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molecules
Review
Essential Oils and Their Constituents Targeting the
GABAergic System and Sodium Channels as
Treatment of Neurological Diseases
Ze-Jun Wang * and Thomas Heinbockel * ID
Department of Anatomy, Howard University College of Medicine, 520 W Str., NW, Washington, DC 20059, USA
*Correspondence: zejunwang@hotmail.com (Z.-J.W.); theinbockel@howard.edu (T.H.);
Tel.: +1-202-8069495 (Z.-J.W.); +1-202-8069873 (T.H.)
Received: 5 February 2018; Accepted: 27 April 2018; Published: 2 May 2018
Abstract:
Essential oils and the constituents in them exhibit different pharmacological activities,
such as antinociceptive, anxiolytic-like, and anticonvulsant effects. They are widely applied as a
complementary therapy for people with anxiety, insomnia, convulsion, pain, and cognitive deficit
symptoms through inhalation, oral administration, and aromatherapy. Recent studies show that
essential oils are emerging as a promising source for modulation of the GABAergic system and
sodium ion channels. This review summarizes the recent findings regarding the pharmacological
properties of essential oils and compounds from the oils and the mechanisms underlying their effects.
Specifically, the review focuses on the essential oils and their constituents targeting the GABAergic
system and sodium channels, and their antinociceptive, anxiolytic, and anticonvulsant properties.
Some constituents target transient receptor potential (TRP) channels to exert analgesic effects. Some
components could interact with multiple therapeutic target proteins, for example, inhibit the function
of sodium channels and, at the same time, activate GABA
A
receptors. The review concentrates on
perspective compounds that could be better candidates for new drug development in the control of
pain and anxiety syndromes.
Keywords:
essential oils; terpenes; GABA receptor; sodium channel; transient receptor potential
(TRP) channel; pain; epilepsy; analgesics; anticonvulsant; anxiolytic; antinociception; CNS;
sensory neurons
1. Introduction
Essential oils (EOs) are concentrated hydrophobic liquid containing volatile aroma compounds
which are extracted from herbs, flowers, and other plant parts. Oil is “essential” in the sense that
it contains the “essence of” the plant’s fragrance. They are recommended for or encouraged to be
applied as a complementary therapy for people with anxiety, pain, bipolar disorder, attention deficit
hyperactivity disorder, and depression [
1
,
2
]. EOs can be absorbed into the body by oral administration,
inhalation, diffusers, baths, and massages. Many studies show that EOs were effective in reducing
pain, anxiety, and stress symptoms in animal models and humans with different CNS disorders [
1
,
2
].
EO constituents belong mainly to two chemical groups: terpenoids (monoterpenes and sesquiterpenes)
and some phenylpropanoid derivatives. Terpenoid group compounds are usually fairly hydrophobic
with molecular weights below 300 Daltons [3].
Activation of the
γ
-aminobutyric acid (GABA) receptor system and the blockade of neuronal
voltage-gated sodium channels (Na
+
channels) are essential for the overall balance between neuronal
excitation and inhibition which is vital for normal brain function and critical for the central nervous
system (CNS) disorders. It has been suggested that EO constituents could exert their biological
Molecules 2018,23, 1061; doi:10.3390/molecules23051061 www.mdpi.com/journal/molecules
Molecules 2018,23, 1061 2 of 24
activities through modulating the GABAergic system and inhibiting Na
+
channels [
4
,
5
]. GABA is the
major inhibitory neurotransmitter in the CNS and the GABA receptor system exerts a major inhibitory
function in the brain. The dysfunction or deficiency of the GABAergic system has been implicated
in epilepsy, pain, and anxiety [
6
]. Neuronal voltage-gated Na
+
channels mediate the propagation
of action potentials along axons, and thus, are thought to be important targets of antiseizure drugs.
Local anesthetics and analgesics prevent the transmission of nerve impulses via their binding to Na
+
channels. Two main types of Na
+
currents, termed tetrodotoxin (TTX)-sensitive and TTX-resistant,
have been identified in the dorsal root ganglion [
7
,
8
]. Studies on Na
+
channels have demonstrated a
greater involvement of Nav1.7, a predominant subtype of TTX-sensitive sodium channels expressed
principally in peripheral neurons [8], in inflammatory pain [9,10] and in pain sensation [11,12].
Recently, many studies have addressed the potential of natural EOs for treatment of anxiety,
convulsion, and pain in humans and in rodents or fish neuropathic models, and the mechanisms
underlying the pharmacological profile. The main constituents of EOs were isolated and chemically
elucidated. Recent studies indicate that many EOs and their constituents exert pharmacological
properties through interactions with the GABAergic system and voltage-gated Na
+
channels. An
increasing number of studies show that: (1) many EOs used for the treatment of anxiety affect the
function of the GABAergic system [
13
–
16
]; (2) many EOs with antinociceptive and anticonvulsant
properties inhibit the function of neuronal voltage-gated Na
+
channels [
17
]; (3) some EOs affect the
function of both the GABAergic system and voltage-gated Na+channels [4,18].
This review summarizes the beneficial effects of EOs and their constituents targeting the
GABAergic system and neuronal voltage-gated Na
+
channels for CNS disorders, in particular with
respect to their antinociceptive, anticonvulsant, anxiolytic, and sedative effects.
2. The Pharmacological Activities of EOs and the Underlying Mechanism of Their Actions
The pharmacological activities of EOs, especially antinociceptive, anticonvulsant,
anti-inflammatory, anxiolytic, and sedative effects are summarized in Table 1which shows
the EOs from different plants, their pharmacological activities, and mechanism of actions.
Table 1.
The summary of essential oils from different plants, their pharmacological properties, and
mechanism of actions.
EO Botanical
Origins Administration Pharmacological Effects Mechanism of Actions Authors/Year/Ref.
Achillea Wilhelmsii C.
Koch i.p. anxiolytic effects
not probably mediated
through GABA and
opioid receptors
Majnooni et al., 2013 [
19
]
Acorus gramineus
Rhizoma INH;p.o.
pentylenetetrazole-induced
convulsion; sedative
effect; CNS inhibitory
effects
increased GABA level;
decreased GABA
transaminase
Koo et al., 2003 [20]
Acorus tatarinowii
Schott analgesic effects inhibited Na+channels Moreira-Lobo et al.,
2010 [17]
Aloysia citrodora
Palau in vitro
effective antioxidant,
radical-scavenging
activities, and neuronal
protection
inhibited [3H] nicotine
binding
Abuhamdah et al.,
2015 [21]
Artemisia herba-alba in vitro
antifungal and
anti-inflammatory
activities
N/A Abu-Darwish et al.,
2015 [22]
Artemisia ludoviciana i.p. antinociceptive activity
partially mediated by the
opioid system
Anaya-Eugenio et al.,
2016 [23]
Artemisia judaica in vitro
antifungal and
anti-inflammatory
activities
N/A Abu-Darwish et al.,
2016 [24]
Molecules 2018,23, 1061 3 of 24
Table 1. Cont.
EO Botanical
Origins Administration Pharmacological Effects Mechanism of Actions Authors/Year/Ref.
Artemisia dracunculus i.p. peripheral and central
antinociceptive activity N/A Maham et al., 2014 [25]
Asarum
heterotropoides INH decreased depression-like
behaviors N/A Park et al., 2015 [26]
Camellia sinensis INH increased sleeping time potentiated GABAA
receptors Hossain et al., 2004 [27]
Citrus aurantium p.o. anxiolyticlike activity serotonergic system
(5-HT1Areceptors) Costa et al., 2013 [28]
Citrus bergamia decreased stress-induced
anxiety
tuning synaptic
plasticity Bagetta et al., 2010 [29]
Citrus sinensis INH acute anxiolytic activity N/A Faturi et al., 2010 [30]
Coriander INH
increased
anxiolytic–antidepressant-like
behaviors, and
N/A Cioanca et al., 2014 [31]
Cymbopogon citratus p.o. anxiolytic-like activity potentiated GABAA
receptor complex Costa et al., 2011 [13]
Cymbopogon
winterianus Jowitt;
and C. citratus (DC)
Stapf.
i.p. anticonvulsant activities via GABAergic
neurotransmission Silva et al., 2010 [32]
Dysphania graveolens p.o. antinociceptive effects N/A Déciga-Campos et al.,
2017 [33]
Hyptis mutabilis
(Rich.) Briq. p.o. sedative and central
anesthetic activities
no involvement of the
GABAA-BDZ system Silva et al., 2013 [34]
Lavandula angustifolia INH anxiolytic-like effects serotonergic system Chioca et al., 2013 [35]
Lippia alba (Mill.) N.E.
Brown p.o. central anesthetic effect involvement of the
GABAergic system
Heldwein et al., 2012 [
36
]
Lemon oil anxiolytic,
antidepressant-like effects
suppression of DA
activity related to
enhanced 5-HTnergic
neurons
Komiya et al., 2006 [37]
Melissa officinalis p.o.
anti-agitation effects in
patients and the
depressant effects in
in-vitro
inhibited GABA-induced
currents
Abuhamdah et al.,
2008 [38]
Nigella sativa Seed
lmain components p.o.
potentiation of
valproate-induced
anticonvulsant effect
increased in GABAergic
response Raza et al., 2008 [39]
Perfume and
phytoncid in vitro anxiolytic anticonvulsant
and sedative activity
potentiating GABAA
receptors
Aoshima and
Hamamoto, 1999 [40]
Piper guineense INH sedative and
anxiolytic-like effects N/A
Tankam and Tto, 2013 [
2
]
Pistacia integerrima
Stewart ex Brandis
Galls
in vitro relaxant and spasmolytic
effects
involvement of
β-adrenoceptors and
calcium channels
Shirole et al., 2015 [41]
Salvia sclarea i.p. or INH anti-depressant-like effect modulating DAnergic
pathway Seol et al., 2010 [42]
Syzygium aromaticum local anesthesia Inhibited sodium
channels Huang et al., 2012 [43]
Tagetes minuta Lsc anxiogenic-like effects negative modulation on
the GABAergic function Marin et al., 1998 [44]
Thymus capitatus
Hoff. et Link. p.o. antinociceptive activity via peripheral nervous
excitability blockade
Gonçalves et al.,
2017 [45]
Valerian officinalis Lp.o. sedatives N/A Houghton, 1999 [46]
Note: N/A: not applicable; p.o.: by mouth, oral; sc: subcutaneous injection; i.p.: intraperitoneal injection;
INH: inhalation.
Molecules 2018,23, 1061 4 of 24
2.1. EOs with Antinociceptive and Anti-Inflammatory Activities
EOs that originate from different plants display antinociceptive and anti-inflammatory properties.
Bergamot (Citrus bergamia) is a fruit best known for its EO used in aromatherapy to minimize symptoms
of stress-induced anxiety and mild mood disorders and cancer pain [
29
]. The antinociceptive effect of
EOs of Salvia sclarea (clary sage), Thymus vulgaris (thyme), and Lavandula angustifolia (true lavender),
were examined in the capsaicin test [
29
,
47
]. The capsaicin test in mice is a reliable model of peripheral
nociception, which produces nociceptive behavior similar to that elicited by the intraplantar injection
of formalin. Among these EOs, the intraplantar injection of bergamot EO produced a significant
antinociceptive effect in mice [29,47].
EOs from the genus Artemisia demonstrated antinociceptive and anti-inflammatory effects.
Artemisia dracunculus (tarragon) has been used for the treatment of pain and gastrointestinal
disturbances in Iranian traditional medicine [
25
]. Maham et al. [
25
] evaluated both central and
peripheral antinociceptive activity of tarragon EO in various experimental models. It was found that the
EO possesses a potent antinociceptive effect. Similarly, another EO from Artemisia ludoviciana was also
reported to possess antinociceptive activity, which was partially mediated by the opioid system [
23
].
The aerial parts of Artemisia herba-alba are widely used to treat inflammatory disorders (colds,
coughing, bronchitis, diarrhea) are infectious diseases (skin diseases, scabies, syphilis). Recent studies
showed that appropriate doses of A. herba-alba EO displayed both antifungal and anti-inflammatory
activities. Thus, the findings justified and reinforced the use of this plant in traditional medicine [
22
].
Abu-Darwish et al. [
22
] characterized the chemical composition of A. herba-alba EO from South Jordan
and found that regular monoterpenes were predominant (39.3%) and the principal components were
α- and β-thujone (27.7%). Artemisia judaica L. is a medicinal and aromatic plant growing in the valley
bottoms of desert areas. Abu-Darwish et al. [
24
] studied the chemical composition and biological
activities of Artemisia judaica EO. They found that A. judaica EO had antifungal and anti-inflammatory
activities. For A. judaica EO constituents, oxygenated monoterpenes are a representative group of
constituents (68.7%) in the oil with piperitone (30.4%), camphor (16.1%), and ethyl cinnamate (11.0%)
as the main compounds.
Cymbopogon citratus is widely used in traditional medicine as an infusion or decoction, sedative,
and analgesic for treating nervous disturbances [
13
]. An antinociceptive effect of EO from C. citratus
has been detected in the rodent hot plate test, an experimental procedure related to central nervous
system activity [48].
Dysphania graveolens is a traditional medicinal plant used in Mexico to treat stomach pain. The
EO from the aerial parts of D. graveolens was recently evaluated in the hot plate and writhing tests in
mice [
33
]. The EO produced an antinociceptive response to thermic and chemical stimuli in a mouse
model [33].
2.2. EOs with Anxiolytic, Anti-Depressive, and Sedative Activities
Popular anxiolytic oils include those of Anthemis nobilis (chamomile), Salvia sclarea (clary),
Rosmarinus officinalis (rosemary), Lavandula angustifolia (lavender), and Rosa damascena (rose) [
42
]. These
EOs have been used medicinally in Europe for thousands of years. In the United States, chamomile
is best known as an ingredient in herbal tea preparations advertised as having mild sedation effects.
The antidepressant effects of EOs of chamomile (Anthemis nobilis), clary (Salvia sclarea), rosemary
(Rosmarinus officinalis), and lavender (Lavandula angustifolia) were assessed using a forced swim test
(FST) in rats [
42
]. It was reported that among the essential oils tested, 5% (v/v) clary oil had the
strongest anti-stressor effect in the FST [
42
]. The anti-depressive effect of clary oil
in vivo
could be
blocked by dopaminergic antagonists, suggesting the effect is closely associated with the modulation
of the dopaminergic (DA) pathway [42].
The fruits, leaves, and roots of Piper guineense have diverse medicinal uses for treating
convulsion, rheumatism, and respiratory diseases in African traditional medicine [
2
]. The inhalation
of P. guineense EO had significant sedative and anxiolytic effects, suggesting that the EO might
Molecules 2018,23, 1061 5 of 24
induce a mild tranquilizing effect. The main compounds of P. guineense EO were linalool (41.8%)
and 3,5-dimethoxytoluene (10.9%). These two main compounds were shown to play a major role in
the sedative activity of P. guineense EO [
2
]. The EO of Piper guineense might exert its sedative effects
partially via the GABAergic receptor system [2].
Komiya et al. [
37
] examined the anti-stress action of the EOs of lavender, rose, and lemon using
an elevated plus-maze task, a forced swimming task, and an open field task in mice. Among the tested
EOs, lemon oil had the strongest anti-stress effect in all three behavioral tasks. Unfortunately, the
authors only indicate that the EOs of lavender, rose, and lemon were supplied by Soda Aromatic Co.,
Ltd. (Tokyo, Japan), but did not mention the botanical origin of EOs. Despite the fact that rose oil did
not show a larger anti-stress effect, it has been reported that rose oil had anti-conflict effects and that
the effects were not mediated by the benzodiazepine binding site of the GABA
A
receptor complex [
49
].
The anxiolytic, antidepressant-like effects of lemon oil were mediated through the suppression of
DA activity related to enhanced serotonergic (5-HT) neurons [
37
]. Lemon oil can be obtained from a
species of the Citrus genus [
37
]. The EO from Citrus aurantium L. was reported to have an anti-stress
related effect [
28
]. Costa et al. (2013) investigated the anxiolytic-like activity of the EO of C. aurantium
in a light/dark box, and the antidepressant activity in a forced swim test [
28
]. The acute treatment with
the EO showed no activity in the forced swim test, which is sensitive to antidepressants. The studies
demonstrated that C. aurantium EO exhibited an anxiolytic-like activity which was mediated by
5-HT1A-receptors [
28
]. The similarity of the mechanism underlying anxiolytic-like activity suggests
that lemon oil and EO from C. aurantium may present the same bioactive compounds or analogs
which target the serotonergic system. The anxiolytic effects of Citrus sinensis (sweet orange) EO were
evaluated on male Wistar rats in the elevated plus-maze followed by the light/dark paradigm [
30
].
At all doses, C. sinensis oil demonstrated anxiolytic activity in at least one of the tests and, at the highest
dose, it presented significant effects in both animal models [30].
Cymbopogon citratus (DC) Stapf., commonly known as lemongrass, and Cymbopogon winterianus
Jowitt, are widely used in traditional medicine as an infusion or decoction, sedative, and analgesic
for treating nervous disturbances [
13
,
50
]. The anticonvulsant activities of the EOs from C. winterianus
and C. citratus were evaluated in mice [
32
]. The results showed that both EOs were more active on
the pentylenetetrazol-induced convulsion model, and C. citratus was even more efficient in increasing
latency to the first convulsion and latency to death. The mechanism of action of the EOs (C. citratus
and C. winterianus.) for the anticonvulsant effect was, at least in part, dependent upon GABAergic
neurotransmission [
32
]. Costa et al. [
13
] investigated the anxiolytic-like activity of C. citratus EO
in a light/dark box and marble-burying test and the antidepressant activity was investigated in
forced-swimming test model in mice. The results demonstrated that acute treatment with the EO
from C. citratus was effective against generalized anxiety disorder and epilepsy in experimental
procedures in mice [
51
]. Studies on the underlying mechanism showed that the anxiolytic-like effect of
its EO was mediated by the GABA
A
receptor complex [
13
]. The main EO compounds were identified
as monoterpene citral (71.29%), a mixture of the stereoisomers geranial and neral, or
β
-myrcene
(16.5%) [13,52].
Asarum heterotropoides was effective in reducing anxiety and inflammation in relief of pain [
53
–
55
].
Park et al. (2015) reported that EO of A. heterotropoides effectively attenuated depression-like behavior
and increased the brain expression of serotonin (5-HT) in response to six minutes of forced swimming
or immobilization stress [26].
The EO of Tugetes minutu L. was found to have anxiogenic-like effects on T-maze and tonic
immobility behavior in domestic chicks probably through the negative modulation of GABAergic
function [44].
Melissa officinalis is known to have sedative, cognitive-enhancing, and relevant physiological
actions. Abuhamdah et al. [
38
] reported that EO from M. officinalis reversibly inhibited GABA-induced
currents in a concentration-dependent manner whereas no inhibition of NMDA- or AMPA-induced
currents was noted. Lippia alba (Mill.) N.E. Brown is known as “false-melissa” in Brazil. This plant has
Molecules 2018,23, 1061 6 of 24
been commonly used for its sedative properties, which also have been demonstrated in some rodent
studies [
36
,
56
,
57
]. Three main chemotypes obtained from L. alba EO were reported and classified
according to their major constituent as citral, carvone, and linalool [
56
]. Recently, the anesthetic effect
of L. alba EO was demonstrated in silver catfish and the GABAergic system was involved in this
effect [
36
]. Thus, the EO of L. alba is considered to be a novel natural sedative and anesthetic agent
that can be potentially used in aquaculture practices due to its ability to reduce stress in fish with a
consequent reduction of economic losses in fish culture [
36
]. Meanwhile, repeated treatment with an
EO from L. alba displayed anxiolytic effects in the elevated T-maze mouse model [58].
Lavender (Lavandula angustifolia) is cultivated worldwide for its EOs, which are used in perfumes,
cosmetics, food processing and, more recently, in aromatherapy products. Lavender inhalation has
been used in folk medicine for the treatment of anxiety. It was reported that lavender scent reduces
the anxiety state in dental patients [
59
]. Chioca et al. [
35
] reported that the EO of the plant probably
exerted its anxiolytic effect through serotonergic but not GABAergic neurotransmission [
35
]. Lavender
contains linalool and linalyl acetate as its main bioactive components [60,61].
Silva et al. [
34
] evaluated the sedative and anesthetic properties of Hyptis mutabilis EO and
the isolated compounds from EO in silver catfish (Rhamdia quelen). Both the EO and the isolated
compounds [(+)-1-terpinen-4-ol and (
−
)-globulol] showed concentration-dependent sedative and
anesthetic effects.
Coriander volatile oil is prepared from Coriander sativum. The oil displays significant anxiolytic-
and antidepressant-like effects [
31
]. Moreover, coriander volatile oil decreased the catalase activity
and increased glutathione level in the hippocampus [
31
]. The multiple exposures to coriander volatile
oil can be useful as a means to counteract anxiety, depression, and oxidative stress in Alzheimer’s
disease conditions. The GC-MS and GC-FID analyses determined the main volatile component of the
coriander volatile oil sample to be linalool (69.4%), which is probably the responsible constituent for
the observed anxiolytic- and antidepressant-like effects. This assumption was confirmed by the fact
that inhaling linalool rich EOs can be useful as a means to counteract anxiety [
35
,
62
]. Other minor
constituents of coriander volatile oil are α-pinene (3.0%–7.0%) and γ-terpinene (1.5–8.0%) [31].
It was reported that the EO of rhizome and leaf of Acorus gramineus displayed sedative and
anticonvulsant properties and also anti-oxidative activity after fragrance inhalation [
20
]. Koo et
al. [
20
] reported that pre-inhalation of the EO of Acorus gramineus markedly delayed the appearance of
pentylenetetrazole-induced convulsion. Moreover, fragrance inhalation progressively prolonged the
pentobarbital-induced sleeping time as the inhalation time was lengthened. This sedative effect after
inhalation or oral administration of A. gramineus EO suggests that this oil may act on the CNS via the
GABAergic system. The main components in the EO are
β
-asarone (40.3%), euasarone (17.0%) and
α-euasarone (12.3%) [20].
Valerian (Valerian officinalis L), a common name given to the crude drug consisting of the
underground organs of species of the genus Valeriana (Valerianaceae), demonstrated sedative
activity [
46
]. The constituents of the volatile oil of valerian are very variable due to population
differences in genetics and environmental factors. The major constituents include the monoterpene
bornyl acetate and the sesquiterpene valerenic acid, which is characteristic of the species, in addition
to other types of sesquiterpene. The non-volatile monoterpenes known as valepotriates were first
isolated in 1966 and contribute to the overall activity by possessing sedative activity based on the
effects on the CNS [
46
]. Valepotriates consist of the furanopyranoid monoterpene skeleton commonly
found in the glycosylated forms [46].
EO from Cananga odorata (ylang-ylang EO, YYO) is usually used in reducing blood pressure,
improving cognitive functioning in aromatherapy in humans. It was recently reported that YYO
displayed anxiolytic effects on anxiety behaviors [
63
]. YYO and the three main constituents of YYO
(benzyl benzoate, linalool, and benzyl alcohol) increased the time that mice visited the open arms
and a lightbox area in the elevated plus-maze and light-dark box tests after acute and chronic YYO
Molecules 2018,23, 1061 7 of 24
exposures [
63
]. YYO and its major constituent benzyl benzoate might act on the serotonergic and
dopaminergic pathways [63].
A mixture of different EOs was reported to have inhibitory effects on CNS. The central
nervous system inhibitory effects of the EO from SuHeXiang Wan (Storax pill) on fragrance
inhalation (aromatherapy) were evaluated. SuHeXiang Wan consists of 15 crude herbs, among
them
Liquidambar orientalis
,Saussurea lappa,Aquilaria agallocha,Santalum album,Boswellia carterii,
Eugenia caryophyllata
,Styrax benzoin,Dryobalanops aromatica, and Cyperus rotundus. All of them have
the term “Xiang” (fragrance) in their Chinese plant names. The fragrance inhalation of the EO from
SuHeXiang Wan progressively prolonged the pentobarbital-induced sleeping time and inhibited brain
lipid peroxidation to which the anticonvulsive action is attributed [
15
]. The studies confirm that
the inhibitory effects of the EO of SuHeXiang Wan on the CNS were mediated by the GABAergic
system [
15
]. Similarly, the perfume, which is a mixture of different EOs, affects the frame of the human
mind. The effects of the perfume and phytoncid on GABA
A
receptors expressed in Xenopus oocytes
were studied [
40
]. The chemical constituents in the perfume such as hinokitiol, pinene, eugenol,
citronellol, and citronellal potentiated the GABA
A
receptor expressed in Xenopus oocytes. These results
suggest that the GABAergic system is a common target of EOs.
In addition to acting on the GABAergic system, the pharmacological effects of EOs may be
mediated through other receptor systems. Different species of Achillea are used in folk medicine
as sedatives, anti-inflammatory agents, analgesic agents, and anthelmintic (antiparasitic) agents.
Majnooni et al. [
19
] reported that the EO of A. wilhelmsii had anxiolytic effects which were probably not
mediated through GABA and opioid receptors. Gas chromatography/mass spectrometry (GC/MS)
analysis of the EO showed that the main compounds of the oil were p-ocimen (23%), 1, 8-cineole (20.8%),
and carvone (19.13%). Pistacia integerrima Stewart ex Brandis galls are used in Indian ethnomedicine
for their anti-asthmatic, sedative, and spasmolytic properties. The EO of the plant had relaxant and
spasmolytic effects which may be mediated by modulating
β
-adrenoceptors and calcium channels [
41
].
2.3. EOs with Anticonvulsant and Other Pharmacological Properties
The major chemical components detected in the Aloysia citrodora EOs, derived from dried and fresh
leaves, included limonene, geranial, neral, 1,8-cineole, curcumene, spathulenol, and caryophyllene
oxide, respectively. A. citrodora leaf EO inhibited [
3
H] nicotine binding to well-washed rat forebrain
membranes, and increased iron-chelation
in vitro
[
21
]. A. citrodora EO displays the effective antioxidant,
radical-scavenging activities, and significant protective properties [21].
Raza et al. [
39
] investigated the antiepileptic effects of Nigella sativa seed volatile oil and the main
components of the oil (that is, thymoquinone,
α
-pinene and p-cymene) using pentylenetetrazole
(PTZ) and maximal electroshock (MES)-induced convulsions [
39
]. The volatile oil protected
mice effectively against PTZ-induced convulsions that may be attributed mainly to its content
of thymoquinone and p-cymene and to a lesser extent,
α
-pinene. Volatile oil and its component
p-cymene effectively suppressed convulsions induced by MES. Their studies suggest that picrotoxin
and bicuculline-sensitive GABA receptors mediate an increase in the GABAergic response.
3. The Pharmacological Properties of Constituents Isolated from EOs and the Underlying
Mechanisms of Action
Natural products have played pivotal roles in neuropharmacology due to their potent and
selective targeting of specific biochemical pathways and receptors, and are highly useful as probe
substances and therapeutic leads. An increasing amount of evidence shows that EOs present potent
bioactive constituents targeting different therapeutic targets [4,5].
Terpenoids and phenylpropanoid derivatives are the main constituents of EOs [
3
]. The most
common terpenoids found in EOs are the monoterpenes and the sesquiterpenes. There is increasing
interest in the pharmacological actions of the constituents found in EOs, especially terpenes [
3
].
Here, we summarize the pharmacological properties of the constituents isolated from EOs and the
Molecules 2018,23, 1061 8 of 24
mechanisms underlying their actions. Table 2is a summary of pharmacological properties of EO
constituents from different plants and the underlying mechanisms of their effects.
Table 2.
The summary of pharmacological properties of constituents from essential oils of different
plants targeting Na+channels and GABAergic system.
Constituents Pharmacological Effects Mechanism of Actions Authors/Year/Ref.
1,8-Cineole antinociceptive, smooth
muscle relaxant
reduction of excitability of peripheral
neurons by blocking voltage-dependent
Na+current
Ferreira-da-Silva et al.,
2015 [64]
neuronal excitant
hyperexcitability and epileptiform
activity in snail neurons by inhibiting
potassium channels
Zeraatpisheh and
Vatanparast, 2015 [65]
1-Nitro-2-phenylethane hypnotic, anti-convulsant and
anxiolytic effects N/A
Oyemitan et al., 2013 [
66
]
vasorelaxant effects in rat
isolated aortic rings
inhibition of contractile events that are
clearly independent of Ca2+ influx
Arruda-Barbosa et al.,
2014 [67]
vasorelaxant effects N/A Interaminense et al.,
2013 [68]
(+)-Borneol
alleviated mechanical
hyperalgesia in models of
chronic inflammatory and
neuropathic pain
enhanced GABAAR-mediated
GABAergic transmission JIang et al., 2015 [69]
(+)- and (−)-Borneol analgesia and anesthesia positive modulation of GABAAR Granger et al., 2005 [14]
(+)-Dehydrofukinone sedative or anesthetic effects interacted with GABAergic receptors; a
suppressor of neuronal excitability Garlet et al., 2016 [70]
(S)-Limonene, Anti-stress effect via the GABAergic system Zhou et al., 2009 [71]
(R)-(+)-Limonene anxiolytic-like effects N/A Lima et al., 2013 [72]
(+)-Dehydrofukinone sedation, anticonvulsant and
anesthesia potentiated GABAAreceptors Garlet et al., 2017 [73]
α-asarone antiepileptic effect enhanced tonic GABAergic inhibition Huang et al., 2013 [54]
antiepileptic effect
Na
+
channel blockade and activation of
GABAAreceptors Wang ZJ et al., 2014 [4]
anticonvulsant blocked Na+channel, potentiated
GABAAreceptors Wang ZJ et al., 2014 [4]
α-(−)-Bisabolol antinociceptive-like effect
decreased peripheral nerve excitability
probably by blockade of voltage-gated
Na+channels
Wang YW et al., 2015 [
74
]
α-Pinene
anxiolytic and hypnotic effects
a partial modulator of GABAA
receptors and directly binding to the
benzodiazepine binding site of GABAA
receptor.
Yang et al., 2016 [75]
β-Citronellol Hypotensive action
antagonized transmembrane Ca2+
influx from the extracellular milieu to
produce myorelaxant actions.
Vasconcelos et al.,
2016 [76]
(R)-(−)-carvone and
(S)-(+)-carvone antimanic-like effects
blockade of voltage-gated Na
+
channels;
activating TRPV1 and TRPA1 channels
Nogoceke et al., 2016 [
77
]
Benzyl benzoate anxiolytic effect probably through 5-HTnergic and
DAnergic pathways Alves et al., 2016 [63]
Carvacrol antinematodal action nicotinic acetylcholine receptors and
GABA receptors Trailovi´c et al., 2015 [78]
analgesic activity
reduced excitability of peripheral
neurons; reduced voltage-dependent
Na+current
Joca et al., 2012, 2015
[79,80]
anxiolytic effects in the
plus-maze test
involvement with GABAergic
transmission Melo et al., 2010 [81]
Estragole anxiolytic and antimicrobial
activities
inhibition of neuronal excitability by
blocking Na+channels
Silva-Alves et al.,
2013 [82]
Eugenol local analgesic inhibition of Na+channels Vatanparast, 2017 [83]
Molecules 2018,23, 1061 9 of 24
Table 2. Cont.
Constituents Pharmacological Effects Mechanism of Actions Authors/Year/Ref.
analgesic reduced neuronal hyperexcitability by
blocking Na+currents Huang et al., 2012 [43]
inhibition of action potentials Moreira-Lobo et al.,
2010 [17]
Isopulegol pentylenetetrazol-induced
convulsions
positive modulation of GABAAR and
antioxidant properties Silva et al., 2009 [84]
Linalool antinociceptive effect
blocked excitability by decreasing the
voltage-dependent Na+current in
dorsal root ganglion neurons
Leal-Cardoso et al.,
2010 [85]
Menthol analgesia
blocked action potentials in frog sciatic
nerves unassociated with TRPM8
activation
Kawasaki et al., 2013 [
86
]
Methyleugenol
anticonvulsant,
antinociceptive and anesthetic
activities
agonist of GABA
A
receptors in cultured
hippocampal neurons Ding et al., 2014 [87]
antinociceptive effect
inhibition of NMDA receptor-mediated
hyperalgesia via GABAAreceptors Yano et al., 2006 [88]
antinociceptive and anesthetic
actions inhibition of Nav1.7 channels Wang ZJ et al., 2015 [5]
Myrtenol and Verbenol sedative, anxiolytic and
anticonvulsive effects
augments phasic and tonic GABAergic
inhibition; positive allosteric
modulation of GABAAreceptors
van Brederode et al.,
2016 [16]
Nerolidol antinociceptive and
anti-inflammatory activity
involvement of the GABAergic system
and proinflammatory cytokines Fonsêca et al., 2016 [89]
Terpinen-4-ol anticonvulsant effects involvement of the GABAergic system,
and decrease Na+current Nóbrega et al., 2014 [90]
Thujone muscle spasms and
convulsions GABA receptor antagonist Mariani et al., 2016 [91]
Thymol antinociception
nerve conduction inhibition; activated
TRPA1 channels; a positive allosteric
modulator of human GABAAR
Xu et al., 2015 [92]
Priestley et al., 2003 [93]
Thymoquinone anticonvulsant effects opioid receptor-mediated increase in
GABAergic tone
Hosseinzadeh and
Parvardeh, 2004 [94]
Note: N/A: not applicable.
3.1. Analgesic and Anticonvulsant Properties
The main components of the EOs of aromatic plants, terpenes, and terpenoids are considered
important agents in the food industry and for medicinal use. The constituents of the EOs of
aromatic plants are emerging therapeutic resources for developing new drugs to treat chronic
pain [
95
]. An increasing number of terpenes and terpenoids are found to have analgesic
anti-inflammatory properties.
3.1.1. Terpenoids with Analgesic Properties Targeting Na+and TRP Channels
1,8-Cineole is a terpenoid present in many EOs of plants with several pharmacological and
biological effects, including antinociceptive, smooth muscle relaxant, and ion channel action.
Additionally, 1,8-cineole blocked action potentials, thereby reducing the excitability of peripheral
neurons [
96
,
97
]. Ferreira-da-Silva et al. [
64
] demonstrated that 1,8-cineole directly affects Na
+
channels
of the superior cervical ganglion neurons by modifying several gating parameters that are likely to
be the major cause of excitability blockade. Eucalyptol reduced the excitability of rat sciatic nerve
and superior cervical ganglion neurons [
96
,
97
]. On the other hand, Zeraatpisheh and Vatanparast [
65
]
reported that 1,8-cineole (eucalyptol) induced hyperexcitability and epileptiform activity in snail
neurons, which is most likely mediated through the direct inhibitory action on the potassium channels.
Menthol (2-isopropyl-5-methylcyclohexanol), which is contained in peppermint or other mint oils,
is well-known to induce analgesia by activating the transient receptor potential (TRP) melastatin-8
Molecules 2018,23, 1061 10 of 24
(TRPM8) channels [
86
]. By recording the compound action potentials (CAPs), Kawasaki et al. [
86
]
examined the effects of menthol and its related compounds on CAP peak amplitude. (
−
)-Menthol
and (+)-menthol concentration-dependently reduced the CAP peak amplitude. (
−
)-Menthone,
(+)-menthone, (
−
)-carvone, (+)-carvone, (+)-carveol, and (+)-pulegone inhibited CAPs with extents
similar to that of menthol (see Figure 1) [
86
]. They found that menthol and its related compounds
reduce CAP peak amplitude in a manner specifically related to their chemical structures and that
menthol activity is not mediated by TRPM8 channels [86].
Molecules 2018, 23, x 11 of 23
record action potential and Na
+
currents with intracellular and patch-clamp techniques,
respectively. It was found that estragole blocked neuronal excitability by direct inhibition of Na
+
channel conductance activation.
Figure 1. The chemical structures of terpenes with analgesic properties targeting the Na
+
and
transient receptor potential (TRP) channels.
Carvone (p-mentha-6,8-dien-2-one) (Figure 1) is a chiral monoterpene ketone that is present in
Mentha spicata (Spearmint) and Carum carvi (Caraway) EOs and has been shown to have
anticonvulsant [102], antinociceptive [103] and anxiolytic-like effects in the elevated T maze [58].
Both (R)-(−)-carvone and (S)-(+)-carvone decreased peripheral nerve activity, likely through the
blockade of voltage-gated Na
+
channels [77,104]. (S)-(+)-Carvone appears to have anticonvulsant
activity against pentylenetetrazole- and picrotoxin-induced seizures [102]. In vivo, both
(R)-(−)-carvone and (S)-(+)-carvone display antimanic-like effects in two mouse models [77].
Kang et al. [105] examined the effects of (−)-carvone and its stereoisomer (+)-carvone (in
caraway) on glutamatergic spontaneous excitatory transmission in SG neurons of adult rat spinal
cord slices by using the whole-cell patch-clamp technique. They found that (−)-carvone and
Figure 1.
The chemical structures of terpenes with analgesic properties targeting the Na
+
and transient
receptor potential (TRP) channels.
Terpenoids (for example, 1,8-cineole, linalool and linalyl acetate) are the main chemical
components of EOs of the Lavandula genus, which includes lavender (Lavandula angustifolia), lavandin
(L. angustifolia hybrid L. latifolia), and bergamot (Citrus bergamia). Lavandin is actually a hybrid created
from true lavender (L. augustifolia) and spike lavender (L. latifolia). Even though the EO containing
linalool and/or linalyl acetate demonstrated an antinociceptive effect [
47
], the main constituents of the
EO, linalool and linalyl acetate (Figure 1), were much more potent than the bergamot EO or other EOs
in inhibiting the response to intraplantar capsaicin [
29
,
47
,
98
]. Linalool has been the compound mostly
Molecules 2018,23, 1061 11 of 24
linked to the anxiolytic effect of lavender [
35
,
60
–
62
,
99
–
101
]. Moreover, Takahashi et al. [
60
] showed
that the anxiolytic-like effect of linalool in mice tested in the elevated plus-maze was potentiated by
linalyl acetate. Also, it was reported that linalool displayed depressant effects on the central nervous
system and olfactory receptors [
85
]. Leal-Cardoso et al. [
85
] investigated the effects of linalool on the
excitability of peripheral neurons of the somatic sensory system. They found that linalool acts on the
somatic sensory system with local anesthetic properties since it blocked the action potential by acting
on voltage-dependent Na+channels.
Carvacrol (5-isopropyl-2-methylphenol) (see Figure 1) is a monoterpenic phenol present in the
EOs of many plants, especially in the genera Origanum and Thymus [
81
]. It is the major constituent
of the EO fraction of oregano and thyme. Carvacrol has attracted attention because of its beneficial
biological activities, especially analgesic activity. Gonçalves et al. [
45
] characterized the constituents of
Thymus capitatus
EO and evaluated their antinociceptive activity by
in vivo
and
in vitro
procedures.
The EO of T. capitatus presented 33 components, mainly monoterpenes and sesquiterpenes, and
carvacrol (80%) was its major constituent. EO of T. capitatus dose-dependently decreased the CAP
amplitude. Such activity was presumably mediated through voltage-gated Na
+
channels [
45
]. Melo
et al. [
81
] examined the behavioral effects of carvacrol using elevated plus-maze (EPM), open field,
rotarod, and barbiturate-induced sleeping time tests in mice. The results indicate that carvacrol had
anxiolytic effects in the plus-maze test which are not influenced by the locomotor activity in the
open-field test [
81
]. The mechanism underlying the anesthetic and analgesic effects is based on a
reduction in neuronal excitability and voltage-gated Na
+
channel inhibition in peripheral neurons [
79
].
The hypothesis of the underlying mechanism was supported by the finding that carvacrol could reduce
the total voltage-gated Na
+
current and tetrodotoxin-resistant (TTX-R) Na
+
current component in a
concentration-dependent manner in isolated dorsal root ganglion neurons [
80
]. In addition to analgesic
activity mediated through the blockade of Na
+
channels [
45
,
80
], Trailovi´c et al. [
78
] tested the effects of
different concentrations of carvacrol on isolated tissues of the large pig nematode Ascaris suum. The
somatic muscle flaps were used for contraction assays and for electrophysiological investigations. The
inhibitory effect of carvacrol on contractions, the inhibition of depolarizations caused by acetylcholine
(ACh), and the reduction of conductance changes directly point to an interaction with nicotinic ACh
receptors in A. suum.
Bisabolol, or more formally
α
-(
−
)-bisabolol or also known as levomenol, is a natural
monocyclic sesquiterpene alcohol (Figure 1). It is a primary constituent of the essential oil
from
Matricaria chamomilla
[
74
]. Bisabolol is known to have anti-irritant, anti-inflammatory, and
anti-microbial properties. Recently, it was reported that bisabolol demonstrated an antinociceptive-like
effect which could be associated with decreased peripheral nerve excitability [
74
]. The decreased
nervous excitability elicited by
α
-(
−
)-bisabolol might be caused by an irreversible blockade of
voltage-dependent Na+channels [74].
Estragole, a volatile terpenoid, is the primary constituent of EO of tarragon (comprising 60–75%).
It has several pharmacological and biological activities, including antioxidant, anxiolytic, and
antimicrobial activities [
82
]. The mechanism of action of estragole on neuronal excitability was recently
investigated. The intact and dissociated dorsal root ganglion neurons of rats were used to record action
potential and Na
+
currents with intracellular and patch-clamp techniques, respectively. It was found
that estragole blocked neuronal excitability by direct inhibition of Na
+
channel conductance activation.
Carvone (p-mentha-6,8-dien-2-one) (Figure 1) is a chiral monoterpene ketone that is present
in Mentha spicata (Spearmint) and Carum carvi (Caraway) EOs and has been shown to have
anticonvulsant [
102
], antinociceptive [
103
] and anxiolytic-like effects in the elevated T maze [
58
]. Both
(R)-(
−
)-carvone and (S)-(+)-carvone decreased peripheral nerve activity, likely through the blockade
of voltage-gated Na
+
channels [
77
,
104
]. (S)-(+)-Carvone appears to have anticonvulsant activity
against pentylenetetrazole- and picrotoxin-induced seizures [
102
].
In vivo
, both (R)-(
−
)-carvone and
(S)-(+)-carvone display antimanic-like effects in two mouse models [77].
Molecules 2018,23, 1061 12 of 24
Kang et al. [
105
] examined the effects of (
−
)-carvone and its stereoisomer (+)-carvone (in caraway)
on glutamatergic spontaneous excitatory transmission in SG neurons of adult rat spinal cord slices by
using the whole-cell patch-clamp technique. They found that (
−
)-carvone and (+)-carvone activate
TRPV1 and TRPA1 channels, respectively, resulting in an increase in spontaneous L-glutamate release
onto SG neurons, with almost the same efficacy [105].
Terpinen-4-ol (Figure 1) is a monoterpenoid alcoholic component of EOs obtained from several
aromatic plants. Nóbrega et al. [
90
] investigated the psychopharmacological and electrophysiological
activities of Terpinen-4-ol in male Swiss mice and Wistar rats [
90
]. Terpinen-4-ol (i.p.) inhibited
pentylenetetrazol-(PTZ-) induced seizures, indicating anticonvulsant effects. The anticonvulsant
action exerted by Terpinen-4-ol involved the GABAergic system but did not bind to the
benzodiazepine-binding site of GABA
A
receptors [
90
]. Furthermore, the electrophysiological results
show that terpinen-4-ol decreased a sodium current through voltage-dependent sodium channels [
103
].
Thus, its anticonvulsant effect may be related to changes in neuronal excitability based on the
modulation of both the GABAergic system and Na+channels.
3.1.2. Terpenes with Analgesic and Anticonvulsant Properties Targeting GABAAReceptors
Hossain et al. [
27
] electrophysiologically tested the effect of fragrant compounds in oolong tea on
GABA
A
receptors which were expressed in Xenopus oocytes. Oolong tea is a traditional Chinese tea that
is made by withering the plants with strong sun exposure and oxidation. cis-Jasmone, jasmine lactone,
linalool oxide, and methyl jasmonate significantly potentiated the response to GABA. The inhalation
of 0.1% cis-jasmone or methyl jasmonate significantly increased the sleeping time of mice induced by
pentobarbital. The results suggest that these fragrant compounds could be absorbed by the brain and
thereby potentiated the GABAAreceptor response to exerting a tranquilizing effect on the brain [27].
Nerolidol is an acyclic sesquiterpene found as a major constituent of several EOs such as
Piper claussenianum
and Burchardia umbellata [
89
]. Fonsêca et al. [
89
] evaluated the antinociceptive
activity of nerolidol using the acetic acid-induced writhing test, the formalin test, and the hot-plate test.
The results showed that nerolidol had antinociceptive activities in chemical nociception models (acetic
acid-induced writhing test and formalin test), but not in the thermal nociception model (hotplate
test). The analgesic activity of nerolidol is possibly related to the GABAergic system, and not to the
opioidergic system or to ATP-sensitive K+-channels [89].
Natural borneol is (+)-borneol (Figure 2). (+)-Borneol is a bicyclic monoterpene present
in the EOs of numerous medicinal plants, including valerian (Valeriana officinalis), chamomile
(
Matricaria chamomilla
), and lavender (Lavandula officinalis). It is used for analgesia and anesthesia in
traditional Chinese medicine [
69
]. (+)-Borneol has remarkable anti-hyperalgesic effects on neuropathic
and inflammatory pain in animal models [
69
]. The results suggest that (+)-borneol may ameliorate
mechanical hyperalgesia by enhancing GABA
A
R-mediated GABAergic transmission in the spinal
cord and could serve as a therapeutic for chronic pain [
69
]. Granger et al. [
14
] reported that both
(+)-borneol and its enantiomer (
−
)-borneol directly potentiate GABA activity at recombinant human
α1β2γ2L GABAAreceptors are expressed in Xenopus laevis oocytes. Both (+)-borneol and (−)-borneol
demonstrated a highly efficacious positive modulating action at GABA
A
receptors [
14
].
In vivo
,
(+)-borneol displays significant antinociceptive effect in models of chronic pain in mice without
producing a motor deficit. These findings suggest that borneol may ameliorate mechanical hyperalgesia
by enhancing GABA
A
R-mediated GABAergic transmission in the spinal cord and could serve as a
therapeutic for chronic pain.
Molecules 2018,23, 1061 13 of 24
Molecules 2018, 23, x 13 of 23
modulating nociceptive transmission from the periphery, the actions of thymol could contribute to
at least a part of its antinociceptive effect [92].
Isopulegol (p-menth-8-en-3-ol) (Figure 2), a monoterpene alcohol of the menthane family, is
present in the EOs of various plants species, such as Eucalyptus citriodora and Zanthoxylum
schinifolium [84]. It was found that similar to diazepam, isopulegol significantly prolonged the
latency for convulsions and mortality of mice in a PTZ-induced convulsion animal model [84]. The
results suggest that the anticonvulsant effects of isopulegol against PTZ-induced convulsions are
possibly related to positive modulation of benzodiazepine-sensitive GABA
A
receptors [84].
Figure 2. The chemical structures of terpenes with analgesic and anticonvulsant properties targeting
GABA
A
receptors.
3.1.3. Phenylpropanoid Derivative Constituents with Analgesic Properties and the Mechanisms of
Action
Methyleugenol (4-allyl-1,2-dimethoxybenzene) (Figure 3), a phenylpropanoid derivative, is a
natural constituent isolated from EOs of many plants, such as Chinese herb Asari Radix et Rhizoma,
having multiple biological effects including anticonvulsant, antinociceptive, and anesthetic
activities. The anesthetic property of methyleugenol has been demonstrated by a loss of the righting
reflex and decreased sensitivity to a tail pinch in rats and mice, and a loss of the corneal reflex in
rabbits [5]. The antinociceptive and anesthetic effects of methyleugenol resulted from the inhibitory
action of methyleugenol on peripheral Na
+
channels [5]. Yano et al. [88] tested the effects of
methyleugenol on antinociception using the formalin test in mice in vivo. They found that the
antinociceptive effect of methyleugenol on the second phase of formalin-induced pain might be due
to the inhibition of NMDA receptor-mediated hyperalgesia via GABA
A
receptors. Ding et al. [87]
tested the action of methyleugenol on GABA
A
receptors. At lower concentrations (~30 μM),
methyleugenol significantly potentiated GABA-induced currents in cultured hippocampal neurons
[87]. Similarly, methyleugenol potentiated GABA-induced currents mediated by recombinant α
1
β
2
γ
2
or α
5
β
2
γ
2
GABA
A
Rs in human embryonic kidney (HEK) cells. In addition to the blockade of Na
+
channels [5], this study adds GABA
A
R activation to the list of molecular targets of methyleugenol
[87].
Figure 2.
The chemical structures of terpenes with analgesic and anticonvulsant properties targeting
GABAAreceptors.
Thymol is a monoterpenoid monocyclic phenolic compound. It is the main component of the EO
of Thymus vulgaris (Lamiaceae). The main therapeutic application of thymol is in dental preparations to
kill odor-producing bacteria and has various actions including antinociception and nerve conduction
inhibition [
92
,
93
,
106
]. Thymol has been reported to activate transient receptor potential (TRP) channels
expressed in heterologous cells [
107
] and act as a positive allosteric modulator of human GABA
A
receptors and a homo-oligomeric GABA receptor from Drosophila melanogaster [
93
]. Thymol
displayed inhibition on spontaneous excitatory transmission in adult rat spinal substantia gelatinosa
(SG) neurons, suggesting that thymol increases the spontaneous release of L-glutamate onto the neurons
by activating TRPA1 channels while producing an outward current without TRP activation [
92
].
Considering that the substantia gelatinosa plays a pivotal role in modulating nociceptive transmission
from the periphery, the actions of thymol could contribute to at least a part of its antinociceptive
effect [92].
Isopulegol (p-menth-8-en-3-ol) (Figure 2), a monoterpene alcohol of the menthane
family, is present in the EOs of various plants species, such as Eucalyptus citriodora and
Zanthoxylum schinifolium
[
84
]. It was found that similar to diazepam, isopulegol significantly prolonged
the latency for convulsions and mortality of mice in a PTZ-induced convulsion animal model [
84
].
The results suggest that the anticonvulsant effects of isopulegol against PTZ-induced convulsions are
possibly related to positive modulation of benzodiazepine-sensitive GABAAreceptors [84].
3.1.3. Phenylpropanoid Derivative Constituents with Analgesic Properties and the Mechanisms
of Action
Methyleugenol (4-allyl-1,2-dimethoxybenzene) (Figure 3), a phenylpropanoid derivative, is a
natural constituent isolated from EOs of many plants, such as Chinese herb Asari Radix et Rhizoma,
having multiple biological effects including anticonvulsant, antinociceptive, and anesthetic activities.
The anesthetic property of methyleugenol has been demonstrated by a loss of the righting reflex and
decreased sensitivity to a tail pinch in rats and mice, and a loss of the corneal reflex in rabbits [
5
].
The antinociceptive and anesthetic effects of methyleugenol resulted from the inhibitory action of
Molecules 2018,23, 1061 14 of 24
methyleugenol on peripheral Na
+
channels [
5
]. Yano et al. [
88
] tested the effects of methyleugenol
on antinociception using the formalin test in mice
in vivo
. They found that the antinociceptive effect
of methyleugenol on the second phase of formalin-induced pain might be due to the inhibition of
NMDA receptor-mediated hyperalgesia via GABA
A
receptors. Ding et al. [
87
] tested the action of
methyleugenol on GABA
A
receptors. At lower concentrations (~30
µ
M), methyleugenol significantly
potentiated GABA-induced currents in cultured hippocampal neurons [
87
]. Similarly, methyleugenol
potentiated GABA-induced currents mediated by recombinant
α1β2γ2
or
α5β2γ2
GABA
A
Rs in human
embryonic kidney (HEK) cells. In addition to the blockade of Na
+
channels [
5
], this study adds
GABAAR activation to the list of molecular targets of methyleugenol [87].
Molecules 2018, 23, x 14 of 23
Figure 3. The chemical structures of phenylpropanoid derivatives with analgesic properties.
Eugenol (4-allyl-2-methoxyphenol) (Figure 3), an aromatic phenylpropanoid molecule found in
plants including Syzygium aromaticum (Clove), has been used in medicine to relieve pain [43]. The
EO of clove, which is made from the aromatic flower buds of a tree in the family Myrtaceae,
Syzygium aromaticum, is known as an important weak local anesthetic for dental pain [17,43].
Eugenol possesses analgesic effects that may be related to the inhibition of voltage-dependent Na
+
channels and/or to the activation of TRPV1 receptors or both. Moreira-Lobo et al. [17] reported that
eugenol inhibited action potentials and modified the excitability of the rat sciatic nerve and
superior cervical ganglion neurons. Huang et al. [43] reported that eugenol reduced the firing of
neuronal action potentials and hyperexcitability through a synergistic blocking effect of Na
+
currents. Recently, Vatanparast et al. [83] studied the effects of eugenol on the excitability of central
neurons of the land snail Caucasotachea atrolabiata and the underlying ionic mechanisms. It was
found that a low concentration of eugenol could have antiepileptic properties, while at a higher
concentration, it induced epileptiform activity. The dose-dependent inhibition of the ionic currents
underlying the rising and falling phases of the action potential seems to be relevant to the eugenol
suppressant and excitatory actions, respectively [83].
3.2. Anxiolytic, Sedative, and Anti-Depressive Properties
EOs with anxiolytic, anti-depressive, and sedative properties usually interact with the
GABAergic system. Some constituents contained in the EOs might act on the GABAergic system to
exert their pharmacological effects.
3.2.1. Terpenes with Anxiolytic and Sedative Properties Targeting the GABAergic System
An increasing number of terpenes have been reported to have anxiolytic and sedative
activities. A promising line of research on terpenes has attributed the sedative and anxiolytic effects
to the modulation of GABA
A
receptor function [16].
The monoterpene (+)-limonene (Figure 4), a chemical constituent of various bioactive EOs, is
the major chemical component (58.4%) of the Citrus
aurantifolia EO [108]. The anxiolytic-like
properties of Citrus EOs from C. aurantium L. and sweet orange aroma have been demonstrated in
rodent models [30,109]. Bergamot (C. bergamia) is a fruit best known for its EO. The oil is used in
aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders and
cancer pain [29]. The anxiolytic-like effects of (+)-limonene were reported in an elevated maze
model of anxiety in mice. However, the molecular target protein of the compound was not studied
in that report [72]. s-Limonene is a component of lemon EO. The studies on the anti-stress effect of
s-Limonene suggest that the effect may be mediated through the GABAergic system [71].
(+)-Dehydrofukinone (Figure 4), also known as dihydrokaranone, is an eremophilane-type
sesquiterpenoid ketone isolated from Nectandra grandiflora Ness (Lauraceae) EO. Recent behavioral
studies have indicated that dehydrofukinone has sedative and anesthetic properties mediated by
GABAergic mechanisms in fish [70], and induces sedation and anesthesia by modulation of GABA
A
Figure 3. The chemical structures of phenylpropanoid derivatives with analgesic properties.
Eugenol (4-allyl-2-methoxyphenol) (Figure 3), an aromatic phenylpropanoid molecule found
in plants including Syzygium aromaticum (Clove), has been used in medicine to relieve pain [
43
].
The EO of clove, which is made from the aromatic flower buds of a tree in the family Myrtaceae,
Syzygium aromaticum
, is known as an important weak local anesthetic for dental pain [
17
,
43
]. Eugenol
possesses analgesic effects that may be related to the inhibition of voltage-dependent Na
+
channels
and/or to the activation of TRPV1 receptors or both. Moreira-Lobo et al. [
17
] reported that eugenol
inhibited action potentials and modified the excitability of the rat sciatic nerve and superior cervical
ganglion neurons. Huang et al. [
43
] reported that eugenol reduced the firing of neuronal action
potentials and hyperexcitability through a synergistic blocking effect of Na
+
currents. Recently,
Vatanparast et al. [
83
] studied the effects of eugenol on the excitability of central neurons of the
land snail Caucasotachea atrolabiata and the underlying ionic mechanisms. It was found that a low
concentration of eugenol could have antiepileptic properties, while at a higher concentration, it induced
epileptiform activity. The dose-dependent inhibition of the ionic currents underlying the rising and
falling phases of the action potential seems to be relevant to the eugenol suppressant and excitatory
actions, respectively [83].
3.2. Anxiolytic, Sedative, and Anti-Depressive Properties
EOs with anxiolytic, anti-depressive, and sedative properties usually interact with the GABAergic
system. Some constituents contained in the EOs might act on the GABAergic system to exert their
pharmacological effects.
3.2.1. Terpenes with Anxiolytic and Sedative Properties Targeting the GABAergic System
An increasing number of terpenes have been reported to have anxiolytic and sedative activities.
A promising line of research on terpenes has attributed the sedative and anxiolytic effects to the
modulation of GABAAreceptor function [16].
The monoterpene (+)-limonene (Figure 4), a chemical constituent of various bioactive EOs, is the
major chemical component (58.4%) of the Citrus aurantifolia EO [
108
]. The anxiolytic-like properties
Molecules 2018,23, 1061 15 of 24
of Citrus EOs from C. aurantium L. and sweet orange aroma have been demonstrated in rodent
models [
30
,
109
]. Bergamot (C. bergamia) is a fruit best known for its EO. The oil is used in aromatherapy
to minimize symptoms of stress-induced anxiety and mild mood disorders and cancer pain [
29
]. The
anxiolytic-like effects of (+)-limonene were reported in an elevated maze model of anxiety in mice.
However, the molecular target protein of the compound was not studied in that report [
72
]. s-Limonene
is a component of lemon EO. The studies on the anti-stress effect of s-Limonene suggest that the effect
may be mediated through the GABAergic system [71].
Molecules 2018, 23, x 15 of 23
receptors in a mouse model [73], suggesting that the natural compound (+)-dehydrofukinone has
therapeutic potential as a suppressor of neuronal excitability.
Thymoquinone (Figure 4), a major constituent of Nigella sativa seeds EO (27.6–57.0%), exhibits
anticonvulsant activity in the PTZ-induced seizure model [94]. The anticonvulsant effects are
probably mediated through an opioid receptor-mediated increase in GABAergic tone. Gilhotra and
Dhingra [110] investigated the role of GABAergic and nitriergic modulation in the antianxiety effect
of thymoquinone. Thymoquinone (20 mg/kg) showed anxiolytic effects with a significant decrease
in plasma nitrite and the reversal of decreased brain GABA content in stressed mice [110].
Pine EO was reported to have anti-inflammatory, antimicrobial, analgesic, and anti-stress
effects [75,111,112]. The main components in the oil are α- and β-pinene, 3-carene, limonene, and
terpinene [113]. α-Pinene [2,6,6,-trimethylbicyclo(3.1.1)-2-hept-2-ene] (Figure 3), a major
monoterpene of pine EOs, shows anxiolytic and hypnotic effects upon inhaled administration and a
sleep enhancing property through a direct binding to GABA
A
receptors by acting as a partial
modulator of GABA
A
receptors [75].
Sideritis plants and their extracts have been used in traditional medicine as sedatives,
anxiolytics, and anticonvulsant agents. Kessler et al. [114] demonstrated that volatile aroma
substances in sideritis tea extracts have a powerful modulatory effect on synaptic α
1
/β
2
GABA
A
Rs
(with or without γ
2
subunits) in a heterologous expression system. Pinenes are the most prevalent
of the volatile aroma components in Siderites extracts and the pinene metabolites myrtenol and
verbenol (Figure 4) have been identified as the most potent positive allosteric modulators of
synaptic-type GABA
A
receptors composed of α
1
β
2
and α
1
β
2
γ
2
subunits [114]. van Brederode et al.
[16] examined the two terpenoids, myrtenol, and verbenol and found augmented tonic GABA
currents mediated by extrasynaptic GABA
A
receptors containing the δ subunit. It was reported that
terpenoid substances potentiated the response to GABA in HEK293 cells transfected with GABA
A
Rs
composed of subunits that typically mediate tonic GABA inhibition in the brain. Their results
suggest that myrtenol and verbenol act as positive allosteric modulators at synaptic and
extrasynaptic GABA
A
receptors, thereby augmenting phasic and tonic GABAergic inhibition [16].
Figure 4. The chemical structures of terpenes with anxiolytic targeting GABA
A
receptors.
Figure 4. The chemical structures of terpenes with anxiolytic targeting GABAAreceptors.
(+)-Dehydrofukinone (Figure 4), also known as dihydrokaranone, is an eremophilane-type
sesquiterpenoid ketone isolated from Nectandra grandiflora Ness (Lauraceae) EO. Recent behavioral
studies have indicated that dehydrofukinone has sedative and anesthetic properties mediated by
GABAergic mechanisms in fish [
70
], and induces sedation and anesthesia by modulation of GABA
A
receptors in a mouse model [
73
], suggesting that the natural compound (+)-dehydrofukinone has
therapeutic potential as a suppressor of neuronal excitability.
Thymoquinone (Figure 4), a major constituent of Nigella sativa seeds EO (27.6–57.0%), exhibits
anticonvulsant activity in the PTZ-induced seizure model [
94
]. The anticonvulsant effects are probably
mediated through an opioid receptor-mediated increasein GABAergic tone. Gilhotra and Dhingra [
110
]
investigated the role of GABAergic and nitriergic modulation in the antianxiety effect of thymoquinone.
Thymoquinone (20 mg/kg) showed anxiolytic effects with a significant decrease in plasma nitrite and
the reversal of decreased brain GABA content in stressed mice [110].
Pine EO was reported to have anti-inflammatory, antimicrobial, analgesic, and anti-stress
effects [
75
,
111
,
112
]. The main components in the oil are
α
- and
β
-pinene, 3-carene, limonene, and
terpinene [
113
].
α
-Pinene [2,6,6,-trimethylbicyclo(3.1.1)-2-hept-2-ene] (Figure 3), a major monoterpene
of pine EOs, shows anxiolytic and hypnotic effects upon inhaled administration and a sleep enhancing
property through a direct binding to GABA
A
receptors by acting as a partial modulator of GABA
A
receptors [75].
Molecules 2018,23, 1061 16 of 24
Sideritis plants and their extracts have been used in traditional medicine as sedatives, anxiolytics,
and anticonvulsant agents. Kessler et al. [
114
] demonstrated that volatile aroma substances in sideritis
tea extracts have a powerful modulatory effect on synaptic
α1
/
β2
GABA
A
Rs (with or without
γ2
subunits) in a heterologous expression system. Pinenes are the most prevalent of the volatile aroma
components in Siderites extracts and the pinene metabolites myrtenol and verbenol (Figure 4) have
been identified as the most potent positive allosteric modulators of synaptic-type GABA
A
receptors
composed of
α1β2
and
α1β2γ2
subunits [
114
]. van Brederode et al. [
16
] examined the two terpenoids,
myrtenol, and verbenol and found augmented tonic GABA currents mediated by extrasynaptic GABA
A
receptors containing the
δ
subunit. It was reported that terpenoid substances potentiated the response
to GABA in HEK293 cells transfected with GABA
A
Rs composed of subunits that typically mediate
tonic GABA inhibition in the brain. Their results suggest that myrtenol and verbenol act as positive
allosteric modulators at synaptic and extrasynaptic GABA
A
receptors, thereby augmenting phasic and
tonic GABAergic inhibition [16].
3.2.2. Terpenes with Other Pharmacological Properties
β
-Citronellol is an alcoholic monoterpene found in EOs such as Cymbopogon citrates, a plant
with antihypertensive properties. Vasconcelos et al. [
76
] assessed its pharmacological effects on
the contractility of rat trachea.
β
-Citronellol exerted inhibitory effects on rat tracheal rings, with
predominant effects on contractions that increased Ca
2+
inflow towards the cytosol by voltage-gated
pathways [
76
].
β
-Citronellol antagonized transmembrane Ca
2+
influx from the extracellular milieu to
produce myorelaxant actions [76].
3.2.3. Non-Terpene Constituents with Anticonvulsant, Anxiolytic Properties, and Their
Underlying Mechanisms
Alpha(
α
)-asarone (Figure 5), a major effective component isolated from the Chinese medicinal
herb Acorus tatarinowii, is clinically used as a medication for treating epilepsy, cough, bronchitis, and
asthma. Huang et al. [
54
] evaluated the action of
α
-asarone on the excitability of rat hippocampal
neurons in culture and on the epileptic activity induced by pentylenetetrazole or kainite injection
in vivo
. They found that
α
-asarone inhibits the activity of hippocampal neurons and produces an
antiepileptic effect in the central nervous system through enhancing tonic GABAergic inhibition [
54
].
Using whole-cell patch-clamp recording,
α
-asarone was reported to inhibit the spontaneous firing of
output neurons, mitral cells, in a mouse olfactory bulb brain slice preparation [4].
Molecules 2018, 23, x 16 of 23
3.2.2. Terpenes with Other Pharmacological Properties
β-Citronellol is an alcoholic monoterpene found in EOs such as Cymbopogon citrates, a plant with
antihypertensive properties. Vasconcelos et al. [76] assessed its pharmacological effects on the
contractility of rat trachea. β-Citronellol exerted inhibitory effects on rat tracheal rings, with
predominant effects on contractions that increased Ca
2+
inflow towards the cytosol by voltage-gated
pathways [76]. β-Citronellol antagonized transmembrane Ca
2+
influx from the extracellular milieu to
produce myorelaxant actions [76].
3.2.3. Non-Terpene Constituents with Anticonvulsant, Anxiolytic Properties, and Their Underlying
Mechanisms
Alpha(α)-asarone (Figure 5), a major effective component isolated from the Chinese medicinal
herb Acorus tatarinowii, is clinically used as a medication for treating epilepsy, cough, bronchitis, and
asthma. Huang et al. [54] evaluated the action of α-asarone on the excitability of rat hippocampal
neurons in culture and on the epileptic activity induced by pentylenetetrazole or kainite injection in
vivo. They found that α-asarone inhibits the activity of hippocampal neurons and produces an
antiepileptic effect in the central nervous system through enhancing tonic GABAergic inhibition
[54]. Using whole-cell patch-clamp recording, α-asarone was reported to inhibit the spontaneous
firing of output neurons, mitral cells, in a mouse olfactory bulb brain slice preparation [4].
It was reported that α-asarone alleviates epilepsy by modulating GABA
A
receptors and
inhibiting neuronal Na
+
channels [4,54]. While many other compounds like borneol were reported to
act as positive allosteric GABA
A
receptor agonists to exert anxiolytic-like effects [14,16,102], recent
studies demonstrated that α-asarone acted as both a positive allesteric GABA
A
receptor agonist as
well as a neuronal Na
+
channel blocker [4,5].
The compound 1-Nitro-2-phenylethane (Figure 5) is the first nitro compound isolated from
plants and is thought to be responsible for the plant’s cinnamon scent [67]. It is the main constituent
of the EO of Aniba canelilla [67]. The mechanisms underlying the vasorelaxant effects of the EO of
Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) were investigated in
the isolated superior mesenteric artery from spontaneously hypertensive rats (SHRs) [68]. Both
EOAC and NP relaxed the contraction evoked by phorbol dibutyrate. Thus, it appears that NP is
the active principal component of EOAC [67,68]. The vasorelaxation appears to be mediated
through the inhibition of contractile events that are independent of Ca
2+
influx from the
extracellular milieu [67].
Figure 5. The non-terpene constituents with anticonvulsant and anxiolytic activities.
The EO of Dennettia tripetala G. Baker (Annonaceae) demonstrated significant analgesic,
anti-inflammatory, hypothermic, sedative, muscle relaxant, and central nervous system depressant
Figure 5. The non-terpene constituents with anticonvulsant and anxiolytic activities.
Molecules 2018,23, 1061 17 of 24
It was reported that
α
-asarone alleviates epilepsy by modulating GABA
A
receptors and inhibiting
neuronal Na
+
channels [
4
,
54
]. While many other compounds like borneol were reported to act as
positive allosteric GABA
A
receptor agonists to exert anxiolytic-like effects [
14
,
16
,
102
], recent studies
demonstrated that
α
-asarone acted as both a positive allesteric GABA
A
receptor agonist as well as a
neuronal Na+channel blocker [4,5].
The compound 1-Nitro-2-phenylethane (Figure 5) is the first nitro compound isolated from plants
and is thought to be responsible for the plant’s cinnamon scent [
67
]. It is the main constituent of the EO
of Aniba canelilla [
67
]. The mechanisms underlying the vasorelaxant effects of the EO of
Aniba canelilla
(EOAC) and its main constituent 1-nitro-2-phenylethane (NP) were investigated in the isolated superior
mesenteric artery from spontaneously hypertensive rats (SHRs) [
68
]. Both EOAC and NP relaxed the
contraction evoked by phorbol dibutyrate. Thus, it appears that NP is the active principal component
of EOAC [
67
,
68
]. The vasorelaxation appears to be mediated through the inhibition of contractile
events that are independent of Ca2+ influx from the extracellular milieu [67].
The EO of Dennettia tripetala G. Baker (Annonaceae) demonstrated significant analgesic,
anti-inflammatory, hypothermic, sedative, muscle relaxant, and central nervous system depressant
activities [
115
]. The EO of D. tripetala contains several compounds including 1-nitro-2-phenylethane
(80%),
β
-eudesmol andnerolidol (4%), 1-linalool (11%),
β
-caryophyllene, and
β
-humuline. The
compound 1-Nitro-2-phenylethane obtained from the oil of D. tripetala exhibited dose-dependent
hypnotic, anticonvulsant and anxiolytic effects, and is the compound largely responsible for the
neuropharmacological effects of the oil [66].
3.3. Terpenes with Convulsive Activities Acting as GABAAReceptor Antagonists
Most components of EOs act as GABA receptor agonists. Only a few compounds from EOs have
been demonstrated to be GABA
A
receptor antagonists. Thujone (Figure 6), a cyclic monoterpenic
ketone, is an active ingredient of wormwood oil and some other herbal medicines [
91
,
116
]. It is known
that thujone is specifically a GABA
A
receptor antagonist and, by inhibiting GABA receptor activation,
may make neurons fire more easily, causing muscle spasms and convulsions [
116
,
117
]. Dihydrocarvone
(Figure 6) is present in oils of the caraway plant and is used for its fragrance as flavoring and for
medicinal purposes. Dihydrocarvone was recently found to act as a negative allosteric modulator of
this receptor [91].
Molecules 2018, 23, x 17 of 23
activities [115]. The EO of D. tripetala contains several compounds including 1-nitro-2-phenylethane
(80%), β-eudesmol andnerolidol (4%), 1-linalool (11%), β-caryophyllene, and β-humuline. The
compound 1-Nitro-2-phenylethane obtained from the oil of D. tripetala exhibited dose-dependent
hypnotic, anticonvulsant and anxiolytic effects, and is the compound largely responsible for the
neuropharmacological effects of the oil [66].
3.3. Terpenes with Convulsive Activities Acting as GABA
A
Receptor Antagonists
Most components of EOs act as GABA receptor agonists. Only a few compounds from EOs have
been demonstrated to be GABA
A
receptor antagonists. Thujone (Figure 6), a cyclic monoterpenic
ketone, is an active ingredient of wormwood oil and some other herbal medicines [91,116]. It is
known that thujone is specifically a GABA
A
receptor antagonist and, by inhibiting GABA receptor
activation, may make neurons fire more easily, causing muscle spasms and convulsions [116,117].
Dihydrocarvone (Figure 6) is present in oils of the caraway plant and is used for its fragrance as
flavoring and for medicinal purposes. Dihydrocarvone was recently found to act as a negative
allosteric modulator of this receptor [91].
Figure 6. The terpenes acting on GABA
A
receptors as antagonists.
4. Conclusions
Based on the findings discussed above, it is clear that natural EOs demonstrate many
neuro-pharmacological properties, such as anti-nociceptive, anti-inflammatory, anxiolytic,
anti-depressive, and sedative properties. An increasing number of studies show that two inhibitory
systems, the GABAergic system and the neuronal voltage-gated Na
+
channels, are most likely
involved in such pharmacological effects. EOs are emerging as a promising source for modulation
of the GABAergic system and Na
+
channels. The neuro-pharmacological activities and the
underlying mechanisms of many constituents obtained from EOs have been reviewed. Most of the
above-mentioned constituents are reported to have either anti-nociceptive or anxiolytic effects
through activating the GABAergic system and by inhibiting neuronal Na
+
channels. Only a few
constituents have been reported to antagonize GABA receptors. The perspective compounds
targeting the GABAergic system and/or voltage-gated Na
+
channels could serve as better candidates
or pharmacophores during new drug development to control pain and anxiety syndromes.
Author Contributions: Z.-J.W. and T.H. wrote and reviewed the paper.
Acknowledgments: This work was supported by grants from Latham Trust Fund, NIH (MD007597) and NSF
(IOS-1355034) to TH.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Lee, Y.L.; Wu, Y.; Tsang, H.W.; Leung, A.Y.; Cheung, W.M. A systematic review on the anxiolytic effects
of aromatherapy in people with anxiety symptoms. J. Altern. Complement. Med. 2011, 17, 101–108.
Figure 6. The terpenes acting on GABAAreceptors as antagonists.
4. Conclusions
Based on the findings discussed above, it is clear that natural EOs demonstrate
many neuro-pharmacological properties, such as anti-nociceptive, anti-inflammatory, anxiolytic,
anti-depressive, and sedative properties. An increasing number of studies show that two inhibitory
systems, the GABAergic system and the neuronal voltage-gated Na
+
channels, are most likely
involved in such pharmacological effects. EOs are emerging as a promising source for modulation
of the GABAergic system and Na
+
channels. The neuro-pharmacological activities and the
Molecules 2018,23, 1061 18 of 24
underlying mechanisms of many constituents obtained from EOs have been reviewed. Most of
the above-mentioned constituents are reported to have either anti-nociceptive or anxiolytic effects
through activating the GABAergic system and by inhibiting neuronal Na
+
channels. Only a few
constituents have been reported to antagonize GABA receptors. The perspective compounds targeting
the GABAergic system and/or voltage-gated Na
+
channels could serve as better candidates or
pharmacophores during new drug development to control pain and anxiety syndromes.
Author Contributions: Z.-J.W. and T.H. wrote and reviewed the paper.
Acknowledgments:
This work was supported by grants from Latham Trust Fund, NIH (MD007597) and NSF
(IOS-1355034) to TH.
Conflicts of Interest: The authors declare no conflict of interest.
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