Search JIM Advanced Search

Journal of Integrative Medicine ›› 2017, Vol. 15 ›› Issue (5): 379-387.doi: 10.1016/S2095-4964(17)60349-2

Special Issue: Natural Drug

• Research Article • Previous Articles     Next Articles

Antinociceptive and anti-inflammatory activities of leaf extracts from Annona tomentosa R.E.Fr

Lilian Uchoa Carneiroa,b, Ilna Gomes da Silvac, Mirian Eliza Alves de Souzaa,b, Wellington da Silva Côrtesa,b, Mário Geraldo de Carvalhoc, Bruno Guimarães Marinhoa,b   

  1. a Postgraduate Program in Physiological Sciences, Institute of Biological and Health Sciences, Federal Rural University of Rio de Janeiro, Rio de Janeiro 23890-000, Brazil
    b Laboratory of Pharmacology, Department of Physiological Sciences, Institute of Biological Sciences and Health, Federal Rural University of Rio de Janeiro, Rio de Janeiro 23890-000, Brazil 
    c Postgraduate Program in Chemistry, Department of Chemistry, Institute of Exact Sciences, Federal Rural University of Rio de Janeiro, Rio de Janeiro 23890-000, Brazil
  • Received:2017-01-01 Accepted:2017-04-14 Online:2017-09-15 Published:2017-09-15
  • Contact: Bruno Guimarães Marinho, PhD; E-mail:;


Annona tomentosa R.E.Fr is a species not endemic to Brazil that belongs to the phytogeographic areas of the Amazon, Cerrado and Pantanal. Popularly known as “araticum rasteiro” or “araticum de moita”, A. tomentosa is edible and tea made from the leaves has been used as an anti-inflammatory by native communities. There is no scientific evidence for these uses of A. tomentosa, especially those related to the control of pain and inflammation. For this reason, in the present study we evaluated the antinociceptive and anti-inflammatory activities of partitions from the methanolic extract of A. tomentosa leaves (A. tomentosa leaf methanolic extract (ATFM) in hexane partition: ATFM-H; ATFM in dichloromethane partition: ATFM-D; ATFM in ethyl acetate partition: ATFM-Ac; ATFM in butanol partition: ATFM-B) in mice.


The antinociceptive effects of leaf extracts from A. tomentosa were evaluated by abdominal writhing and tail-flick tests, while the anti-inflammatory effects were evaluated by paw oedema and air-pouch tests. The locomotor activity was evaluated with the open-field test. Furthermore, we evaluated the possible action mechanism of A. tomentosa, using naloxone, nitro-L-arginine methyl ester, glibenclamide, atropine, naltrindole and norbinaltorphimine in tail-flick tests. The productions of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β were also evaluated.


The chromatographic fractionation of the partitions of the methanolic extract from the leaves of A. tomentosa revealed the presence of diterpenes, flavonoids, and steroids compounds. From the analysis of the hexane partition kaurenoic acid was identified as the major component. ATFM-H and ATFM-D had a significant antinociceptive effect in acute pain models in mice. The ATFM-H showed central antinociceptive effect from the involvement of the δ opioid receptors, without causing alterations in the locomotor activity of the mice, while ATFM-D was effective in decreasing paw oedema and TNF-α and IL-1β production.


These results demonstrate that leaf extracts from A. tomentosa present antinociceptive and anti-inflammatory effects that can to be used in relieving algesic and inflammatory conditions.

Key words: Annona tomentosa, Cytokines, opioid, nociception

1 Ruíz SE, Morett AL. Las Anonas en el México Prehispánico. Chapingo, Edo. de México. Memorias Congreso Internacional de Anonáceas. México.1997. French.
2 Assis MCD, Zappi DC, Filardi FLR, Rodrigues RS.Growing knowledge: an overview of Seed Plant diversity in Brazil.Rodriguésia. 2015; 66(4): 1085-1113.
3 Santos DY, Salatino ML.Foliar flavonoid of Annonaceae from Brazil: taxonomic significance.Phytochemistry. 2000; 55(6): 567-573.
4 Waldhoer M, Bartlett SE, Whistler JL.Opioid receptors.Annu Rev Biochem. 2004; 73: 953-990.
5 Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dollé P, Tzavara E, Hanoune J, Roques BP, Kieffer BL.Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene.Nature. 1996; 383(6603): 819-823.
6 Contet C, Kieffer BL, Befort K.Mu opioid receptor: a gateway to drug addiction.Curr Opin Neurobiol. 2004; 14(3): 370-378.
7 Stein C, Machelska H.Modulation of peripheral sensory neurons by the immune system: implications for pain therapy.Pharmacol Rev. 2011; 63(4): 860-881.
8 Labuz D, Machelska H.Stronger antinociceptive efficacy of opioids at the injured nerve trunk than at its peripheral terminals in neuropathic pain.J Pharmacol Exp Ther. 2013; 346(3): 535-544.
9 Williams JT, Ingram SL, Henderson G, Chavkin C, Von Zastrow M, Schulz S, Koch T, Evans CJ, Christie MJ.Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance.Pharmacol Rev. 2013; 65(1): 223-254.
10 Baron R, Binder A, Wasner G.Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment.Lancet Neurol. 2010; 9(8): 807-819.
11 Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T.Th1/Th17 immune response is induced by mesenteric lymphnode dendritic cells in Crohn’s disease.Gastroenterology. 2009; 137(5): 1736-1745.
12 Sato T, Kanai T, Watanabe M, Sakuraba A, Okamoto S, Nakai T.Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease.Gastroenterology. 2004; 126(3): 829-839.
13 Liao W, Lin JX, Leonard WJ.IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation.Curr Opin Immunol. 2011; 23(5): 598-604.
14 Dos Santos GC, Fernandes RD, Barros TR, Abreu HS, Suzart LR, de Carvalho MG, Braz-Filho R, Marinho BG. Antinociceptive and anti-inflammatory activities of the methanolic extract from the stem bark ofLophantera lactescens. Planta Med. 2015; 81(18): 1688-1696.
15 Leitão SG, dos Santos TC, Monache FD, Matheus ME, Fernandes PD, Marinho BG. Phytochemical profile and analgesic evaluation ofVitex cymosa leaf extracts. Braz J Pharmacogn. 2011; 21(5): 874-883.
16 Li Y, Zheng B, Tian H, Xu X, Sun Y, Mei Q, Lin X, Liu L.Yupingfeng powder relieves the immune suppression induced by dexamethasone in mice.J Ethnopharmacol. 2017; 200: 117-123.
17 Otuki MF, Ferreira J, Lima FV, Meyre-Silva C, Malheiros A, Muller LA, Cani GS, Santos AR, Yunes RA, Calixto JB.Antinociceptive properties of mixture of α-amyrin and β-amyrin triterpenes: evidence for participation of protein kinase C and protein kinase A pathways.J Pharmacol Exp Ther. 2005; 313(1): 310-318.
18 Tabarelli Z, Berlese DB, Sauzem PD, Rubin MA, Missio TP, Teixeira MV, Sinhorin AP, Martins MAP, Zanatta N, Bonacorso HG, Mello CF.Antinociceptive effect of novel pyrazolines in mice.Braz J Med Biol Res. 2004; 37(10): 1531-1540.
19 19 Gonçalves GM, Capim SL, Vasconcellos MLAA, Marinho BG. Antihyperalgesic effect of [(±)-(2,4,6-cis)-4-chloro- 6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl]methanol: participation of the NO/cGMP/KATP pathway and κ-opioid receptor.Behav Pharmacol. 2016; 27(6): 506-515.
20 Koster R, Anderson M, De Beer EJ.Acetic acid for analgesic screening.Fed Proc. 1959; 18: 412.
21 D’Amour FE, Smith DL. A method for determining loss of pain sensation.J Pharmacol Exp Ther. 1941; 72: 74-79.
22 Erdos EG.Handbook of experimental pharmacology. New York: Springer-Verlag. 1979.
23 Vigil SV, De Liz R, Medeiros YS, Fröde TS.Efficacy of tacrolimus in inhibiting inflammation caused by carrageenan in a murine model of air pouch.Transpl Immunol. 2008; 19(1): 25-29.
24 Barros HM, Tannhauser MA, Tannhauser SL, Tannhauser M.Enhanced detection of hyperactivity after drug withdrawal with a simple modification of the open-field apparatus.J Pharmacol Method. 1991; 26(4): 269-275.
25 Block LC, Santos ARS, De Souza MM, Scheidt C, Yunes RA, Santos MA, Delle Monache F, Filho VC.Chemical and pharmacological examination of antinociceptive constituents ofWedelia paludosa. J Ethnopharmacol. 1998; 61(1): 85-89.
26 Nguelefack TB, Fotio AL, Watcho P, Wansi SL, Dimo T, Kamanyi A.Analgesic properties of the aqueous and ethanol extract of the leaves ofKalanchoe crenata (Crassulaceae). Phytother Res. 2004; 18(5): 385-388.
27 Oliveira SM, Gewehr C, Dalmolin GD, Cechinel CA, Wentz A, Lourega RV, Sehnem RC, Zanatta N, Martins MA, Rubin MA, Bonacorso HG, Ferreira J.Antinociceptive effect of a novel tosylpyrazole compound in mice.Basic Clin Pharmacol Toxicol. 2009; 104(2): 122-129.
28 Yi T, Zhao ZZ, Yu ZL, Chen HB.Comparison of the antiinflammatory and anti-nociceptive effects of three medicinal plants known as “Snow Lotus” herb in traditional Uighur and Tibetan medicines.J Ethnopharmacol. 2010; 128(2): 405-411.
29 Pinheiro MM, Miltojevic AB, Radulovic NS, Abdul-Wahab IR, Boylan F, Fernandes PD.Anti-inflammatory activity of Choisya ternate Kunth essential oil, ternanthranin, and its two synthetic analogs (methyl and propyl N-methylanthranilates).PLoS One. 2015; 10(3): e0121063.
30 Milano J, Oliveira SM, Rossato MF, Sauzem PD, Machado P, Beck P, Zanatta N, Martins MA, Mello CF, Rubin MA, Ferreira J, Bonacorso HG.Antinociceptive effect of novel trihalomethyl-substituted pyrazoline methyl esters in formalina and hot-plate tests in mice.Eur J Pharmacol. 2008; 581(1-2): 86-96.
31 Zhang L, Hu JJ, Lin JW, Fang WS, Du GH.Antiinflammatory and analgesic effects of ethanol and aqueous extracts ofPterocephalus hookeri (C.B. Clarke) Höeck. J Ethnopharmacol. 2009; 123(3): 510-514.
32 Yi T, Lo H, Zhao Z, Yu Z, Yang Z, Chen H.Comparison of the chemical composition and pharmacological effects of the aqueous and ethanolic extracts from a Tibetan “Snow Lotus” (Saussurea laniceps) herb. Molecules. 2012; 17(6): 7183-7194.
33 Janssen PA, Niemegeers CJ, Dony JG.The inhibitory effect of fentanyl and other morphine-like analgesics on the warm water-induced tail withdrawal reflex in rats.Arzneimittelforschung. 1963; 13: 502.
34 Vale TG, Matos FJA, de-Lima TCM, Viana GSB. Behavioural effects of essential oils fromLippia alba (Mill) N.E Brown chemotypes. J Ethnopharmacol. 1999; 67(2): 127-133.
35 Silva J, Abebe W, Sonsa SM, Duarte VG, Machado ML, Matos FJA.Analgesic and antiinflammatory effects of essential oil ofEucalyptus. J Ethnopharmacol. 2003; 89(2- 3): 277-283.
36 Hill RG.The status of naloxone in the identification of pain control mechanisms operated by endogenous opioids.Neurosci Lett. 1981; 21(2): 217-222.
37 37 Smith JS, Zubieta JK, Price JC, Flesher JE, Madar I, Lever JR, Kinter CM, Dannals RF, Frost JJ. Quantification of δ-opioid receptors in human brain with N1′-([11C] methyl) naltrindole and positron emission tomography.J Cereb Blood Flow Metab. 1999; 19(9): 956-966.
38 Peng J, Sarkar S, Chang SL.Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR.Drug Alcohol Depend. 2012; 124(3): 223-228.
39 Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gavériaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kieffer BL. Mice deficient for δ- and μ-opioid receptors exhibit opposing alterations of emotional responses.Nat Genet. 2000; 25(2): 195-200.
40 Gaveriaux-Ruff C, Nozaki C, Nadal X, Hever XC, Weibel R, Matifas A, Reiss D, Filliol D, Nassar MA, Wood JN, Maldonado R, Kieffer BL.Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia.Pain. 2011; 152(6): 1238-1248.
41 Pradhan AA, Befort K, Nozaki C, Gaveriaux-Ruff C, Kieffer BL.The delta opioid receptor: an evolving target for the treatment of brain disorders.Trends Pharmacol Sci. 2011; 32(10): 581-590.
42 Gaveriaux-Ruff C, Kieffer BL.Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches.Behav Pharmacol. 2011; 22(5-6): 405-414.
43 Costa G, Ferreira JP, Vitorino C, Pina ME, Sousa JJ, Figueiredo IV, Batista MT.Polyphenols fromCymbopogon citratus leaves as topical anti-inflammatory agents. J Ethnopharmacol. 2016; 178: 222-228.
44 Sadeghi H, Hajhashemi V, Minaiyan M, Movahedian A, Talebi A.Further studies on anti-inflammatory activity of maprotiline in carrageenan-induced paw edema in rat.Int Immunopharmacol. 2013; 15(3): 505-510.
45 Sekut L, Junior Menius JA, Brackeen MF, Connolly KM.Evaluation of the significance of elevated levels of systemic and localized tumor necrosis factor in different animal models of inflammation.J Lab Clin Med. 1994; 124(6): 813-820.
46 Dinarello CA.Proinflammatory cytokines.Chest. 2000; 118(2): 503-508.
47 Woolf CJ.What is this thing called pain?J Clin Invest. 2010; 120(11): 3742-3744.
48 Alessandri AL, Sousa LP, Lucas CD, Rossi AG, Pinho V, Teixeira MM.Resolution of inflammation: mechanisms and opportunity for drug development.Pharmacol Ther. 2013; 139(2): 189-212.
49 Schein CH.The shape of the messenger: using protein structure information to design novel cytokine-based therapeutics.Curr Pharm Des. 2002; 8(24): 2113-2129.
50 Ebnet K, Vestweber D.Molecular mechanisms that control leukocyte extravasation: the selections and the chemokines.Histochem Cell Biol. 1999; 112(1): 1-23.
51 Dinarello CA.The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1.New Engl J Med. 2000; 343(10): 732-734.
No related articles found!
Full text



[1] Wei-xiong Liang. Problems-solving strategies in clinical treatment guideline for traditional Chinese medicine and integrative medicine. Journal of Chinese Integrative Medicine, 2008, 6(1): 1-4
[2] Zhao-guo Li. Discussion on English translation of commonly used sentences in traditional Chinese medicine: part one. Journal of Chinese Integrative Medicine, 2008, 6(1): 107-110
[3] Jun Hu, Jian-ping Liu. Non-invasive physical treatments for chronic/recurrent headache. Journal of Chinese Integrative Medicine, 2008, 6(1): 31
[4] Xue-mei Liu, Qi-fu Huang, Yun-ling Zhang, Jin-li Lou, Hong-sheng Liu, Hong Zheng. Effects of Tribulus terrestris L. saponion on apoptosis of cortical neurons induced by hypoxia-reoxygenation in rats. Journal of Chinese Integrative Medicine, 2008, 6(1): 45-50
[5] . Uniform requirements for manuscripts submitted to biomedical journals: Writing and editing for biomedical publication (Chinese version, part two). Journal of Chinese Integrative Medicine, 2010, 8(11): 1001-1005
[6] Daniel Weber, Janelle M Wheat, Geoffrey M Currie. Inflammation and cancer: Tumor initiation, progression and metastasis,and Chinese botanical medicines. Journal of Chinese Integrative Medicine, 2010, 8(11): 1006-1013
[7] Hong Liu , Guo-liang Zhang, Li Shen , Zhen Zeng, Bao-luo Zhou, Cheng-hai Liu, Guang Nie . Application and evaluation of a pseudotyped virus assay for screening herbs for anti-H5Nl avian influenza virus. Journal of Chinese Integrative Medicine, 2010, 8(11): 1036-1040
[8] Zhao-guo Li . A discussion of English translation of 1995 and 1997 Chinese National Standards of Traditional Chinese Medical Terminologies for Clinical Diagnosis and Treatment. Journal of Chinese Integrative Medicine, 2010, 8(11): 1090-1096
[9] Rui Jin, Bing Zhang. A complexity analysis of Chinese herbal property theory: the multiple formations of herbal property (Part 1). Journal of Chinese Integrative Medicine, 2012, 10(11): 1198-1205
[10] Hui-min Liu, Xian-bo Wang, Yu-juan Chang, Li-li Gu. Systematic review and meta-analysis of randomized controlled trials of integrative medicine therapy for treatment of chronic severe hepatitis. Journal of Chinese Integrative Medicine, 2012, 10(11): 1211-1228