Journal of Ethnopharmacology 103 (2006) 241245

Antinociceptive effect of the aqueous extract obtained from roots

of Physalis angulata L. on mice
G.N.T. Bastos a , A.R.S. Santos c , V.M.M. Ferreira a , A.M.R. Costa a ,
C.I. Bispo a , A.J.A. Silveira b , J.L.M. Do Nascimento a,
a Departamento de Fisiologia, Centro de Ci
encias Biologicas, Universidade Federal do Para, Belem 66075-900, Brazil
Departamento de Qumica, Centro de Ciencias Exatas e Naturais, Universidade Federal do Para, Belem 66075-900, Brazil
c Departamento de Ci
encias Fisiologicas, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, Florianopolis 88040-900, Brazil
b

Received 22 June 2004; received in revised form 5 August 2005; accepted 9 August 2005
Available online 19 September 2005

Abstract
In this study, we attempted to identify the possible antinociceptive action of aqueous extract (AE) obtained from roots of Physalis angulata,
known in Brazil as Camapu, used to treat various pain-related physiological conditions. The AE of Physalis angulata (1030 mg/kg) given by
i.p. or p.o. route, 0.5 and 1 h prior, produced significant inhibition of abdominal constrictions caused by acetic acid, with ID50 values of 18.5
(17.419.8) and 21.5 (18.924.4) mg/kg and inhibitions of 83 8 and 66 5%, respectively. The AE (1060 mg/kg, i.p.) also caused significant
inhibition of the late-phase of formalin-induced pain, with an ID50 value of 20.8 (18.423.4) mg/kg and inhibition of 100%. Treatment of mice
with AE (60 mg/kg, i.p.) or with morphine (10 mg/kg, i.p.) produced a significant increase of the reaction time in the hot-plate test. These results
demonstrate, for the first time, that the AE of Physalis angulata produce marked antinociception against the acetic acid-induced visceral pain
and inflammatory pain responses induced by formalin in mice. The mechanism by which the AE produces antinociception still remains unclear.
However, pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for the antinociceptive action
and also to identify the active principles present in Physalis angulata. Moreover, the antinociceptive action demonstrated in the present study
supports, at least partly, the ethnomedical uses of this plant.
2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Physalis angulata; Antinociception; Formalin test; Writhing test; Hot-plate test

1. Introduction
Physalis angulata L. belongs to the Solanaceae family and
includes about 120 species with herbal characteristics and perennial habits (Correa, 1962; Kissmann and Groth, 1995). It is
distributed throughout the tropical and subtropical regions of the
world (Kissmann and Groth, 1995; Santos et al., 2003). Extracts
or infusions from this plant have been used in various countries
in popular medicine as a treatment for a variety of illnesses,
such as malaria, asthma, hepatitis, dermatitis and rheumatism
(Chiang et al., 1992a; Lin et al., 1992; Santos et al., 2003; Soares
et al., 2003). In Brazil, Physalis angulata is popularly known as
Camapu, Bucho de Ra, Jua de Capote or Mata-Fome
(Branch and Silva, 1983), and its juice is considered to be seda-

Corresponding author. Tel.: +55 91 2111545; fax: +55 91 2111601.

E-mail address: jlmn@ufpa.br (J.L.M. Do Nascimento).

0378-8741/$ see front matter 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2005.08.008

tive and depurative against rheumatism and earache. The leaves

are sometimes used against inflammations of the bladder, spleen
and liver. The whole plant cooked is recommended in baths for
inflammatory processes, such as rheumatism (Lorenzi, 1982).
It has been demonstrated that some of the extracts or active
principles obtained from Physalis angulata have a broad spectrum of biological activities, including antibacterial, molluscicidal, antiprotozoal, anticancer, cytotoxic and immunomodulatory
activities (Kastelein and Camargo, 1990; Lee et al., 1991; Chiang
et al., 1992a,b; Lin et al., 1992; Caceres et al., 1995; Freiburghaus
et al., 1996; Pietro et al., 2000; Ismail and Alam, 2001; Januario
et al., 2002; Santos et al., 2003; Soares et al., 2003).
Phytochemical studies of Physalis angulata have demonstrated the presence of steroids, known as physalins (D, I, G, K,
B, F, E), physagulins (E, F and G), with anolides and flavonoids
(Row et al., 1978, 1980; Lee et al., 1991; Chiang et al., 1992a,b;
Shingu et al., 1992; Ismail and Alam, 2001). In the present study,
we have attempted to investigate the antinociceptive action of

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G.N.T. Bastos et al. / Journal of Ethnopharmacology 103 (2006) 241245

the aqueous extract obtained from roots of Physalis angulata

on chemical and thermal models of nociception in mice for the
purpose of validating its ethnomedical use.
2. Material and methods
2.1. Preparation of the aqueous extract (AE) of Physalis
angulata
The plant was collected in Para State, Brazil, during the
year 2000 and classified by Dr. Ricardo Seichas (Department
of Botany, Museu Emlio Goeldi). A voucher specimen (ref.
653) was deposited in the Joao Murca Pires herbarium of the
Paras Emlio Goeldi Museum (Belem, PA, Brazil). After collecting the material, roots of Physalis angulata were separated
for extraction. The roots weighing 150 g were cleaned in a water
stream, extracted with 700 ml of Milli-Q water, and concentrated
at a final volume of 14%. The decoct was cooled and stored in
a freezer at 20 C for subsequent lyophilization, producing
2.712 g of the extract.
2.2. Animals
Swiss male mice (3035 g) were obtained from the Evandro Chagas Animal Resources Centre, Belem, Para, Brazil.
They were randomly assigned to groups of 10 animals and
maintained in plastic boxes, with food and water ad libitum,
under a 12 h light/12 h dark cycle. The room temperature was
maintained at 22 1 C. The animals were acclimatized to the
laboratory for at least 2 h before the experiments that were
carried out between 8:00 and 13:00 h in order to avoid circadian influence. All experiments reported in this study were
carried out in accordance with current guidelines for the care
of laboratory animals and ethical guidelines for investigation of experimental pain in conscious animals. All efforts
were made to minimize the number of animals used and their
suffering.
2.3. Abdominal constriction by intraperitoneal injection of
acetic acid
Abdominal contraction, induced by i.p. injection of
acetic acid 1%, consisted of a contraction of the abdominal
muscle together with a stretching of the hind limbs (Tonos
et al., 1999). The animals were pre-treated intraperitoneally
(i.p.) with morphine (10 mg/kg) and aspirin (100 mg/kg),
used as positive control, or with the AE of Physalis angulata
(10, 20 or 30 mg/kg) 0.5 h before, or orally with the AE of
Physalis angulata (10, 20 or 30 mg/kg) 1 h before, acetic
acid injection. The control groups received the same volume,
0.9% of NaCl (10 ml/kg). After challenge, pairs of mice
were placed in separate boxes and the number of abdominal
constrictions was counted every 5 min over a 1 h period.
Antinociceptive activity was expressed as the reduction in the
number of abdominal constrictions, i.e. the difference between
control animals (NaCl) and animals pre-treated with AE or
morphine.

2.4. Formalin-induced licking

The procedure used was similar to that described
previously (Santos et al., 1998). Twenty microliters of 2.5%
formalin solution (0.92% formaldehyde) was injected intraplantarly (i.pl.) under the ventral surface of the right hindpaw.
The animals were placed individually in clear plexiglass cages
(33 cm 23 cm 21.5 cm) and observed from 0 to 30 min following formalin injection. The amount of time spent licking the
injected paw was timed with a chronometer and was considered
as indicative of nociception. The initial nociceptive response
normally peaked 5 min after formalin injection (early-phase) and
1530 min after formalin injection (late-phase), representing the
tonic and inflammatory pain responses, respectively (Hunskaar
and Hole, 1987). The animals were pre-treated intraperitoneally
with the AE of Physalis angulata (10, 20, 30 or 60 mg/kg), or
with morphine (10 mg/kg) or indomethacin (10 mg/kg) which
were used as positive controls, 0.5 h beforehand. The control animals received the same volume of vehicle (10 ml/kg, i.p.) used to
dilute these drugs. Following intraplantar injection of formalin,
each animal was immediately placed into a clear plexiglass cage,
and the time it spent licking the injected paw was determined.
2.5. Hot-plate test
The hot-plate test was used to measure the response latencies according to the method described previously (Santos
et al., 1998). In the experiments the hot-plate was maintained at
55 1 C. Before beginning the experiments, the basal reaction
time response of all animals was taken. The animals were pretreated with saline (10 ml/kg, i.p.), morphine (10 mg/kg, i.p.) or
AE of Physalis angulata (30 and 60 mg/kg, i.p.) and 0, 0.25, 0.5,
1, 1.5, 2 and 2.5 h later, they were put on the heated surface of the
plate at 55 1 C. The time necessary for the initial response to
the painful stimulus (elevation of the paws, licking or jumping)
was taken as defining the response. In order to minimize damage
to the animals paws, the cut-off time was 30 s.
2.6. Drugs
The drugs used were: formalin and acetic acid (Merck, Sao
Paulo, Brazil), indomethacin and aspirin (Sigma Chemical Co.,
St. Louis, MO, USA), morphine hydrochloride (Cristalia-Brazil,
Sao Paulo, Brazil). All substances used were dissolved in saline
solution, with the exception of indomethacin and aspirin that
were dissolved in 5% NaHCO3 and Tween 80 plus 0.9% NaCl
solution, respectively. The final concentration of Tween 80 did
not exceed 5% and did not cause any effect per se.
2.7. Statistical analysis
The results are presented as mean S.E.M., except the ID50
values (i.e. the doses of aqueous extract of Physalis angulata
necessary to reduce response by 50% relative to control value)
which are reported as geometric means accompanied by their
respective 95% confidence limits. The ID50 values were calculated from at least three dosages of AE, determined by linear

G.N.T. Bastos et al. / Journal of Ethnopharmacology 103 (2006) 241245

243

regression from individual experiments using appropriate software (GraphPad software, San Diego, CA). The statistical significance of differences between groups was obtained by means
of analyses of variance followed by NewmannKeuls multiple
comparison test. P-values less than 0.05 (P < 0.05) were considered to be significant.
3. Results
The results in Fig. 1A and B show that the AE of Physalis
angulata, given by i.p. or p.o. (100 mg/kg) routes 0.5 or 1 h
beforehand, caused a dose-related inhibition of acetic acidinduced visceral nociceptive response in all of the analyzed periods. The calculated mean ID50 values for these effects were 18.5
(17.419.8) and 21.5 (18.924.4) mg/kg, and inhibitions were
83 8 and 66 5% for AE given by i.p. and p.o. routes, respectively. The pre-treated animals using both morphine (10 mg/kg,
i.p. 0.5 h beforehand) and aspirin (100 mg/kg, i.p. 0.5 h beforehand) were used as positive control, which produced significant
inhibition of acetic acid-induced visceral nociceptive response
in all of the analyzed periods (Fig. 1A). The maximal inhibition
of acetic acid-induced pain produced by morphine and aspirin,
in the doses used, were 100 and 82 5%, respectively (Fig. 1A).
The AE of Physalis angulata, administered intraperitoneally
(1060 mg/kg), produced marked and dose-related inhibition
against the inflammatory (late-phase) pain, but not against neurogenic (early-phase) pain, caused by intraplantar injection of
formalin in mice (Fig. 2A and B). The calculated mean ID50
value for the late-phase was 20.8 (18.43.4) mg/kg, and inhibition was 100%. Similarly, indomethacin (10 mg/kg, i.p.) caused
significant inhibition (76 7%) of the late-phase, but not the

Fig. 3. Effect of aqueous extract of Physalis angulata ((), 30 mg/kg; (),

60 mg/kg) or morphine ((
), 10 mg/kg), given intraperitoneally, on the hot-plate
test in mice. Each point represents the mean S.E.M. of 10 animals. The points
marked by the open square indicate the control values (animals injected with
saline, 10 ml/kg) and the asterisks denote the significance levels in comparison
with control groups, *** P < 0.001. In some cases, the error bars of the mean are
hidden within the symbols.

early-phase, of formalin-induced nociception (Fig. 2A and B).

In contrast, the treatment of animals with morphine (10 mg/kg,
i.p.), given 0.5 h prior, produced marked inhibition of both the
neurogenic pain (early-phase, 78 4%) and inflammatory pain
(late-phase, 100%) of the formalin test in mice (Fig. 2A and B).
The results in Fig. 3 show that the treatment of animals
with morphine (10 mg/kg, i.p.) caused a marked increase in
the latency of the animals in all analyzed periods according
to assessment in the hot-plate test, under conditions where the
AE of Physalis angulata (60 mg/kg, i.p.) produced a significant

Fig. 1. Effect of aqueous extract of Physalis angulata [(), 10 mg/kg; (), 20 mg/kg; (
), 30 mg/kg, given intraperitoneally (panel A) and orally (panel B)],
morphine ((
), 10 mg/kg, i.p.) or aspirin ((), 100 mg/kg, i.p.) against acetic acid-induced visceral pain in mice. Each point represents the mean S.E.M. of 10
animals. The points marked by the open square indicate the control values (animals injected with saline, 10 ml/kg) and the asterisks denote the significance levels in
comparison with control groups, * P < 0.05, ** P < 0.01, *** P < 0.001. In some cases, the error bars of the mean are hidden within the symbols.

Fig. 2. Effect of aqueous extract of Physalis angulata, morphine or indomethacin given intraperitoneally, against the early-phase (05 min, panel A) or late-phase
(1530 min, panel B) of formalin-induced nociception in mice. Each column represents the mean S.E.M. of 10 animals. The column C indicates the control values
(animals injected with saline, 10 ml/kg) and the asterisks denote the significance levels in comparison with control groups, *** P < 0.001.

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G.N.T. Bastos et al. / Journal of Ethnopharmacology 103 (2006) 241245

increase in the latency of the animals in the hot-plate assay 1,

1.5 and 2 h before the administration of AE (Fig. 3).
4. Discussion
The results of the present study show that the AE of Physalis
angulata, administered either intraperitoneally or orally to mice,
produces significant antinociceptive action against chemical
(acetic acid-induced visceral pain or formalin-induced nociception) and thermal (hot-plate test) models of nociception in mice.
Recently, Choi and Hwang (2003) have demonstrated
that the methanolic extract of Physalis angulata flowers
clearly exhibits anti-inflammatory action against carrageenaninduced paw oedema, arachidonic acid-induced ear oedema and
formaldehyde-induced arthritis, as well as anti-allergic properties against 2,4-dinitrofluorobenzene-induced contact hypersensitivity reaction (type IV) in mice.
This work for the first time shows that the AE of the roots
of Physalis angulata, when given intraperitoneally or orally,
produces dose-related and significant antinociception according to assessment of the abdominal constrictions elicited by
acetic acid, a model used to evaluate the potential analgesic
activity of drugs. It has been suggested that acetic acid acts by
releasing endogenous mediators that stimulate the nociceptive
neurons (Collier et al., 1968). It is sensitive to non-steroidal
anti-inflammatory drugs (NSAIDs) and to narcotics and other
centrally acting drugs (Collier et al., 1968; Santos et al., 1998;
Reichert et al., 2001). The results of the present study confirm
previous data of literature by demonstrating that morphine (a
narcotic drug) and aspirin (a NSAID) cause significant inhibition
of acetic acid-induced pain. Furthermore, the AE of the roots of
Physalis angulata was more potent and efficacious than aspirin.
It was, however, less potent, but with a similar efficacy in relation
to morphine in inhibiting the acetic acid-induced visceral nociceptive response. Another interesting result of this current study
was the fact that p.o. administration of the AE of the roots of
Physalis angulata presented similar potency and efficacy with
i.p. administration in preventing the acetic acid-induced pain.
Thus, the result of the present study demonstrates that the AE
of the roots of Physalis angulata possesses, at least partly, the
same bioavailability when administered by intraperitoneal or
oral routes in the acetic acid test.
Recently, Ribeiro et al. (2000) have demonstrated that the
nociceptive activity of acetic acid may be due to the release of
cytokines, such as TNF-, interleukin-1 and interleukin-8, by
resident peritoneal macrophages and mast cells. Very recently,
Soares et al. (2003) have shown that seco-steroids (such as
physalins B, F or G, but not D) isolated from Physalis angulata cause a reduction in nitric oxide production when their
macrophages are stimulated with lypopolysaccaride (LPS) and
interferon-. In addition, physalin B significantly reduces the
increase in TNF-, interleukin-6 and interleukin-12 levels when
their macrophages are stimulated with LPS and also reduces the
levels of TNF- in the serum of LPS-treated mice. Furthermore,
physalin B, F and G are effective in preventing the septic shock
induced by LPS in mice (Soares et al., 2003). Thus, the previous findings and these results presented here might indicate that

the antinociceptive action of the AE of Physalis angulata in the

acetic acid-induced writhing test could be due to inhibition of
the release of TNF-, interleukin-1 and interleukin-8 by resident peritoneal cells. However, this possibility remains to be
tested in future studies.
The results of the present study have also shown that morphine, but not indomethacin, is largely effective in preventing
both the early- and late-phases of formalin-induced pain. Other
studies have shown that formalin releases various inflammatory
mediators (Hunskaar et al., 1986; Hunskaar and Hole, 1987;
Santos and Calixto, 1997). However, indomethacin (a nonsteroidal anti-inflammatory drug) is ineffective against the
early-phase of formalin-induced pain. It is well known that
the NSAIDs (such as aspirin, acetaminophen and diclofenac),
known to inhibit cyclooxygenase (COX) activity, are largely
ineffective or cause very weak inhibition against the early-phase
of the formalin test (Hunskaar and Hole, 1987; Malmberg and
Yaksh, 1992; Santos et al., 1998 and present study). In addition, NSAIDs can attenuate, in a dose-related manner, the latephase of formalin-induced licking (Hunskaar and Hole, 1987;
Malmberg and Yaksh, 1992; Santos et al., 1998 and present
study). Our results show, however, that the AE of Physalis angulata, given by intraperitoneal route, produces graded inhibition
only of the late-phase (inflammatory nociception) of the formalin test in mice. These data suggests that the AE of Physalis
angulata can also produce antinociceptive action through inhibition of COX and consequently prostaglandin synthesis. However, the possibility that Physalis angulata acts on COX remains
to be tested in future studies.
Another interesting result of the current study was the fact
that both AE of Physalis angulata and morphine, at doses which
inhibited the nociception caused by acetic acid and formalin,
produced a marked and significant antinociception in the hotplate assay. Although the hot-plate test is commonly used to
assess narcotic analgesics, other centrally acting drugs, including sedatives and muscle relaxants or psychotomimetics have
shown activity in this test (Eddy and Leimbach, 1953). However, in contrast to the effect for morphine, indomethacin and
other NSAIDs have no effect according to the hot-plate test
(Yamamoto and Nozaki-Taguchi, 1996; Santos et al., 1998).
Recently, it has been shown that the treatment of mice with the
methanolic extract of Physalis angulata flowers has no effect
on the hot-plate test (Choi and Hwang, 2003). We can speculate that the difference between our findings in relation to the
hot-plate assay and those in the literature might be due to: (a)
differences in the species (ICR or Swiss) of mice and/or procedures employed; (b) differences of the active principles present
in the selected parts (root or flower) of the plant and (c) differences, due to environmental factors, in the concentration of
active principles acting on the Physalis angulata and the difference in the solvent (different polarity) used to obtain the extract
analyzed in the present work.
Unpublished results of our group also demonstrate that the
treatment of mice with AE of Physalis angulata (1060 mg/kg)
produces no changes in behaviour, such as the appearance of
involuntary movements, piloerection, stimulatory or sedative
effects, respiratory depression or other signs at 4, 24 or 48 h

G.N.T. Bastos et al. / Journal of Ethnopharmacology 103 (2006) 241245

after administration of the AE. The data indicates that the AE of

Physalis angulata present a low acute toxicity. However, these
findings are preliminary and further studies are required to clarify this point.
In summary, the results of the present study demonstrate for
the first time that the AE of Physalis angulata produce doserelated antinociceptive action in chemical (acetic acid-induced
visceral pain or formalin-induced nociception) and thermal (hotplate test) models of nociception in mice. The mechanism by
which the AE produces antinociception still remains unclear,
but pharmacological and chemical studies are continuing so as
to characterize the mechanism(s) responsible for the antinociceptive action and also to identify the active principles present
in Physalis angulata. Furthermore, the antinociceptive action
demonstrated in the present study supports, at least partly, the
ethnomedical uses of this plant.
Acknowledgements
This study was supported by grants from the National
Council of Scientific and Technological Development (CNPq),
SECTAN-FUNTEC-Para and PROPESP- UFPa, Brazil. The
author is grateful to Dr. Reinaldo de Amorim Carvalho, Instituto
de Pesquisa Evandro Chagas, for the experimental animals used
in this research.
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