of 14.81%. The hot plate

method determined the analgesic effect with

heat stimulation based on latency time.

Analgesic activity was observed every 30 minutes

for 5 hours, as shown in Figure 1. The negative

control group showed a decrease in the average

latency time, with peak analgesia occurring at 90

minutes; meanwhile, the positive control group

was given diclofenac sodium, effective as an

analgesic and an NSAID class. The diclofenac

sodium contained analgesic effectiveness of 4-6

hours [15]. The maximum analgesic effect of

diclofenac sodium occurred at 120 minutes [16].

Evaluation Mechanism of Analgesic Action.

The evaluation mechanism of the analgesic effect

was determined by examining the muscarinic,

dopamine and opiate receptors. Thirty-six rats

were divided into six groups. Evaluate the

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After the 120^thminute, there was a decrease in

the analgesic effect. The treatment group doses

of 100, 200, and 400 mg/kg bw showed the peak

analgesic time at the 180^thminute, and the

maximum peak was obtained at a dose of 400

mg/kg bw (Figure 1).

Figure 1: Latency time to heat stimulation

The decrease in the analgesic response of the

positive control and the treatment group was

caused by the metabolism of compounds into an

inactive form, thereby reducing the effect [17].

The decrease in response to analgesic effects was

also caused by repeated exposure to painful

stimuli, which can cause an increase in pain [18].

The difference in individual thresholds makes

pain more subjective and challenging to

categorize within a specific range. Statistical

analysis showed a significant difference (p <0.05)

in latency time between treatment groups. There

was also a significant difference (p <0.05)

between the positive control (diclofenac sodium)

and the treatment group dose of 400 mg/kg bw.

Percentage analgesic activity showed a decrease

in pain response. The 400 mg/kg bw dose group

showed the highest percentage of analgesic

activity compared to other doses and higher than

the positive control group (Figure 2). Therefore,

the 400 mg/kg bw analgesic activity was the best

dose for suppressing pain. The results of this

study supported the wound-healing activity

capabilities that have been reported [3]. Other

species from Dillenia, such as Dillenia indica

reported that the ethyl acetate extracts of D.

indica (100 and 300 mg/kg) possessed good

central as well as peripheral analgesic activity as

compared with pentazocine and indomethacin

(10 mg/kg) respectively ]19].

Some compounds that act as analgesics include

triterpenoids, steroids, phenolics and flavonoids.

Previous studies have shown that D. ochreata

contained triterpenoids, such as centulic acid.

Triterpenoids serve as analgesics by suppressing

proinflammatory cytokines. including TNF-, INFγ,

IL-6, and IL-12 [11]. The compound also inhibits

the production of prostaglandin E2 (PGE2),

thereby producing an analgesic effect [20].

Steroid

compounds

can

stimulate

the

biosynthesis of lipomodulin protein, which can

inhibit the enzymatic phospholipase action. This

enzyme releases arachidonic acid and its

metabolites, thereby possessing analgesic and

anti-inflammatory

effects

[21].

Phenolic

compounds act as analgesics by suppressing the

formation of free radicals, which cause tissue

damage.

The

free

radicals

trigger

the

biosynthesis of arachidonic acid, a mediator of

inflammation and pain [22]. Furthermore,

flavonoids act as analgesics by inhibiting the

action of the cyclooxygenase (COX) enzyme,

which causes a decrease in the amount of

prostaglandin production, thereby reducing pain.

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Data are expressed as mean ± SD (n=5). Letters indicate a significant difference (p<0.05).

Figure 2. Percentage analgesic activity

Formalin Test

significant pain perception [23]. The licking time

in the negative control group for each phase was

more valuable because 1% Na CMC does not

have properties as an analgesic. The treatment

group had an analgesic activity percentage of

46.92% and 61.19% for Phase I and II, respectively

(Table 2).

Analgesic activity was determined using the

formalin method by observing the length of time

the rat licks its paw. Licking time was a pain

parameter in the formalin test, and a higher

observed rate in rats correlated with more

Table 2: Licking time in the formalin test

Groups

Licking time (second) average ± SD

% analgesic activity

Fase I

Fase II

Fase I

0%

46.92%

Fase II

0%

61.19%

Negative

Dose 400 mg/kg bw

55.56±5.97^b

29.49±3.42^a

118.70±4.17^c

46.07±8.75^a

Data are expressed as average ± SD (n=6). Different letters indicated the significantly different (p<0.05)

Statistical

analysis

showed

a

significant

Deraniyagala et al. (2014) [25] reported that

another species, Dillenia retusa, inhibited the

early and late phases of the formalin test by

working centrally and peripherally but is more

effective in the inflammatory phase. Figure 1

shows that the ethanol extract of D. ochreata leaf

(400 mg/kg bw) has more analgesic activity than

diclofenac sodium. This result shows that the

ethanol extract of D. ochreata leaf can suppress

central and peripheral pain, while diclofenac

sodium only works peripherally. In addition, the

hot plate method is more suitable for evaluating

centrally-acting analgesics [2]. A previous study

showed that the advantage of formalin as a pain

inductor is the ability to differentiate between

mechanisms that occur in central and peripheral

pain [23].

difference (p<0.05) in licking time between the

negative control and treatment groups. There

was a significant difference (p<0.05) in licking

time between phases I and II for the negative

group. However, there was no significant

difference (p>0.05) in the treatment group.

Further analysis showed a significant difference

(p<0.05) among several phases. In particular,

there were significant differences between the

negative and positive groups (phase I and II).

The codeine (5 mg/kg bw) was reported to have a

54.32% analgesic power in phase I and 61.08% in

phase II [24]. The data shows that D. ochreata leaf

extract had both central and peripheral effects,

showing an analgesic power comparable to

codeine in suppressing phase

I

and II.

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Mechanism of Analgesic Effect

analysis showed significant differences between

opioid receptor groups. Similarly, there was a

significant difference (p<0.005) between the

before and after treatment in the negative group.

In the positive group, there was no significant

difference between the before and after

treatment, as shown by p>0.05. The evaluation of

the analgesic mechanism of the three methods

(Table 3) showed that the ethanol extract of D.

ochreata leaf works through opioid receptors.

The analgesic mechanism of ethanol extract of D.

ochreata leaf was evaluated by comparing the

receptor antagonists of the negative and positive

control group (Table 3).

Statistical analysis

showed no significant differences (p>0.05)

between muscarinic and dopaminergic receptor

groups. There was also no significant difference

(p>0.05) between before and after treatment in

the negative and positive groups. The parametric

Table 3: Evaluation of the mechanism of analgesic effect.

Latency time (seconds) ± SD

Groups

Before treatment

After treatment

Muscarinic receptor

I.

NaCl Fisiologis + extract dose

400 mg/kg bw (negative)

3.35±0.19^a

3.44±0.10^b

3.70±0.13^a

II.

II. Atropine Sulfate + extract

dose 400 mg/kgBW (positive)

3.92±0.49^b

Dopamine receptor

III.

NaCMC 1% + extract dose 400

mg/kg bw (negative)

3.22±0.31^a

3.37±0.14^b

3.49±0.38^a

3.80±0.36^b

IV.

Metoclopramide HCl + extract

dose 400 mg/kg bw (positive)

Opioid receptor

V.

NaCl Fisiologis + extract dose

3.32±0.11^a

3.53±0.10^c

3.80±0.38^b

3.39±0.08^c

400 mg/kg bw (negative)

Nalokson HCl + extract dose

400 mg/kg bw (positive)

VI.

Data are expressed as mean ± SD (n=6); different letters indicated a significant difference (p<0.05).

The agonist substances (opioid mimetics) cause

the release of endogenous opioids, such as

endofins and enkephalins. A previous study

showed that opioid peptides mediate analgesia

both centrally and peripherally due to the ability

to suppress both phases of the formalin test [26].

of naloxone HCl with D. retusa fruit extract

decreased the pain effects of rats after 2 hours.

Triterpenoids suppress visceral pain through the

mechanisms of endogenous opioids, nitric oxide,

and the opening of K (ATP) channels [29].

Meanwhile, steroids are antinociceptive in the

central nervous system [30], producing effects

through central receptors or increasing the

release of endogenous opioid peptides [31]. The

ability of flavonoids to reduce pain stimulation

was due to the active participation of µ and δ

opioid receptors. Furthermore, flavonoids target

δ receptors to reduce pain in rat paw oedema

[32, 33].

The

endogenous

opioids

directly

inhibit

peripheral nociceptive afferent neurons, thereby

reducing transmission from the periphery [27].

Administration of an opioid antagonist in the

form of Naloxone HCl with with ethanol extract

of D. ochreata leaf resulted in a decrease in pain

reactions when stimulation was administered

using a hot plate. Naloxone HCl, acting as an

antagonist, blocked the intracellular signalling

initiated by the extracted binding to the receptor,

thereby eliminating the analgesic effect [28].

These results are consistent with the report of

Deraniyagala et al. (2014) [25] that the interaction

Standardization of the extract.

Standardization of extract was carried out to

determine the quality of the extract through

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testing a series of parameters related to quality

standard requirements [14]. The result of the

standardization ethanol extract of D. ochreata

leaves can be seen in

Table 4.

Table 4: Standardization of the ethanol extract of D. ochreata leaves

Parameter

Result

Requirement [14]

Specific parameter

Organoleptic

Thick, blackish

distinctive odour with a slight

bitter taste

Water soluble extractive content (%)

Ethanol soluble extractive content (%)

Non spesific parameter

Water content (%)

Susut Pengeringan (%)

Total ash content (%)

65.33 ± 3.05

88.00 ± 2.00

˃ 31

˃ 70.5

6.00 ± 1.00

6.38 ± 1.13

8.18 ± 0.01

0.16 ± 0.01

< 10

< 16.6

< 0.9

Acid insoluble ash content (%)

Metal contamination (mg/Kg)

-

Pb content

Cd content

0.0628 mg/kg

0.0077 mg/kg

< 10 mg/kg

< 0.3 mg/kg

Microbial contamination (cfu/mL)

-

Plate content

Yeast content

0

< 10⁴

< 10³

-

The specific parameter's value showed that the

extract was thick, blackish, with a distinctive

odour and a slightly bitter taste; the water-

soluble extractive content was 65.33% ± 3.05,

while the ethanol-soluble extractive content was

88.00% ± 2.00. The results of spesific parameter

meet the standards parameter was requirement

[14]. The non-specific parameters showed the

water content value was 6.00% ± 1.00. Its set as

viscous extract [34], the drying shrinkage value

was 6.38% ± 1.13, the total ash content was 8.18%

± 0.01, and acid insoluble ash content was 0.16%

± 0.01, Pb contamination content was 0.0628

mg/kg, and Cd content was 0.0077 mg/kg. The

total plate number and yeast content from the

ethanolic extract of D. ochreata leaves were not

This extract exerted pressure on the central

(46.92%) and peripheral (61.19%). In addition, the

analgesic effect of ethanol extract from D. chreata

leaf worked through the opioid receptors with a

decrease in pain reactions from 3.53±0.10 to

3.39±0.08 seconds. The extract of D. ochreata

leaves fulfils the standardization parameters of

the extract.

Acknowledgement

The authors express their sincere gratitude to the

Department

of

Chemistry,

Faculty

of

Mathematics and Natural Sciences, University of

Sriwijaya, for providing the facilities and support

necessary for the successful implementation of

this research.

found,

indicating

secondary

metabolites

contained in D. ochreta leaves extract inhibiting

the growth of microorganisms in the extract. The

value of non-specific parameters also meets the

standard parameter requirement.

Author Contributions

Conceptualization, M.M. and F.F.; Methodology,

F.G. H.Y; Software, F. G. H. Y.; Validation, M.M.,

F.F. and F.G.; Formal Analysis, M.M., F.G.;

Investigation, F.G.; Resources, M.M.; H. Y.; Data

Curation, M.M., F.G., F.F. H.Y; Writing – Original

Draft Preparation, M.M., F.G.; Writing – Review &

Editing, H. Y., F.F.; Visualization, M.M., F.G.;

Conclusion

The ethanol extract of Dillenia ochreata leaf

showed higher analgesic activity (24.85%) than

the positive control (18.32%) and statistical

analysis showed a significant difference (p<0.05).

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Chempublish Journal, 9(1) 2025,120-129

Supervision, M.M.; Project Administration, F.F. H.

Y.; Funding Acquisition, M.M.

[8]

Sene M, Ndiaye D, Gassama A, Barboza FS,

Mbaye MD, and Yoro SYG. Analgesic and

Anti-inflammatory

Activities

of

Conflict of Interest

Triterpenoid Molecules Isolated from the

Leaves of Combretum glutinosum Perr. Ex

DC (Combretaceae)". Journal of Advances in

The authors declare no conflict of interest

Medical

201819(4):

10.9734/JAMPS/2018/v19i430096

Gong JH, Zhang CM, Wu B, Zhang ZX, Zhou,

Zhu JH, Liu LH, Rong Y, Yin Q, Chen YT,

Zheng R, Yang GZ, Yang XF, and Chen S.

Central and peripheral analgesic active

components of triterpenoid saponins from

Stauntonia chinensis and their action

mechanism. Frontiers in Pharmacology.

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