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Evaluation of analgesic activity of ethanolic leaf extract of Acacia auriculiformis A. Cunn. ex Benth and its biofraction: Experimental and computational approach
*Corresponding author: Liesl Maria Fernandes e Mendonca, Assistant Professor, Department of Pharmacology, Goa College of Pharmacy, Panaji-Goa, India. lieslpharma@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Dhatkar AA, Fernandes e Mendonca LM, Da Vitoria Lobo JM. Evaluation of analgesic activity of ethanolic leaf extract of Acacia auriculiformis A. Cunn. ex Benth and its biofraction: Experimental and computational approach. Indian J Physiol Pharmacol. doi: 10.25259/ IJPP_26_2026
Abstract
Objectives:
The study aimed at evaluating the analgesic potential of the ethanolic leaf extract of Acacia auriculiformis (EEAA) and its acetone-enriched A. auriculiformis (AEAA) fraction, using experimental and computational approaches.
Materials and Methods:
The ethanolic leaf extract and its bioactive fraction were prepared using the reflux method. The antioxidant potential of EEAA and AEAA was assessed using in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide and hydrogen peroxide scavenging assays, while the analgesic activity was evaluated using a hot plate analgesiometer and tail immersion methods in Wistar albino rats at a dose of 200 mg/Kg and 400 mg/Kg over a period of 7 days. The probable phytoconstituents in EEAA and AEAA were analysed using liquid chromatography–mass spectrometry (LC-MS) analysis, and the identified constituents were docked in silico using the Kappa opioid receptor (KOR). Statistical analysis was performed using one-way analysis of variance followed by Dunnett’s test.
Results:
AEAA demonstrated superior-free radical scavenging capacity in all three assays. Both EEAA and AEAA exhibited dose-dependent analgesic effects, with AEAA at 400 mg/Kg exhibiting a statistically significant increase in activity (p < 0.05) in both the analgesic models. Furthermore, LC-MS analysis revealed the presence of various phytoconstituents. The selected phytoconstituents, when docked with KOR in silico demonstrated strong binding affinities, indicating a possible mechanism underlying their analgesic action.
Conclusion:
The findings of the study highlight the promising therapeutic analgesic potential of A. auriculiformis, especially its AEAA fraction, and warrant further investigation to isolate and characterise the bioactive constituents.
Keywords
Acacia auriculiformis
Analgesic activity
Antioxidant activity
Kappa opioid receptor
LC-MS analysis
Molecular docking
INTRODUCTION
Pain is a multifaceted sensory and emotional experience that arises from actual or potential tissue damage and involves intricate interactions between peripheral nociceptors, spinal neurons and higher brain centres. It can be classified as nociceptive, inflammatory or neuropathic, each governed by distinct yet overlapping neurochemical or molecular pathways.[1]
Chronic pain, in particular, disrupts normal somatosensory processing and often co-exists with psychological comorbidities such as mood disorders, anxiety and depression, highlighting the shared pathophysiological circuits between nociception and mood regulation.[1-3]
The Kappa opioid receptor (KOR), part of the endogenous opioid system and one of the three main opioid receptor subtypes (mu, delta, kappa), plays a crucial role in modulating both pain and emotional responses. The activation of KOR produces analgesia by inhibiting the release of neurotransmitters involved in nociceptive signalling, particularly substance P and glutamate, at the spinal and supraspinal levels.[4,5]
However, KOR agonists can also influence mood, sometimes producing dysphoric effects. In addition, oxidative stress has been implicated as a major contributor to the development and maintenance of chronic pain. It occurs when an imbalance between reactive oxygen species (ROS) and antioxidant defences leads to lipid peroxidation, mitochondrial dysfunction and neuronal sensitisation.[6] ROS have been shown to modulate nociceptive pathways by activating transient receptor potential (TRP) channels, sensitising N-methyl-Daspartate (NMDA) receptors and disrupting mitochondrial energy metabolism in pain-transmitting neurons.[7,8]
Studies have confirmed elevated oxidative biomarkers in individuals with chronic pain conditions and demonstrated that antioxidant supplementation can reduce nociceptive responses.[9,10] Given the limitations of conventional analgesics, including gastrointestinal irritation from nonsteroidal anti-inflammatory drugs, tolerance and dependence from opioids and withdrawal issues, there is growing interest in identifying safer, plant-derived alternatives. Medicinal plants are rich sources of bioactive compounds such as flavonoids, alkaloids, tannins, saponins and terpenoids, many of which exhibit analgesic, anti-inflammatory and antioxidant activities through diverse mechanisms, including opioid receptor interaction, inhibition of pro-inflammatory mediators (tumour necrosis factor-α [TNF-α], interleukin-1 [IL-1β]) and ROS scavenging.[11,12]
The Fabaceae family, particularly the genus Acacia, is known for its pharmacologically active constituents and has been widely used in traditional medicine for treating ailments like inflammation, pain and skin disorders. Acacia auriculiformis A. Cunn. ex Benth., a fast-growing evergreen or deciduous tree native to Southeast Asia, has shown diverse pharmacological effects, including anti-inflammatory, anti-diabetic, antioxidant and central nervous system-depressant properties.[13-15]
Phytochemical investigations have revealed that its leaves contain flavonoids, tannins, glycosides and saponins, which may act synergistically to exert antioxidant and analgesic effects.[16]
Despite traditional claims and its rich phytochemical profile, there is no scientific data on the analgesic efficacy of A. auriculiformis leaf extracts. Thus, this study was designed to evaluate the antinociceptive potential of ethanolic extract A. auriculiformis (EEAA) and its acetone-enriched A. auriculiformis (AEAA) fraction in experimental animal models using thermal pain assays using hot plate and tail immersion tests. In addition, in silico molecular docking was employed to investigate possible interactions of major phytoconstituents with the kappa-opioid receptor, providing mechanistic insights into the observed pharmacological effect.
MATERIALS AND METHODS
Drugs and chemicals
The analytical-grade chemicals and solvents utilised in the study were sourced from the Chemical Inventory of Goa College of Pharmacy. Fresh biochemical reagents were prepared for the experiments. Pentazocine was obtained from DCI Pharmaceutical Pvt. Ltd. Ethanol, acetone, petroleum ether, methanol and 2,2-diphenyl-1-picrylhydrazyl (DPPH) were obtained from Molychem.
Collection and authentication of plant materials
Fresh leaves of A. auriculiformis A. Cunn. ex Benth were collected from Bicholim, Goa, in November 2024. The leaves were identified, confirmed and authenticated by Dr. Ashish V. Prabhugaonkar, Assistant Professor, Department of Botany, Dhempe College of Arts and Science, Miramar-Goa, dated 13 December 2024.
The leaves were washed and shade-dried for 15–20 days, further powdered using a mechanical grinder, and then packed and stored in an air-tight container at room temperature until extraction.
Preparation of extract
Preparation of EEAA
1.1 Kg of dried powdered A. auriculiformis leaves was defatted by refluxing with petroleum ether for 90 min; the process was repeated thrice. The dried marc was then refluxed with ethanol for 1.5 h, repeated three times and the combined extracts were filtered (Whatman No. 1), evaporated to dryness and stored at 4°C as the EEAA.
Preparation of AEAA
50 g of EEAA was refluxed with acetone for 1.5 h; the process was repeated three times. The filtered extract was evaporated and air-dried to yield the AEAA fraction, which was stored at 4 °C until further use.
Ethics committee approval
All experimental protocols were reviewed and accepted by the Institutional Animal Ethics Committee (IAEC) before commencement of the experiment (GCP/IAEC/2024/04).
Animals used
Male Wistar albino rats weighing 150–250 g were used in this study and were procured from Lacsmi Biofarms Pvt. Ltd, Pune (CCSEA Reg No.277/PO/RcBt/S/09/CPCSEA), India. The animals were kept at standard temperatures (25 ± 2°C) and relative humidity levels (55 ± 10%). The animals were fed with pellets and water ad libitum. A 12-h light and dark cycle was maintained. All experiments were carried out in compliance with the guidelines of the Committee for the Control and Supervision of Experiments on Animals, Government of India and the animals were acclimatised to laboratory conditions for a week before the trial began.
In vitro antioxidant activity
DPPH radical scavenging assay
The antioxidant activity of the EEAA, AEAA and standard ascorbic acid was assessed using the DPPH-free radicals scavenging assay, incorporating slight modifications to the methods outlined by Gülçin et al.[17] The reaction mixture included 1 mL of DPPH, 1 mL of test extract, biofraction or standard ascorbic acid (2–10 µg/mL) and 1 mL of methanol and was shaken. After 30-min of incubation at room temperature in the dark, absorbance was measured at 517 nm. A colour change from purple to yellow indicated free radical scavenging activity. DPPH-free radical was computed and represented as an inhibition percentage:
Hydrogen peroxide radical scavenging assay
Hydrogen peroxide scavenging activity was assessed with slight modification to that described by Gülçin et al.,[18] 1.5 mL of extract, biofraction or ascorbic acid (2–10 µg/mL) was mixed with 0.3 mL ferrous ammonium sulphate in a test tube, and incubated in the dark for 5 min. 1.5 mL of 1,10-phenanthroline was further added, mixed and incubated for 15 min at room temperature. Absorbance was measured at 510 nm, and hydrogen peroxide-free radical scavenging activity was calculated using the formula:
Nitric oxide radical scavenging assay
Nitric oxide scavenging activity was evaluated using the Griess reaction with extract, biofraction, and ascorbic acid (2–10 µg/mL), following a modified method by Amaeze et al.[19]A 3 mL reaction mixture (sodium nitroprusside, PBS and extract/standard) was incubated for 150 min. Thereafter, 0.5 mL was mixed with sulphanilic acid (1 mL), left for 5 min, then treated with 1 mL of naphthylethylenediamine hydrochloride and incubated for 30 min. Absorbance was recorded at 540 nm. Nitric oxide-free radical scavenging activity was calculated using the formula:
Experimental design
Dose selection
The acute oral toxicity studies performed according to OECD Guideline 425, on ethanolic leaf extract of A. auriculiformis demonstrated it to be safe up to 2000 mg/Kg. Therefore, 200 mg/Kg and 400 mg/Kg doses were selected for the study.
Treatment groups
For analgesic evaluation, the rats were divided into six groups: Control (1% Tween 80), Standard (Pentazocine 10 mg/Kg), EEAA (200 and 400 mg/Kg) and AEAA (200 and 400 mg/Kg), administered orally for 7 days. Hot plate and tail immersion tests were performed for 30 min post-dosing on Days 1 and 7.
Screening models for analgesic activity
Hot plate method
The procedure was carried out following the method described by Vogel.[20] The animals were placed on Eddy’s hot plate, and the temperature was maintained at 55 ± 0.5°C. To prevent skin damage, a 60 s cut-off was set. Response time (licking/jumping) was recorded with a stopwatch at 30, 60, 90, 120 and 240 min. after oral (p.o) dosing.
Tail immersion test
The tail immersion method was used to assess the central analgesic property. Animals were divided into 6 groups. They are placed into individual restrainers, leaving the tail hanging out freely. The lower 5 cm portion of the tail was marked and immersed in a beaker of water maintained at 55 ± 0.5°C. Tail withdrawal time (reaction time) was recorded using a stopwatch at 30, 60, 90, 120 and 240 min., with a cut-off time of 15 s.[20]
Identification of phytoconstituents present in EEAA and AEAA by LC-MS analysis
The liquid chromatography-mass spectrometry analysis was performed for EEAA and AEAA using a Shimadzu high-performance liquid chromatography system equipped with Pump LC-10ADVp, Detector SPD-10AVp, Auto Sampler SIL HTA, Degasser DGU-12A and Column Oven CTO-10AVp. The data acquisition and also the analysis were conducted using LC Solution Software, Version 1.25 SP4. For LC-MS/MS analysis, a Waters XBridge C18 column (50 × 4.6 mm, particle size 3.5 µm) was used. The mobile phase consisted of Solvent A: 0.1% Formic Acid in water and Solvent B: Acetonitrile (MS grade). The gradient elution program was set as time (min)/%B – 0.01/15; 6.00/75; 8.00/75; 11.00/15; 15.00/15, with the run stopped at 15.01 min. The flow rate was maintained at 1.2 mL/min, and the mode of elution was gradient. The diluent used was a mixture of methanol, acetonitrile, water, 0.1% formic acid, and trifluoroacetic acid. Detection was done using an ultraviolet-visible detector.
In silico docking simulation studies
Preparation of the protein
Protein 3D structures were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank database (RCSB) 4DJH (KOR for analgesic). Files were downloaded in *.pdb format. Proteins were prepared by adding hydrogen and removing water molecules. And X, Y, Z coordinates were recorded from BIOVIA Discovery Studio.
Preparation of the ligand
3D structures of the compounds identified from A. auriculiformis leaves were obtained from PubChem. Structures were downloaded in *.sdf format. Ligand *.sdf files were converted to *.pdb using an online SMILES translator. Both ligand and protein *.pdb files were converted to *.pdbqt using AutoDockTools 1.5.7.
Docking and visualisation of protein-ligand interactions
Docking simulations were performed using AutoDockTools 1.5.7. Docked ligand-protein complexes were visualised with PyMOL. Interactions were analysed using BIOVIA Discovery Studio 2024.
Statistical analysis
Results of all the above-mentioned models were statistically analysed using one-way analysis of variance by Dunnett’s test, in which the results obtained from experimental samples were compared with the control. All the results were expressed as mean ± standard error of the mean (*p < 0.05, **p < 0.01, ***p < 0.001, ****p<0.0001) for analgesic study (n = 6), as well as for the antioxidant study (n = 3). This analysis was performed on GraphPad Prism version 10.0.0.
RESULTS
Yield
The per cent yield of EEAA was found to be 7.751% w/w, while that of AEAA was 53 % w/w.
In vitro antioxidant activity
The results of the in vitro free radical scavenging assays of EEAA and AEAA are illustrated in Table 1.
| Samples | Free radical scavenging assays (IC50 = µ | g/mL) | |
|---|---|---|---|
| DPPH | Hydrogen peroxide | Nitric oxide | |
| EEAA | 7.41±0.95 µg/mL | 21.97±1.44 µg/mL | 4.45±0.29 µg/mL |
| AEAA | 12.85±1.32 µg/mL | 11.85±2.85 µg/mL | 5.47±0.23 µg/mL |
| Standard (ascorbic acid) | 5.09±0.20 µg/mL | 4.65±0.08 µg/mL | 2.27±0.09 µg/mL |
Values are expressed as mean±SEM (n=3), DPPH: (2,2-diphenyl-1-picrylhydrazyl) , EEAA: Ethanolic leaf extract of Acacia auriculiformis, AEAA: Acetone-enriched A. auriculiformis, SEM: Standard error mean, IC50: (half-maximal inhibitory concentration)
In vivo analgesic study
The results of the analgesic effects of EEAA and AEAA, which were evaluated through the Hot plate and Tail immersion methods, are shown in Figures 1 and 2.
LC-MS analysis
LC-MS analysis identified eight compounds: Auriculoside (MW: 450.4 g/mol), Teracacidin (MW: 290.27 g/mol), Epicatechin (MW: 290.27 g/mol), Quercitrin (MW: 448.38 g/ mol), Procyanidin B2 (MW: 578.52 g/mol), Procyanidin B4 (MW: 578.52 g/mol), 4’-O-Methylepicatechin-7-O-glucuronide (MW: 480.22 g/mol) and Kaempferol (MW: 286.24 g/mol) [Supplementary Data S1].
In-silico molecular docking
The in silico molecular docking results of compounds identified from A. auriculiformis, including Auriculoside, Teracacidin, Epicatechin, Quercitrin, Procyanidin B2, Procyanidin B4, 4’-O-methylepicatechin-7-O-glucuronide and Kaempferol with Pentazocine (KOR, PDB ID: 4DJH), are presented in Figure 3 and binding affinities of the compounds are mentioned in Table 2.
| Compounds | PubChem CID | Ligand binding sites | Binding affinity (Kcal/mol) |
|---|---|---|---|
| Standard (Pentazocine) | 441278 | TRP124, CYS210, VAL118, LEU135, GLN115, VAL134, ILE316, ASP138 | -7.4 |
| Auriculoside | 442260 | TYR312, TYR320, ASP138, VAL108, ILE316, ILE 290, MET142, HIS291, ILE294, LYS227, VAL230 | -8.8 |
| Teracacidin | 44187798 | ILE290, ILE316, TRP287, TYR320, VAL230, MET142, ILE294 | -8.9 |
| Epicatechin | 72276 | VAL230, ILE294, HIS291, MET142, ILE290, ASP138, TRP287, ILE316 | -8.9 |
| Quercitrin | 5280459 | ASP138, ILE294, MET142, ILE290, ILE316, TRP287, TYR320, GLN115 | -9.0 |
| Procyanidin B2 | 122738 | TYR219, TYR312, TYR320, THR111, GLN115, VAL118, TRP124, CYS210, ASP223, LYS227 | -9.2 |
| Procyanidin B4 | 147299 | ASP223, TYR219, ASP138, TYR312, GLN115, CYS210, LYS227 | -8.6 |
| 4’-O-Methylepicatechin- 7-O-glucuronide | 101244288 | ILE294, ASP138, ASP223, LEU212, ILE316, GLY319, TYR320, VAL108, TRP287, MET142, ILE290 | -9.0 |
| Kaempferol | 5280863 | ILE294, MET142, ILE290, ILE316, TRP287, TYR320, | -8.9 |
DISCUSSION
The present study demonstrated the significant analgesic potential of the ethanolic leaf extract of A. auriculiformis (EEAA) and its acetone biofraction (AEAA), as evidenced by their performance in hot plate and tail immersion tests. Both extracts, at doses of 200 and 400 mg/Kg, significantly prolonged response latencies at 60, 120 and 240 min on Days 1 and 7.
The pronounced and sustained increase in nociceptive threshold, especially with AEAA at 400 mg/Kg (****p < 0.0001), indicates strong central and peripheral analgesic activity with a clear dose-dependent response. These behavioural observations correlate well with molecular docking data, where major phytoconstituents such as procyanidins B2 and B4, quercitrin and kaempferol exhibited high binding affinities to the KOR, which is a key target in nociceptive modulation.
Procyanidin B2, in particular, exhibited a binding energy of –9.2 kcal/mol, surpassing that of the standard KOR agonist Pentazocine (–7.4 kcal/mol), and engaged crucial receptor residues such as ILE316, TYR320, TRP124 and ASP138, indicating strong receptor-ligand interactions and potential agonistic behaviour.
The KOR, when activated, inhibits adenylate cyclase activity, reduces intracellular cyclic adenosine monophosphate and modulates ion channel activity by closing voltage-gated calcium channels and opening potassium channels, thereby inducing neuronal hyperpolarisation and suppressing nociceptive neurotransmitter release. These actions collectively diminish nociceptive transmission, consistent with the elevated response thresholds seen in the animal models of the study.[4,5,8]
Flavonoids such as quercitrin and kaempferol are recognised for their diverse analgesic mechanisms, which include the inhibition of cyclooxygenase-2 and subsequent prostaglandin E2 synthesis, a key player in peripheral sensitisation.[21] In addition, they modulate transient receptor potential (TRP) channels such as TRPV1, which mediate thermal nociception,[22]and inhibit pro-inflammatory transcription factors such as nuclear factor kappa B and mitogen-activated protein kinase, thus reducing inflammatory hyperalgesia.[23]
Proanthocyanidins, owing to their polymeric structure, exert neuroprotective effects by scavenging free radicals, inhibiting lipid peroxidation and preserving mitochondrial integrity.[24,25]
Some of the compounds present in the extract, such as kaempferol and epicatechin, have demonstrated significant (***p < 0.001) analgesic activity as per the literature, evidenced by an increase in reaction latency in both the hot plate and tail immersion tests. This prolongation of response time suggests an effective attenuation of pain perception.[26-28]
Another important contributor to the analgesic activity of A. auriculiformis is its antioxidant property, which is particularly prominent in AEAA. Oxidative stress is a known amplifier of pain perception, especially in chronic and neuropathic conditions. ROS sensitise nociceptors, impair mitochondrial function and activate glial cells, promoting the release of pro-inflammatory cytokines such as TNF-α and IL-1β.[3,6] The radical scavenging capacity of AEAA, as confirmed through antioxidant assays, suggests that its polyphenolic constituents may mitigate ROS-induced nociceptive sensitisation. These polyphenols not only stabilise mitochondrial membranes but also upregulate endogenous antioxidant enzymes, thereby restoring cellular redox balance and attenuating peripheral sensitisation.[10]
Chronic pain conditions, including those arising from spinal cord injury or central sensitisation, are characterised by increased ROS and increased inflammatory responses, which exacerbate pain.[1,2,29]
The hot plate test is more selective for detecting strong mu opioid receptor agonists that act at the supraspinal level, while the tail immersion test preferably detects KOR agonists that act at the spinal reflex-driven withdrawal responses. Since Pentazocine acts primarily at the KOR and partially at the mu opioid receptor, it demonstrated superior analgesic activity in the tail immersion test as compared to the hot plate test.[30,31]
Taken together, the analgesic activity of A. auriculiformis likely results from a synergistic interplay between central mechanisms involving opioid receptor modulation and peripheral antioxidant defence. The engagement of the KOR by active flavonoids and proanthocyanidins suppresses nociceptive signalling at the central level, while the antioxidant properties counteract oxidative stress and inflammatory sensitisation in the periphery. This dual action provides an effective strategy for managing complex pain states involving both neurogenic and inflammatory components.[7,9]
These findings not only validate the ethnopharmacological use of A. auriculiformis in managing pain-related disorders but also highlight its potential as a phytotherapeutic analgesic agent, warranting further clinical investigation.
CONCLUSION
The results of the investigation indicate that the EEAA leaves exhibit a pronounced analgesic effect. Tested doses of AEAA 400 mg/Kg produced significant Analgesic activity compared to the control group. However, further studies are warranted to elucidate the precise mechanism of action and to isolate and characterise the specific active constituents responsible for the observed pharmacological effects.
Acknowledgement:
The authors are extremely grateful to Dr. G.K. Rao, Principal, and Dr. Madhusudan P. Joshi, HOD, Department of Pharmacology, for their constant guidance, motivation, and support for research work. The authors are also grateful to DCI Pharmaceutical Pvt. Ltd. For providing Pentazocine.
Ethical approval:
The research/study was approved by the Institutional Animal Ethics Committee (IAEC) at Goa College of Pharmacy, approval number GCP/IAEC/2024/04, dated 4th December 2024.
Declaration of patient consent:
Patient’s consent not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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