Pharmaceutical Biology

ISSN: 1388-0209 (Print) 1744-5116 (Online) Journal homepage: https://www.tandfonline.com/loi/iphb20

Pereskia aculeata: A plant food with

antinociceptive activity

Nícolas de Castro Campos Pinto, Ana Paula do Nascimento Duque, Natália

Ramos Pacheco, Renata de Freitas Mendes, Erick Vicente da Silva Motta,
Paula Maria Quaglio Bellozi, Antônia Ribeiro, Marcos José Salvador & Elita
Scio

To cite this article: Nícolas de Castro Campos Pinto, Ana Paula do Nascimento Duque,
Natália Ramos Pacheco, Renata de Freitas Mendes, Erick Vicente da Silva Motta, Paula Maria
Quaglio Bellozi, Antônia Ribeiro, Marcos José Salvador & Elita Scio (2015) Pereskia aculeata:
A plant food with antinociceptive activity, Pharmaceutical Biology, 53:12, 1780-1785, DOI:
10.3109/13880209.2015.1008144

To link to this article: https://doi.org/10.3109/13880209.2015.1008144

Published online: 19 Jun 2015.

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ISSN 1388-0209 print/ISSN 1744-5116 online
Editor-in-Chief: John M. Pezzuto
Pharm Biol, 2015; 53(12): 1780–1785
! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2015.1008144

ORIGINAL ARTICLE

Pereskia aculeata: A plant food with antinociceptive activity

Nı́colas de Castro Campos Pinto1, Ana Paula do Nascimento Duque1, Natália Ramos Pacheco1, Renata de Freitas
Mendes1, Erick Vicente da Silva Motta1, Paula Maria Quaglio Bellozi1, Antônia Ribeiro1, Marcos José Salvador2, and
Elita Scio1
1
Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science of Federal University of Juiz de Fora, Juiz de
Fora, MG, Brazil and 2Pharmacy Course, PPG BTPB-UNICAMP, Department of Plant Biology, Institute of Biology, State University of Campinas,
Campinas, SP, Brazil

Abstract Keywords
Context: Pereskia aculeata Miller (Cactaceae) is a cactus distributed from south to northeast of Antinociception, alkaloid, barbados
Brazil, where its leaves are commonly used as a vegetable, in skin wound healing, and to treat gooseberry, Cactaceae, vegetable
inflammation.
Objectives: The objective of this study was to perform the chemical characterization and to History
evaluate the antinociceptive activity of the hydromethanolic fraction obtained from the
methanol extract of P. aculeata leaves. Received 7 August 2014
Materials and methods: Chemical characterization was performed by UPLC–MS analysis. The Revised 4 November 2014
antinociceptive activity was evaluated by the acetic acid-induced writhing, formalin, and tail- Accepted 11 January 2015
flick tests in mice, administering the single oral doses of 100, 200, and 300 mg/kg 1 h before Published online 18 June 2015
each test.
Results: Tryptamine, abrine, mescaline, hordenine, petunidin, di-tert-butylphenol isomers, and
quercetin were identified. The antinociceptive activity was inversely proportional to the
administered doses in the acetic acid test, as the dose of 100 mg/kg reduced by 78% the
number of writhings, while the doses of 200 and 300 mg/kg reduced by 64% and 41%,
respectively. In the formalin test, the dose of 300 mg/kg inhibited by 50% and 86% the licking
paw time in the first and second phases, respectively, while the doses of 200 mg/kg (45% and
62%, respectively) and 100 mg/kg (15% and 48%, respectively) were less effective. The sample
did not respond to the tail-flick test. Those results suggested a peripheral and central
antinociception devoid of an opioid effect.
Conclusion: Pereskia aculeata not only is a plant food with high nutritional value but also
presents analgesic potential. It is the first time that this bioactivity is reported for this species.

Introduction Tryptophan is the most abundant amino acid in these proteins.

The leaves also contain high levels of total dietary fiber,
Pereskia aculeata Miller (Cactaceae), known as Barbados
vitamins A, C, and folic acid, in addition to minerals, such as
gooseberry, is a climbing plant native to South America
calcium, magnesium, manganese, and zinc (Pinto & Scio,
and adapted only at low altitudes and naturally distributed
2014; Takeiti et al., 2009).
from south to northeast of Brazil, where its succulent
Besides used in food, the leaves of P. aculeata are also
leaves are commonly used by the natives as a vegetable in
used in Brazilian traditional medicine as emollients due to
traditional cuisine (Peterson et al., 2009; Pinto & Scio, 2014).
their high mucilaginous content, in skin wound healing, and to
The nutritional value of the leaves is related mainly to
treat inflammation. Cytotoxicity against the tumor cell lines
the high content of proteins (25.5% w/w), which is much
HL60 and MCF-7, and antioxidant effects were reported
higher when compared with other vegetables frequently
(Pinto et al., 2012). In addition, some species of Pereskia
used as foods, including bean (18–20% w/w), common corn
genus are reported to be used as natural remedies in cancer-
(7.6–10.0% w/w), lettuce (1.3% w/w), or kale (1.6% w/w)
related diseases, rheumatism, inflammation, headache, gastric
(Mercê et al., 2001). In many low-income communities, the
pain, ulcers, hemorrhoids, atopic dermatitis, for pain relief
leaves of P. aculeata are considered as the main proteins
and as tonics to revitalize the body (Sim et al., 2010a,b).
source, so this vegetable is also known as ‘‘meat of the poor’’.
Nevertheless, there are only few studies about chemical
composition of P. aculeata leaves and their therapeutic
Correspondence: Elita Scio, Laboratory of Bioactive Natural Products, potential, although natural products, especially those used in
Department of Biochemistry, Institute of Biological Science of Federal
University of Juiz de Fora, Juiz de Fora, MG 36036 900, Brazil. Tel: +55 traditional medicine, are still a major source of new bioactive
32 2102 3208. Fax: +55 32 2102 3216. E-mail: elita.scio@ufjf.edu.br compounds (Newman & Cragg, 2012). Thus, this study aimed
DOI: 10.3109/13880209.2015.1008144
to perform the chemical characterization and to evaluate the
antinociceptive activity of the hydromethanolic fraction
obtained from methanol crude extract of P. aculeata leaves.
Materials and methods
Plant material and preparation of hydromethanolic
fraction
Leaves of P. aculeata were collected in Juiz de Fora (MG,
Brazil) in August 2010, in the morning. The plant was
identified and a voucher specimen (No. 57539) was deposited
in the Herbarium Leopoldo Krieger of Federal University of
Juiz de Fora for future evidence. The leaves were air dried in a
well-ventilated place at room temperature (25  C) for 15 d.
Once dried, the material (approximately 1 kg) was powdered
using a knife mill (Marconi MA048, Piracicaba, SP, Brazil)
and then extracted by maceration with methanol until
exhaustion. The extract was concentrated on a rotary evap-
orator (R-3 BUCHI, Flawil, Switzerland) under monitored
temperature (50 ± 2  C) to obtain the crude methanol extract
(140 g), which was dissolved in water/methanol (8:2 v/v) and
then fractioned with different solvents in the order of
increasing polarity: hexane, dichloromethane, ethyl acetate,
and butanol. This process resulted in a remaining hydro-
methanolic fraction (HMF – 12 g) which was concentrated
on a rotary evaporator, as described above, and stored in a
refrigerator at 4  C.
Evaluation of antinociceptive activity of
hydromethanolic fraction
Animals
Male Swiss mice (20–30 g) bred in Center of Reproductive
Biology (Federal University of Juiz de Fora, Brazil) were
used. The animals were kept under standard temperature
(22  C), 12/12 h light/dark cycle, with food (Nuvital,
Colombo, PR, Brazil) and water ad libitum. Before perform-
ing each test, the animals were kept without food for a period
of 12 h. The groups consisted of 6–8 mice. All experimental
procedures are in accordance with the Ethical Principles of
Animal Research adopted by Brazilian College of Animal
Experimentation (COBEA – Protocol no. 009/2009).
Acetic acid-induced writhing test
Groups of mice received different doses of HMF (100, 200, or
300 mg/kg), vehicle (negative control), or indomethacin
(Henrifarma, Cambuci, SP, Brazil) 10 mg/kg, used as the
reference drug. All solutions were prepared in saline with
Tween 80 (Sigma-Aldrich, St. Louis, MO) 12% (v/v) and
administered orally at 10 mL/kg. One hour after administra-
tion of respective treatments, mice were ip injected with
acetic acid 0.6% 10 mL/kg. For 30 min, the number of
writhings (constriction of abdominal wall with extension
of hind paws) was counted (Koster et al., 1959).
Formalin test
One hour after oral administration of vehicle, indomethacin,
HMF at different doses (100, 200, or 300 mg/kg), or 30 min
after ip administration of morphine (Cristália, Itapira, SP,
Antinociceptive potential of Pereskia aculeata 1781
Brazil) 7.5 mg/kg (10 mL/kg); 20 mL of 2% formalin (v/v) was
injected into the sup-plantar tissue of the right hind paw. The
licking paw time was determined during 5 min (first phase)
and between 15 and 30 min (second phase) after formalin
injection (Hunskaar et al., 1985).
Tail-flick test
Each mouse was immobilized inside a small plastic tube with
ventilation, so that the tail remained outside the tube. One-
third of the tail was immersed in a 55  C ± 1 water bath and
the baseline reaction time was measured twice at 20 min
intervals. Then, 1 h after oral administration of vehicle, HMF
in different doses (100, 200, or 300 mg/kg), or 30 min after ip
injection of morphine 7.5 mg/kg (10 mL/kg), the reaction time
was measured again at 20 min intervals up to 2 h. A 15 s cut-
off time was used to prevent tissue damage (D’Amour &
Smith, 1941).
Statistical analysis
The results were expressed as mean ± SEM and one-way
ANOVA followed by the Newman–Keuls test was used for
statistical analysis. Two-way ANOVA followed by the
Bonferroni test was used for the tail-flick test. p50.05 was
considered significant. The percentage of antinociception was
calculated compared with vehicle as follows:
 
HMF mean value
% inhibition ¼  100
vehicle mean value
Ultra-performance liquid chromatography–mass
spectrometry (UPLC–MS) analysis
Sample preparation
HMF (1 mg) was dissolved in methanol (10 mL). The solution
was filtered using a 0.22 mm filter and then diluted with
HPLC grade methanol (Tedia, Fairfield, OH) to 100 ppm.
Electrospray ionization–mass spectrometry fingerprint
The sample HMF was diluted in a solution containing 50%
(v/v) HPLC grade methanol and 50% (v/v) deionized water
and 0.5% of ammonium hydroxide. Electrospray ionization–
mass spectrometry fingerprint (ESI-MS) fingerprints in the
positive ion mode were acquired and accumulated over 60 s,
and spectra were scanned in a range between m/z 100 and
1000, using a Micromass-Waters Q-TOF mass spectrometer
(Waters, Manchester, UK). Capillary and cone voltages were
set at 3.00 kV and 30.00 V, respectively, with a source
temperature of 150  C and a desolvation temperature of
350  C. The collision energy was 30 eV. ESI-MS was
performed by direct infusion with typical flow rate of
10 mL/min using a syringe pump (Harvard Apparatus,
Holliston, MA). The collision gas pressure was optimized to
produce extensive fragmentation of the ion under investiga-
tion. The compounds were identified by comparison of their
MS/MS fragmentation spectra with literature data.
Ultra-performance liquid chromatography analysis
Ultra-performance liquid chromatography (UPLC) was per-
formed using a Waters UPLC system (Waters, Manchester, UK).
1782 N.d.C.C. Pinto et al. Pharm Biol, 2015; 53(12): 1780–1785

Chromatographic separation was performed on an phase, inhibiting the nociception by 86%. The doses of 200
ACQUITY TQD (1.7 mm, 50 mm  2.1 mm i.d.) (Waters and 100 mg/kg reduced the painful stimulus by 62% and 48%,
Corporation, Milford, MA). Mobile phase A was water respectively (Figure 2b).
containing 0.1% formic acid. Mobile phase B was aceto-
nitrile. The column temperature was ambient. The UPLC Tail-flick test
flow rate was 0.25 mL/min. A HMF solution of 5 mL was No activity was observed for HMF in the tail-flick test in none
injected into the UPLC system. A mobile phase gradient was of the tested doses (Figure 3).
used with the percentage of B in A varying as follows: initial
concentration, 35% B; 7 min, 55% B; 10 min, 55% B; Ultra-performance liquid chromatography–mass
13 min, 35% B. spectrometry (UPLC–MS) analysis and search for
indole compounds
Search for indole compounds
The compounds identified in HMF by UPLC–MS/MS are
Since P. aculeata leaves are abundant in proteins rich in detailed in Table 1, and the chemical structures are shown in
tryptophan, the precursor of indole alkaloids (Dewick, 2009;
Takeiti et al., 2009), Hopkins and Cole reaction (Hopkins &
Cole, 1901) was used to verify the presence of indole
compounds. Briefly, a small amount of HMF was solubilized
in a glyoxylic acid solution, and then concentrated sulfuric
acid was added slowly. A violet ring appears when sample
contains indole compounds.

Results
Evaluation of antinociceptive activity of HMF
Acetic acid-induced writhing test
The acetic acid-induced writhing test showed that the
antinociceptive activity of HMF was inversely proportional
to the administered doses, since the dose of 100 mg/kg was
the most active, reducing by 78% the number of writhings,
while the doses of 200 and 300 mg/kg inhibited the painful
stimulus by 64% and 41%, respectively, as shown in Figure 1.
Figure 2. Effect of different doses of oral HMF on first (a) and second
Formalin test (b) phases of the formalin test in mice. Vehicle, indomethacin 10 mg/kg,
and HMF 100, 200, and 300 mg/kg were administered orally while
The results showed that the antinociceptive activity of HMF morphine 7.5 mg/kg was administered intraperitoneally 60 and 30 min,
was dose dependent in the formalin test, unlike occurred in respectively, before formalin injection. The licking paw time was
counted for 5 min after formalin injection. The values of each column
the acetic acid-induced writhing test. In the first phase, the represent the mean ± SEM. ANOVA followed by the Newman–Keuls
dose of 300 mg/kg was the most effective, reducing about test, used as post hoc. Significant values: ***p50.001, **p50.01, and
50% the licking paw time compared with the negative control, *p50.05 compared with vehicle.
while the doses of 200 and 100 mg/kg inhibited the
nociception by 45% and 15%, respectively (Figure 2a). The
dose of 300 mg/kg was also the most active in the second

Figure 1. Effect of different doses of oral HMF on acetic acid-induced
writhing test in mice. Vehicle, indomethacin 10 mg/kg, and HMF 100,
200, and 300 mg/kg were administered orally 60 min before acetic acid
0.6% injection. The number of writhings was counted for 30 min. The
values of each column represent the mean ± SEM. ANOVA followed
by the Newman–Keuls test, used as post hoc. Significant values:
***p50.001 and *p50.05 compared with vehicle.
Figure 3. Effect of different doses of oral HMF on tail flick test in mice.
Vehicle, indomethacin 10 mg/kg and HMF 100, 200, and 300 mg/kg
were administered orally while morphine 7.5 mg/kg (10 mL/kg) was
administered intraperitoneally 60 and 30 min, respectively, before one-
third of the tail was immersed in a 55  C ± 1 water bath. The reaction
time was measured at 20 min intervals up to 2 h. A 15 s cut-off time was
used to prevent tissue damage. The values of each column represent the
mean ± SEM. Two-way ANOVA followed by the Bonferroni test, used as
post hoc. Significant values: **p50.01 and *p50.05 compared with
vehicle.
DOI: 10.3109/13880209.2015.1008144 Antinociceptive potential of Pereskia aculeata 1783

Figure 4. In addition, a violet ring appeared in the Hopkins oral administrations of plant extracts with central activities
and Cole reaction, which suggested the presence of indole have been reported, such as the extract of Allium macro-
compounds. stemon (Alliaceae) and Heteropterys brachiata
(Malpighiaceae) (Huerta-Reyes et al., 2013; Lee et al.,
Discussion 2010). As plant extracts or fractions contain many com-
In spite of being a more appropriate assay for opioids, this pounds, a competitive or non-competitive antagonism may
acetic acid-induced writhing test is widely used as a model of occur. In non-competitive antagonism, the threshold dose of
induction of inflammatory origin pain, as the acetic acid an agonist may be not considerably high, but the maximum
solution induces the synthesis of arachidonic acid metabolites response is decreased by an antagonist, which may be active
and other inflammation mediators (Ha et al., 2013). Thus, the beyond the receptor, such as effects on intracellular second
antinociceptive effects of non-steroidal anti-inflammatories messengers (Williamson et al., 1996). To better understand if
and peripheral analgesics may also be observed from this the mechanisms of the antinociceptive activity of HMF are
model. Moreover, there is an important involvement of central, peripheral or both, the formalin and tail-flick tests
serotonergic and noradrenergic neurons at pain modulation were accomplished.
induced by acetic acid, thus drugs that act in noradrenergic The formalin test is a chemical model of pain induction
receptors, tricyclic antidepressants, and selective serotonin that may determine if the mechanism of action of an analgesic
reuptake inhibitors also respond to this test (Dickenson & drug occurs centrally or peripherally. The subplantar injection
Ghandehari, 2007; Galceran et al., 2011). of formalin causes a biphasic behavioral response character-
The higher doses of HMF were less effective, which is ized by paw licking during an initial phase that occurs until
not surprising, as similar saturated dose–response curves after 5 min after the injection, which is related to the direct
activation of nociceptors in C and Ad afferent fibers
(neurogenic pain); and during a second phase that occurs
Table 1. Compounds identified in the hydromethanolic fraction from between 15 and 30 min after the injection, associated to the
methanolic extract of Pereskia aculeata leaves by UPLC–MS/MS
analysis in the positive ion mode.
release of inflammatory mediators, including prostaglandins,
histamine, bradykinin, and serotonin (inflammatory pain).
Compounds Retention time (min) [M + H]+ (m/z) Opioid analgesics, such as morphine, inhibit the nociception
caused by formalin in both phases, while anti-inflammatories,
Tryptamine 1.52 162
Abrine 1.97 219 including indomethacin, are capable of suppress only the
Hordenine 2.18 166 second phase (Monteiro et al., 2014). Non-opioid analgesics
Di-tert-butylphenol isomers 2.42, 2.55, 2.85 207 that act centrally and peripherally are active in both phases of
Mescaline 3.05 212
the formalin test; however, they are more effective in the
Petunidin 4.87 318
Quercetin 5.57 302 second phase, in which, generally, lower doses are suffi-
cient to cause the antinociceptive effect (Shibata et al., 1989).

Figure 4. Chemical structures of the com-

pounds identified in hydromethanolic frac-
tion of methanol crude extract of Pereskia
aculeata leaves (HMF) by UPLC/MS/MS in
the positive ion mode.
1784 N.d.C.C. Pinto et al.
Thus, the results suggested that the mechanism of action of
HMF did not involve opioid receptors activation, but it was
probably associated to a central and peripheral activity. The
differences between the effectiveness of the different doses
tested in formalin and acetic acid-induced writhing tests may
occur as these are distinct models of pain induction, with
distinct pain-induced agents and mechanisms.
The tail-flick test consists in evaluating the response of a
drug in consequence of a thermogenic stimulus. The mech-
anisms associated to this response are not totally clear;
however, it is recognized that this test is effective only to
determine the analgesic activity of opioid agonists (Le Bars
et al., 2001). The response of HMF in the tail-flick test
reinforced the results found in the formalin test, as both tests
suggested that HMF did not demonstrated opioid action in
both cases.
Pinto et al. (2012) reported the presence of phenols,
tannins, coumarins, anthrones, flavonoids, and alkaloids in
HMF. In this study, some of these chemical constituents were
identified, including tryptamine, abrine, mescaline, horde-
nine, petunidin, di-tert-butylphenol isomers, and quercetin.
According to the literature, they were also detected in other
species of Cactaceae and Pereskia (Doetsch et al., 1980;
Kobayashi et al., 2000; Neal et al., 1971; Sim et al., 2010a,b;
Stintzing & Carle, 2005).
Pereskia aculeata leaves are abundant in protein rich in
tryptophan, an indole amino acid (Takeiti et al., 2009). In
plants, tryptophan is the precursor of indole alkaloids,
compounds with structural similarities to bioactive amines.
Most of these alkaloids, when biologically active, affect the
adrenergic, serotonergic, dopaminergic or cholinergic sys-
tems, including tryptamine, abrine, harmine, strychnine,
psilocybin, reserpine, among many others (Dewick, 2009).
These systems are directly related to the spinal cord pain
control (Garcı́a-Ramı́rez et al., 2014). In addition, pheny-
lethylamine alkaloids, including hordenine and mescaline,
which were identified in HMF, are very similar to norepin-
ephrine in terms of chemical structure and may act like
adrenergic drugs (Casado et al., 2008; Dewick, 2009).
Furthermore, it is well documented the inhibition of noci-
ceptive response of quercetin in several animal models (Filho
et al., 2008). Thus, it is possible that the alkaloids identified
and quercetin might be involved in the antinociceptive
activity of HMF.
Conclusion
This study showed that the leaves of P. aculeata are not only a
vegetable of high nutritional value but are also endowed with
chemical constituents with analgesic potential, which effects
are likely to occur at peripheral and central level, although
they are probably not related to opioid receptors activation. It
is possible that the presence of alkaloids and quercetin in
HMF might be involved in the antinociceptive activity. As far
as we know, this study is the first report on the analgesic
potential of this plant food.
Acknowledgements
The authors are grateful to Dr. Daniela Zappi for the botanical
identification of the species, to Delfino Antônio Campos for
Pharm Biol, 2015; 53(12): 1780–1785
technical assistance and to the Reproduction Biology Center
of the Federal University of Juiz de Fora for providing
the mice.
Declaration of interest
The authors report that they have no conflicts of interest. This
work was supported by the grant from FAPEMIG CEX APQ
01137-09, FAPESP, CNPq, and CAPES.
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