Lamiaceae in Mexican Species, a Great but Scarcely Explored Source of Secondary Metabolites with Potential Pharmacological Effects in Pain Relief

Abstract

The search for molecules that contribute to the relief of pain is a field of research in constant development. Lamiaceae is one of the most recognized families world-wide for its use in traditional medicine to treat diseases that include pain and inflammation. Mexico can be considered one of the most important centers of diversification, and due to the high endemism of this family, it is crucial for the in situ conservation of this family. Information about the most common genera and species found in this country and their uses in folk medicine are scarcely reported in the literature. After an extensive inspection in bibliographic databases, mainly Sciencedirect, Pubmed and Springer, almost 1200 articles describing aspects of Lamiaceae were found; however, 217 articles were selected because they recognize the Mexican genera and species with antinociceptive and/or anti-inflammatory potential to relieve pain, such as Salvia and Agastache. The bioactive constituents of these genera were mainly terpenes (volatile and non-volatile) and phenolic compounds such as flavonoids (glycosides and aglycone). The aim of this review is to analyze important aspects of Mexican genera of Lamiaceae, scarcely explored as a potential source of secondary metabolites responsible for the analgesic and anti-inflammatory properties of these species. In addition, we point out the possible mechanisms of action involved and the modulatory pathways investigated in different experimental models. As a result of this review, it is important to mention that scarce information has been reported regarding species of this family from Mexican genera. In fact, despite Calosphace being one of the largest subgenera of Salvia in the world, found mainly in Mexico, it has been barely investigated regarding its potential biological activities and recognized bioactive constituents. The scientific evidence regarding the different bioactive constituents found in species of Lamiaceae demonstrates that several species require further investigation in preclinical studies, and of course also in controlled clinical trials evaluating the efficacy and safety of these natural products to support their therapeutic potential in pain relief and/or inflammation, among other health conditions. Since Mexico is one of the most important centers of diversification, and due to the high endemism of species of this family, it is crucial their rescue, in situ conservation, and investigation of their health benefits.

Full text

molecules
Review
Lamiaceae in Mexican Species, a Great but Scarcely Explored
Source of Secondary Metabolites with Potential
Pharmacological Effects in Pain Relief
Alberto Hernandez-Leon 1, † , Gabriel Fernando Moreno-Pérez 1, 2, †, Martha Martínez-Gordillo 3,
Eva Aguirre-Hernández 4, María Guadalupe Valle-Dorado 5, María Irene Díaz-Reval 6,
María Eva González-Trujano 1, * and Francisco Pellicer 1


Citation: Hernandez-Leon, A.;
Moreno-Pérez, G.F.;
Martínez-Gordillo, M.;
Aguirre-Hernández, E.; Valle-Dorado,
M.G.; Díaz-Reval, M.I.;
González-Trujano, M.E.; Pellicer, F.
Lamiaceae in Mexican Species, a
Great but Scarcely Explored Source of
Secondary Metabolites with Potential
Pharmacological Effects in Pain Relief.
Molecules 2021,26, 7632. https://
doi.org/10.3390/molecules26247632
Academic Editors: Natalizia Miceli
and Raffaele Capasso
Received: 20 November 2021
Accepted: 9 December 2021
Published: 16 December 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
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iations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1Laboratorio de Neurofarmacología de Productos Naturales, Dirección de Investigaciones en Neurociencias,
Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México 14370, Mexico;
albertoh-leon@imp.edu.mx (A.H.-L.); mmspoodles@gmail.com (G.F.M.-P.); pellicer@imp.edu.mx (F.P.)
2Programa de Posgrado en Ciencias Biológicas, Facultad de Medicina, Universidad Autónoma de México,
Ciudad Universitaria, Ciudad de México 04510, Mexico
3Herbario de la Facultad de Ciencias, Departamento de Biología Comparada, Facultad de Ciencias,
Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México 04510, Mexico;
mjmg@ciencias.unam.mx
4
Laboratorio de Productos Naturales, Departamento de Ecología y Recursos Naturales, Facultad de Ciencias,
Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México 04510, Mexico;
eva_aguirre@ciencias.unam.mx
5
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad
Universitaria, Ciudad de México 04510, Mexico; lvalle_59@hotmail.com
6Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima 28045, Mexico;
idiazre@ucol.mx
*Correspondence: evag@imp.edu.mx; Tel.: +5255-4160-5084
† These authors contributed equally to this work.
Abstract:
The search for molecules that contribute to the relief of pain is a field of research in constant
development. Lamiaceae is one of the most recognized families world-wide for its use in traditional
medicine to treat diseases that include pain and inflammation. Mexico can be considered one of the
most important centers of diversification, and due to the high endemism of this family, it is crucial
for the in situ conservation of this family. Information about the most common genera and species
found in this country and their uses in folk medicine are scarcely reported in the literature. After an
extensive inspection in bibliographic databases, mainly Sciencedirect, Pubmed and Springer, almost
1200 articles describing aspects of Lamiaceae were found; however, 217 articles were selected because
they recognize the Mexican genera and species with antinociceptive and/or anti-inflammatory
potential to relieve pain, such as Salvia and Agastache. The bioactive constituents of these genera were
mainly terpenes (volatile and non-volatile) and phenolic compounds such as flavonoids (glycosides
and aglycone). The aim of this review is to analyze important aspects of Mexican genera of Lamiaceae,
scarcely explored as a potential source of secondary metabolites responsible for the analgesic and
anti-inflammatory properties of these species. In addition, we point out the possible mechanisms
of action involved and the modulatory pathways investigated in different experimental models.
As a result of this review, it is important to mention that scarce information has been reported
regarding species of this family from Mexican genera. In fact, despite Calosphace being one of the
largest subgenera of Salvia in the world, found mainly in Mexico, it has been barely investigated
regarding its potential biological activities and recognized bioactive constituents. The scientific
evidence regarding the different bioactive constituents found in species of Lamiaceae demonstrates
that several species require further investigation in preclinical studies, and of course also in controlled
clinical trials evaluating the efficacy and safety of these natural products to support their therapeutic
potential in pain relief and/or inflammation, among other health conditions. Since Mexico is one of
the most important centers of diversification, and due to the high endemism of species of this family,
it is crucial their rescue, in situ conservation, and investigation of their health benefits.
Molecules 2021,26, 7632. https://doi.org/10.3390/molecules26247632 https://www.mdpi.com/journal/molecules

Molecules 2021,26, 7632 2 of 27
Keywords: Lamiaceae; Salvia;Agastache; pain; nociception; inflammation
1. Introduction
The term Labiatae comes from the Latin word “labia”, which means “lip”, and refers
to the peculiar morphological characteristic of all the species that belong to this family,
which have the corolla split into an upper lip and a lower one. This term precedes the
name Lamiaceae, which comes from the Greek “laimos” referring to the “gaping mounth”
of the corolla [
1
]. The Lamiaceae family belongs to the order Lamiales, in the clade Lamids,
in the Eudicots [
2
]. It is the sixth largest family of angiosperms comprising 12 subfamilies,
16 tribes, 9 subtribes, 236 genera, and over 7173 species [
1
,
3
]. A wide range of substances
isolated from plants belonging to this family produce antibacterial, cytotoxic, antioxidant,
anti-inflammatory and insecticidal activities [
4
]. Various studies report that the members of
this family are a source of phytochemical compounds with health benefits or play an active
role in the improvement of diseases, mainly due to the content and type of compounds, the
main ones being essential oils, terpenoids, phenolic acids and flavonoids [
5
,
6
], many of
which can be used to relieve pain.
It is well documented that healing with medicinal plants is as old as humanity itself,
perhaps mainly due to pain. Hippocrates (5th century BC) was the first Greek writer
to use the word analgesia in a medical rather than a philosophical context, as well as
derivative words related to pain when using plants to relieve it. Dioscorides (1st century
BC) was a Greek philosopher who explored the therapeutic properties of plants, including
those used for pain relief, describing the narcotic effects of the plant mandragora. As a
military physician and pharmacognosist, Dioscorides differentiated among a few species
from the genus Mentha (Lamiaceae), which were grown and used to relieve headache and
stomachache. Hey used expressive and precise adjectives and well-defined characteristics
of pain, such as location, duration, or relation to other symptoms, to elucidate a disease
process [7].
Nowadays, according to the International Association for the Study of Pain, “pain”
has been defined as an unpleasant sensory and emotional experience associated with, or
resembling experiences associated with, actual or potential tissue damage [
8
]. It can be
classified as functional (nociceptive or inflammatory) [
9
] or dysfunctional (neurogenic,
neuropathic and psychogenic) because of its origin or etiology [
10
], or as acute or chronic
because of its temporality [
9
]. In acute pain, nociceptors are activated in the site of tissue
damage, while chronic pain is commonly triggered by injury or an illness, and it can be
perpetuated by factors other than the cause of pain [
10
]. Acute pain associated with tissue
damage can last for less than 1 month, but sometimes it can last for more than 6 months,
at which point it becomes chronic pain. Preclinical studies have shown that neuronal
expression of new genes (the basis for neuronal sensitization and remodeling) occur within
20 min of injury. Chronic pain can cause long-term behavior and histological changes within
approximately one day after interventions, such as transient nerve ligation [
8
]. Among the
characteristics that commonly occur in patients with chronic and dysfunctional pain are
hyperalgesia (exacerbated sensitivity to painful stimuli), allodynia (painful response to
harmless stimuli) and hyperesthesia (abnormal sensitivity to sensory stimuli) [11].
Nociception is not the same as the term pain, it is the mechanism through which
harmful stimuli are transmitted to the central nervous system (CNS). This term is used in
the preclinical evaluation of the plants or bioactive constituents. Nociceptors are neurons
sensitive to noxious stimuli and are in the skin, blood vessels, muscles, fascia, joints and
viscera. They are predominantly myelinated (A-
δ
) or unmyelinated (c) fibers, activated
by noxious stimuli (mechanical, thermal, cold and chemical), which carry these signals
to the CNS [
12
–
14
]. All tissues, with the exception of the CNS neuropil, are innervated
by afferent fibers, although their properties differ markedly, depending on whether they

Molecules 2021,26, 7632 3 of 27
are somatic (skin, joints, muscles) or visceral fibers (cardiovascular or respiratory tissue,
gastrointestinal or renal tract), and reproductive systems [15].
Pathophysiological mediators of pain and inflammation are generated by several
important sources. These mediators can act through a multiplicity of receptors that are
widely distributed in central and peripheral nerves and coupled to heterotrimeric G pro-
teins, as occurs in opioids and 5-HT
1A
inhibitory receptors associated with multiple second
messengers formation (cAMP, cGMP, DAG, IP3, intracellular Ca
+2
, NO) and protein kinases
(A, C or G) to promote the phosphorylation of multiple targets [
10
]. Other pharmacological
receptors involve activity through ion channels, e.g., excitatory amino acids or acetylcholine
(which activates the nicotinic receptor), to control the ionic permeability of the membrane
and muscle contraction [15,16].
In the case of inflammation, it involves an integration of several inflammatory media-
tors, such as prostaglandin E2, bradykinin, substance P, histamine, adenosine and serotonin,
sensitizing nociceptors after mechanical and thermal stimuli. It is commonly reported that
mediators in an inflammatory condition are cytokines. In this respect, Toll-like receptors
(TLRs) activate proinflammatory cytokine profiles in macrophages, altering the homeostatic
regulation of the immune system. Macrophages are essential components of the innate and
adaptive immune systems, and therefore play a central role in inflammation, host defense,
and tissue repair [
17
,
18
]. Depending on the microenvironment, these cells are functionally
classified into two main types: classically activated proinflammatory M1 macrophages and
alternately activated M2 macrophages. M1 macrophages are induced by Th1 cytokines
such as interferon
γ
(IFN
γ
) and tumor necrosis factor
α
(TNF-
α
) or by lipopolysaccha-
ride (LPS) and typically attack microorganisms and tumor cells, and express inducible
nitric oxide synthase (iNOS) and most of the TLRs [
18
]. In contrast, M2 macrophages
are induced by Th2 cytokines such as interleukins (ILs)-4, -13, and -10 and transforming
growth factor
β
(TGF-
β
). Könner and Brüning [
19
] demonstrated that TLR2 and TLR4 are
closely related to the systemic inflammatory response. TLRs (of which there are 10 types in
humans and 12 in mice), contain adapter proteins, the recruitment of which is followed
by a signaling pathway that activates nuclear factor kappa B (NF-kB), activator protein 1
(AP-1), signal transducer and activator of transcription 1 (STAT-1) and interferon regulatory
factor (IRF), which mediate inflammation as well as cytokines release [
20
,
21
]. NF-kB is an
important nuclear transcription factor in the regulation of the inflammatory response. It
participates in biological processes that involve inflammation, immunity, differentiation,
cell growth, tumorigenesis and apoptosis [
22
]. NF-kB is regulated by binding to inhibitory
molecules such as the nuclear factor of kappa light polypeptide gene enhancer in B-cells
inhibitor, alpha (IkB
α
). The NF-kB p65 subunits dissociate from their inhibitory protein
IkB
α
by translocating from the cytoplasm to the nucleus where they influence the expres-
sion of proinflammatory cytokines such as TNF-
α
, IL-1
β
, IL-6 and IL-8 [
23
]. Therefore,
the prevention of nuclear translocation of NF-kB may work as a potential therapeutic
target. The transcription factor Nrf2 is largely responsible for the inducible expression of
proteins involved in the response to oxidative stress, cell protection and the inhibition of
the expression of inflammatory cytokines, such as IL-6 and IL-1
β
. Furthermore, Nrf2 is
associated with the NF-kB-mediated transcription of proinflammatory cytokines genes [
24
].
The signaling pathway of mitogen-activated protein kinases (MAPKs) consists of a fam-
ily of serine/threonine kinases that are activated by several stimuli, including different
inflammatory factors [
25
]. MAPK proteins control fundamental cellular processes, such as
proliferation, differentiation, metabolism, inflammation and apoptosis. As MAPK and NF-
kB can synergistically collaborate to induce proinflammatory cytokines [
25
,
26
], secondary
metabolites of phytopharmaceuticals with inhibitory capacity of NF-kB and MAPK may
have potential therapeutic advantages in the treatment of inflammatory diseases. It has
been demonstrated that many plant constituents can interact with one or more than one of
those previously mentioned biological targets, which are involved in producing, enhancing
or relieving pain alone, or are associated with inflammation because of tissular damage.

Molecules 2021,26, 7632 4 of 27
Several aspects of Lamiaceae are addressed in this review, emphasizing that Mexican
genera have not been explored enough as source of medicinal species. We provide evidence
of the minimal number of species explored to investigate potential secondary metabolites
responsible for their antinociceptive and anti-inflammatory properties and point out the
mechanisms of action involved and modulatory pathways by using different experimental
models. The integration of relevant information on some species belonging to Mexican
genera of Lamiaceae and substances derived from these and other investigated plants
reinforces the evidence already reported regarding various species from different regions
around the world on their medicinal properties as promising alternatives for potential
analgesics and anti-inflammatory drugs.
2. Results
2.1. Lamiaceae Description
The species belonging to this family are generally characterized by being annual
or perennial herbaceous plants or shrubs, sub-shrubs and less commonly trees or vines;
occasionally with stolons or rhizomes; often with aromatic oils; stems being erect or
prostrate, generally tetragonal, due to the presence of large bundles of collenchyma, with
no spines [
27
], and with or without a glandular trichome indument. Opposite leaves,
generally decussate, sometimes whorled, simple or less frequently compound (Vitex),
dentate or crenate; the petiole being present or absent; and stipules being absent [28].
Terminal or axillary inflorescences, thyrsoids, are usually found with cymes or whorls
arranged in spikes, racemes, panicles or a capitulum, and bracts are usually present, being
persistent or deciduous. The flowers are usually bisexual, hypogynous, zygomorphic, and
rarely actinomorphic; have a persistent, gamosepalous, tubular to widely campanulate
calyx; have four to five (to nine) lobes, which are imbricated; have a gamopetalous corolla,
generally with five lobes, equal or sub-equal, frequently bilabiate, and in that case the
upper lip bilobed and the lower lip are trilobed, with imbricated lobes, and a short or long
tube; have four stamens, which are didynamous, rarely equal, sometimes reduced to two
and sometimes with staminodia present, and epipetalous; generally have free filaments;
have anthers longitudinally dehiscent; have a hypogynous disc, which usually fleshy, and
sometimes divided into four glands; have a bicarpellary gynoecium, which is usually
tetralocular due to a false septum, upper ovary, one style, which is gynobasic, and less
frequently terminal, and a filiform, usually with two stigmatic lobes, equal or unequal;
have four ovules, one per locule, erect, and the fruit is tetralobed and, indehiscent, usually
with four nuts, which are dry, smooth or slightly tuberculated or reticulated-rough. The
seeds are usually number four [
3
,
27
,
28
]. Photographs providing examples of species of
Lamiaceae from Mexican Salvias (Calosphace subgenus) are shown in Figure 1.
2.2. Geographical Distribution
In various regions worldwide, members of the Lamiaceae can be found. This family
contains 236 genera and approximately 7173 species, growing in areas with tropical and
temperate climates from 0 to 2500 m above sea level [
3
]. Several species are found to be
abundant in mountainous areas, with a temperate climate, although it is possible to find
the Hyptis and Asterohyptis genera in dry and hot areas [
28
,
29
]. There are six regions of
high diversity in the world [
27
,
30
]: the Mediterranean and Central Asia [
31
], Africa and
Madagascar [
32
], China [
33
], Australia, South America [
34
] and North America (including
Mexico) [28,35] (See Figure 2A).
In Mexico, Lamiaceae is the family with the eighth greatest diversity and the number
of species of this family in Mexico represents 5.5% of the species belonging to this family
worldwide. For that reason, Mexico can be considered one of the most important centers
of diversification, and due to the high endemism of this family, it is crucial for the in situ
conservation of this family [35] (Figure 2B).

Molecules 2021,26, 7632 5 of 27
Molecules 2021, 26, x FOR PEER REVIEW 5 of 29
Figure 1. Photographs of examples of Lamiaceae from Mexican Salvias (Calosphace subgenus). (A): S. circinnata Cav., (B):
S. calderoniae Bedolla & Zamudio, (C): S. concolor Lamb. ex Benth., (D): S. divinorum Epling & Játiva, (E): S. involucrate Cav.,
(F): S. leucantha Cav., (G): S. karwinskii Benth., (H): S. mexicana L. (I): S. microphylla Kunth, (J): S. oaxacana Fernald, (K): S.
pubescens Benth., (L): S. semiartrata, (M): S. tilantongensis J.G. González & Aguilar-Sant. and (N): S. wagneriana Zucc.
Figure 1.
Photographs of examples of Lamiaceae from Mexican Salvias (Calosphace subgenus). (
A
): S. circinnata Cav.,
(
B
): S. calderoniae Bedolla & Zamudio, (
C
): S. concolor Lamb. ex Benth., (
D
): S. divinorum Epling & Játiva, (
E
): S. involucrate
Cav., (
F
): S. leucantha Cav., (
G
): S. karwinskii Benth., (
H
): S. mexicana L. (
I
): S. microphylla Kunth, (
J
): S. oaxacana Fernald,
(K): S. pubescens Benth., (L): S. semiartrata, (M): S. tilantongensis J.G. González & Aguilar-Sant. and (N): S.wagneriana Zucc.

Molecules 2021,26, 7632 6 of 27
Molecules 2021, 26, x FOR PEER REVIEW 6 of 29
2.2. Geographical Distribution
In various regions worldwide, members of the Lamiaceae can be found. This family
contains 236 genera and approximately 7173 species, growing in areas with tropical and
temperate climates from 0 to 2500 m above sea level [3]. Several species are found to be
abundant in mountainous areas, with a temperate climate, although it is possible to find
the Hyptis and Asterohyptis genera in dry and hot areas [28,29]. There are six regions of
high diversity in the world [27,30]: the Mediterranean and Central Asia [31], Africa and
Madagascar [32], China [33], Australia, South America [34] and North America (including
Mexico) [28,35] (See Figure 2A).
Figure 2. (A) Worldwide distribution of plants of the Lamiaceae family [1] and (B) in Mexico (Modified from Martínez-
Gordillo et al. [28]).
In Mexico, Lamiaceae is the family with the eighth greatest diversity and the number
of species of this family in Mexico represents 5.5% of the species belonging to this family
worldwide. For that reason, Mexico can be considered one of the most important centers
of diversification, and due to the high endemism of this family, it is crucial for the in situ
conservation of this family [35] (Figure 2B).
2.3. Lamiaceae and Some of Its Genera in Mexico
Lamiaceae is one of the most diverse families in Mexico, after only Asteraceae, Faba-
ceae, Poaceae, Orchidaceae, Cactaceae, Euphorbiaceae, and Rubiaceae, representing
13.55% of the genera and 8.23% of the world’s species, with an endemism of 66.2% [35].
Mexico has 31 genera and 598 species. The most diverse genus is Salvia, with 306 species,
where the subgenus Calosphace is one of the most diverse, with 295 species from the 580
included in the group [36]. Oaxaca is the state with the greatest diversity, while Jalisco
houses the largest number of endemic species. Even though no genus of the family is en-
demic in the country, plants of the Cunila or Hedeoma genera have an endemism of up to
60% [35].
According to Harley et al. [3], from the 236 genera of Lamiaceae, 226 were assigned
to seven subfamilies: Ajugoideae, Lamioideae, Nepetoideae, Prostantheroideae, Scutellarioideae,
Symphorematoideae, and Viticoideae. Cymarioideae, Peronematoideae, and Premnoideae were
added later [37]. From these, six are found in Mexico. Finally, Callicarpa and Tectona were
transferred from the Verbenaceae family being recognized as independent subfamilies
latterly [31] (See Figure 3).
Figure 2.
(
A
) Worldwide distribution of plants of the Lamiaceae family [
1
] and (
B
) in Mexico (Modified from Martínez-
Gordillo et al. [28]).
2.3. Lamiaceae and Some of Its Genera in Mexico
Lamiaceae is one of the most diverse families in Mexico, after only Asteraceae,
Fabaceae, Poaceae, Orchidaceae, Cactaceae, Euphorbiaceae, and Rubiaceae, represent-
ing 13.55% of the genera and 8.23% of the world’s species, with an endemism of 66.2% [
35
].
Mexico has 31 genera and 598 species. The most diverse genus is Salvia, with 306 species,
where the subgenus Calosphace is one of the most diverse, with 295 species from the 580
included in the group [
36
]. Oaxaca is the state with the greatest diversity, while Jalisco
houses the largest number of endemic species. Even though no genus of the family is
endemic in the country, plants of the Cunila or Hedeoma genera have an endemism of up to
60% [35].
According to Harley et al. [
3
], from the 236 genera of Lamiaceae, 226 were assigned
to seven subfamilies: Ajugoideae,Lamioideae,Nepetoideae,Prostantheroideae,Scutellarioideae,
Symphorematoideae, and Viticoideae.Cymarioideae,Peronematoideae, and Premnoideae were
added later [
37
]. From these, six are found in Mexico. Finally, Callicarpa and Tectona
were transferred from the Verbenaceae family being recognized as independent subfamilies
latterly [31] (See Figure 3).
2.4. Pain and Some of Mexican Lamiaceae Genera to Alleviate It
Currently, a wide variety of herbs are found in the markets of several cities around
the world [
38
], where the Lamiaceae family contains species of economic value because
of its culinary or flavoring and medicinal properties. Species from this family have been
widely used since ancient times, as spices and herbal teas in traditional medicine. Ve-
longiarious members of this family are specifically used as a source of essential oils [
27
].
In fact, a variety of healing properties is attributed to each plant from Lamiaceae [
29
].
Several of them are repeatedly recommended to treat the same disease, suggesting that
similar constituents are included in them [
39
] (Table 1). Despite this, reports describing
pharmacological evidence on the antinociceptive and anti-inflammatory effects, bioac-
tive compounds isolated and mechanism of action from Mexican Lamiaceae species are
scarce in the literature. Most of the investigations have evaluated polar extracts from
nature exploring the following genera: Hyptis,Lavandula,Leonurus,Melissa,Marrubium,
Mentha,Ocimum,Origanum,Sage,Satureja,Stachys,Scutellaria,Sideritis, and Teucrium [
40
].
Antinociceptive and anti-inflammatory effects were observed in polar extracts of Marru-
bium evaluated in formalin and carrageenan tests [
41
,
42
]. The analgesic-like response of
the ethanol and hydroalcoholic extracts of Hyptis were evaluated in the writhing, formalin,

Molecules 2021,26, 7632 7 of 27
tail immersion, carrageenan and hyperalgesia induced by glutamate or capsaicin tests in
mice [
43
,
44
]. In a similar manner, the hydroalcoholic and aqueous extracts of species from
Teucrium [
45
–
47
] or Scutellaria [
48
] have shown these activities. Analysis of hydroalcoholic
extracts of species from the Stachys genus was carried out in mice using formalin, acetic
acid-induced writhing, and light tail-flick tests [
39
], and that of Leonurus cardiaca L. was
performed by using formalin, tail-flick, and hot-plate tests in mice [49].
Molecules 2021, 26, x FOR PEER REVIEW 7 of 29
Figure 3. Cladogram of Lamiaceae showing the monophyletic clades, where the different subfami-
lies are recognized. Subfamilies recognized by Olmstead: Ajugoideae, Lamioideae, Nepetoideae, Pros-
tantheroideae, Scutellarioideae, Symphorematoideae, Tectonoideae, Callicarpoideae and Viticoideae (Modi-
fied from Li et al. [37]).
2.4. Pain and Some of Mexican Lamiaceae Genera to Alleviate It
Currently, a wide variety of herbs are found in the markets of several cities around
the world [38], where the Lamiaceae family contains species of economic value because of
its culinary or flavoring and medicinal properties. Species from this family have been
widely used since ancient times, as spices and herbal teas in traditional medicine.
Velongiarious members of this family are specifically used as a source of essential oils
[27]. In fact, a variety of healing properties is attributed to each plant from Lamiaceae [29].
Several of them are repeatedly recommended to treat the same disease, suggesting that
similar constituents are included in them [39] (Table 1). Despite this, reports describing
pharmacological evidence on the antinociceptive and anti-inflammatory effects, bioactive
compounds isolated and mechanism of action from Mexican Lamiaceae species are scarce
in the literature. Most of the investigations have evaluated polar extracts from nature
exploring the following genera: Hyptis, Lavandula, Leonurus, Melissa, Marrubium, Mentha,
Ocimum, Origanum, Sage, Satureja, Stachys, Scutellaria, Sideritis, and Teucrium [40].
Antinociceptive and anti-inflammatory effects were observed in polar extracts of
Marrubium evaluated in formalin and carrageenan tests [41,42]. The analgesic-like
response of the ethanol and hydroalcoholic extracts of Hyptis were evaluated in the
writhing, formalin, tail immersion, carrageenan and hyperalgesia induced by glutamate
or capsaicin tests in mice [43,44]. In a similar manner, the hydroalcoholic and aqueous
extracts of species from Teucrium [45–47] or Scutellaria [48] have shown these activities.
Analysis of hydroalcoholic extracts of species from the Stachys genus was carried out in
mice using formalin, acetic acid-induced writhing, and light tail-flick tests [39], and that
of Leonurus cardiaca L. was performed by using formalin, tail-flick, and hot-plate tests in
mice [49].
Figure 3.
Cladogram of Lamiaceae showing the monophyletic clades, where the different subfamilies
are recognized. Subfamilies recognized by Olmstead: Ajugoideae,Lamioideae,Nepetoideae,Prostan-
theroideae,Scutellarioideae,Symphorematoideae,Tectonoideae,Callicarpoideae and Viticoideae (Modified
from Li et al. [37]).
Table 1. Lamiaceae species used in traditional medicine for pain, inflammation treatment and/or as antioxidants.
Scientific
Name
Medical Properties Used
Plant Organs Preparation
Analgesic Anti-
Inflammatory Antioxidant
Clinopodium vulgare L. [50] X Aerial parts
Hydroalcoholic extract
C. mexicanun (Benth.) Govaerts [51] X Leaves Organic extracts
Eremostachys laciniata (L.) Bunge. [52] X Aerial parts Hydrodistillation,
Methanol extract
Glechoma longituba Kupr. [53] X Aerial parts Infusion
Hedeoma drummondii Benth. [54] X Aerial parts Maceration
H. multiflorum Benth. [55] X Aerial parts Infusion
Holmskioldia sanguinea Retz. [56] X Leaves Methanol extract
Hyptis suaveolens (L.) Poit. [57] X Aerial parts
Hydroalcoholic extract
H. spicigera Lam. [58] X X Aerial parts Hydrodistillation
Lamium álbum L. [59] X X Aerial parts
Hydroalcoholic extract
Lavandula angustifolia Mill. [60,61] X X X Leaves,
aerial parts
Hydrodistillation,
Ethanol extract
Leonorus cardiaca L. [62] X Aerial parts
Hydroalcoholic extract
Leonotis leonorus L. [63] X X Aerial parts Organic extracts
Leucas aspera Link [64] X X Roots Maceration
Marrubium vulgare. L. [65] X Leaves,
aerial parts
Tincture,
Organic extracts
Mentha piperita L. [66] X X Leaves Hydrodistillation
M. suaveolens Ehrh. [67] X X X Aerial parts Methanol extract
Ocimum americanum L. [68] X Aerial parts Methanol extract

Molecules 2021,26, 7632 8 of 27
Table 1. Cont.
Scientific
Name
Medical Properties Used
Plant Organs Preparation
Analgesic Anti-
Inflammatory Antioxidant
O. basilicum L. [69] X X Aerial parts Hydrodistillation
Phlomis purpurea L. [70] X X Aerial parts Methanol extract
P. nissolii L. [71] X Leaves Decoction
Premna herbacea Roxb. [72] X X Roots Ethanol extract
P. integrifolia L. [73] X Roots Organic and aqueous
extracts
Prunella vulgaris L. [74] X X Inflorescence Ethanol extract
Rosmarinus officinalis L. [75,76] X X X Aerial parts,
leaves
Maceration,
Methanol extract
Salvia officinalis L. [77–79] X X X Aerial parts,
Leaves
Infusion, Decoction,
Hydroalcoholic extract
S. hispanica L. [80] X Aerial parts Organic extracts
Scutellaria indica L. [81] X Aerial parts Organic extracts
S. baicalensis Georgi. [82] X X Aerial parts,
Roots
Aqueous extract,
Organic extract
Sideritis bilgeriana P.H. Davis [83] X X X Aerial parts Maceration
S. congesta P.H. Davis & Hub.-Mor. [
84
]
X Aerial parts Maceration
Stachys byzantina C. Koch. [85] X X Aerial parts Organic extracts
S. inflata Benth. [86] X Aerial parts
Hydroalcoholic extract
Thymus serpyllum L. [87] X Aerial parts Hydrodistillation
T. vulgaris L. [88] X Leaves Hydrodistillation
Vitex agnus-castus L. [89] X Leaves Methanol extract
V. megapotamica Cham. [90] X X Leaves
Hydroalcoholic extract
The scientific names were confirmed in The Plant List. Available online: http://www.theplantlist.org/ (Accessed on 2 December 2021).
In this manuscript, there is a special interest in plants belonging to this family, since
they are widely and traditionally used in Mexican folk medicine for the relief of pain
and/or inflammation, as are some species of the genera Salvia and Agastache.
2.5. Salvia Species Used in Pain Relief
Salvia’s name comes from the Latin salvare, which means to save and heal. One of the
most ancient species of this genus is Salvia officinalis L. despite its Mediterranean origin,
it is also of great medicinal use in Mexico, and is commonly known as sage. It was used
by Egyptians, Greeks, and Romans to treat ulcerations. Nowadays, its anti-inflammatory
properties are useful for the treatment of buccal conditions such as amigdalitis, faringitis
and gingivitis, which might be because of the bioactive effect of components such as ursolic
acid [
91
]. Its anti-inflammatory and antioxidant properties are influenced by the cytokine’s
mediators considering its marked properties that inhibit the increase in IL-33 and TNF-
α
levels and the amplification of NF-kB expression and its activation [92].
Another species of Mediterranean origin with great medicinal utility to relieve pain
in Mexico is Rosmarinus officinalis L., a Lamiaceae species recently reclassified as Salvia
Rosmarinus Spenn. [
40
]. This species, cultivated in Mexico, possesses a broad spectrum
of antinociceptive activities already evidenced in several acute and chronic experimental
models, such as the writhing, formalin and gout arthritic-like pain tests, by preparing polar
and non-polar extracts [
93
,
94
]. The responsible bioactive compounds of this species are
flavonoids and triterpenoids, including hesperidin and ursolic, oleanolic, and micromeric
acids [
94
]. Their mechanisms of action involve calcium channels and central inhibitory
receptors or peripheral actions depending on the kind of pain induced [
94
,
95
]. The in-
volvement of several mechanisms of action allowed the researchers to obtain a synergistic
antinociceptive response in the presence of clinical analgesics and other medicinal plants
used to alleviate pain [96].

Molecules 2021,26, 7632 9 of 27
Scarce information was found in the literature describing Salvia and Agastache genera
distributed in Mexico and used for pain reliefDue to this, our group explored some of these
genera to obtain pharmacological evidence of their medicinal properties, for example the
cases of S. divinorum Epling & Jativa, S. semiatrata Zucc. and S. amarissima Ortega, as well
as their main constituents as promising anti-inflammatory, antioxidant and antinociceptive
agents, highlighting their mode of action in experimental models of pain as follows:
Salvia divinorum (1962) is a member of the Sage family that has been historically used
for divination and shamanism by the Mazatecs from Oaxaca, Mexico, because of this
hallucinogenic properties with a short duration. However, its leaf extracts have also been
reported as useful medicinal species to relieve pain [
97
]. It has shown a wide spectrum
of antinociceptive activities in preclinical studies using acute nociception in abdominal
pain and in the neurogenic and inflammatory test of formalin [
98
] but also in chronic pain
models, such as in neuropathic pain involving electroencephalographic changes [
99
]. Its
bioactive compounds are from salvinorin, mainly salvinorin A, a neoclerodane diterpene,
by involving kappa opioid, 5-HT1A serotonin and CB1 cannabinoid receptors as the main
mechanisms of action [99–101].
Salvia amarissima is another endemic species in Mexico used in traditional medicine
to treat disorders attributed to a cold state such as anxiety in the CNS, as well as gas-
trointestinal ailments and pain relief. It has been evaluated using several preclinical
animal models of pain preparing different kinds of extracts, where medium polar
and polar extracts have been the most bioactive [
102
]. It has also been observed that
medium polar constituents are involved in the inhibition of neurogenic and inflamma-
tory nociceptive responses through the participation of opioid and TRPV1 and 5-HT
1A
serotonin receptors [
103
]. The presence of a neoclerodane terpene named amarisolida
A and the flavonoid pedalitin have been implicated in the bioactive and abundant
constituents [
102
]. Their properties have also been reported in metabolic alterations
such as diabetes, since they produce a significant antihyperglycemic action
in vivo
during an oral sucrose tolerance test by an alfa-glucosidase inhibitory activity [
104
].
The presence of flavonoids and terpenoid bioactive constituents has also been asso-
ciated with another enzymatic and regulatory protein inhibition such as in protein
tyrosine phosphatase 1B (PTP-1B), where different kinds of amarisolide have been
characterized [
105
], as well as flavonoids such as rutin, isoquercitrin and pedalitin al-
ready associated with anxiolytic and/or antinociceptive activities [
106
,
107
]. Diterpenes
derived from S. amarissima also possess modulatory capability in protein multidrug
resistance and cytotoxic activity [
108
]. All these properties together suggest their useful
application in the comorbidity of diabetes and pain such as in neuropathic pain or even
in cancer.
Salvia semiatrata is a species used as a tranquilizer and to relieve pain in folk medicine
in Santiago Huauclilla, Oaxaca, Mexico. Preclinical evidence was recently reported re-
garding its significant effects as an anxiolytic and antinociceptive in several experimental
models in which the presence of the neo-clerodane diterpene 7-keto-neoclerodan-3,13-dien-
18,19:15,16-diolide was identified as being partially responsible [
109
]. Pain is as strongly
associated with anxiety as with depressive disorders, this comorbility can exacerbate the
other significantly [
110
]. This kind of comorbidity can be modulated by the dual activity of
herbal therapy, as it was observed in anxiolytic and antinociceptive effects of S. semiatrata
using similar doses [109].
2.6. Agastache Species to Alleviate Pain and Inflammation
Agastache mexicana (Kunth) Lint & Epling is a plant in high demand that has long
been used in Mexican folk medicine to treat anxiety, insomnia, and stomachache, among
other afflictions associated to pain. A. mexicana has been divided in two subspecies:
A. mexicana ssp. mexicana (Toronjil morado) and A. mexicana ssp. xolocotziana (Toronjil
blanco), both of which are used in traditional medicine to alleviate visceral pain; how-
ever it was found that only a polar extract from ssp. mexicana produced spasmolytic-

Molecules 2021,26, 7632 10 of 27
like effects [
111
]. This antinociceptive response was demonstrated in a significant and
dose-dependent manner in an
in vitro
study, where ursolic acid and acacetin evaluated
by the enteral and parenteral route of administration were both partial responsible con-
stituents [
112
]. In contrast, ssp. xolocotziana was associated with a spasmogenic response.
The spasmolytic effects of A. mexicana were related to an activation of nicotinic recep-
tors, prostaglandins and calcium channels, but not nitric oxide mechanisms [
113
]. It is
well-known that the abundant presence of certain constituents depends on the manner
of preparation of the vegetal material [
111
]. In the methanol extracts of A. mexicana, the
abundant presence of flavonoids such as acacetin and tilianin has been found [
113
]. Extracts
from different polarities have been compared in different experimental models of pain,
such as the writhing test in mice, the formalin and plantar tests in mice or rats, as well
as the pain-induced functional impairment assay in rats (a gouty arthritis pain model) to
demonstrate significant and dose-dependent antinociceptive responses. The effect was
more evident in the less polar extracts in part due to the presence of ursolic acid [
114
].This
triterpene produced its antinociceptive effect mediated by the presence of cGMP and an
additive synergism with 5HT
1A
receptors, but also produced antagonistic activity towards
TRPV1 receptors in neurogenic and inflammatory nociception with an ED
50
= 44 mg/kg. A
lower dosage was required to produce an antinociceptive effect in abdominal pain with an
ED50 = 2 mg/kg [115].
Another species from Lamiaceae independent of the Agastache genus, but also known
as “toronjil” in Mexico is Clinopodium mexicanum (Benth.) Govaerts, which is used in
Mexican traditional medicine to induce sleep, as well as in a sedative and analgesic remedy
with the common name of “Toronjil de Monte”. Its aqueous extract was able to inhibit
central nociception using a thermal stimulus in mice supporting its depressant activity,
where glavanone glycosides such as neoponcirin, poncirin and isonaringin were involved
as bioactive constituents [51].
2.7. Secondary Metabolites Identified in Lamiaceae Species with Analgesic and/or
Anti-Inflammatory Activities
Given the broad range of known mechanisms for pain transmission, numerous natural
compounds of different origins are reported in the literature to directly or indirectly modu-
late pain transmission to produce analgesic effects. Most of these constituents modulate the
release of endogenous analgesic mediators or inhibit algogenic neurotransmitters through
pre- or post-synaptic mechanisms at both the central and peripheral levels.
2.7.1. Terpenes
Volatile Terpenes
Terpenes are a group of secondary metabolites with a great diversity of chemical
structure. This type of compound comprises approximately 90% of the components of
the essential oils of aromatic plants [
116
]. The essential oil of the species of the Lamiaceae
is particularly rich in volatile monoterpenes, sesquiterpenes and diterpenes, which are
made up of 10, 15 and 20 carbon atoms, respectively [
1
]. Terpenes are very diverse in both
structure and function, but chemically they derive from the polymerization of isoprene; in
fact, their classification is based on the number of isoprene units that bind to each other:
hemi (one unit), mono (two units), sesqui (three units), di (four units), ses (five units), tetra
(eight units), and polyterpenes (n-units). Monoterpenes, the main active ingredients in
essential oils, consist of two isoprene units that are made up of five carbons joined [117].
Among the monoterpenes, the main reported compounds are
α
-pinene,
β
-pinene,
1,8-cineole, menthol, limonene, and
γ
-terpinene. The monoterpenes commonly present in
the Lamiaceae family and whose antinociceptive, anti-inflammatory and/or antioxidant
mechanisms of action have been evaluated, as well as their described chemical structure,
are listed in Table 2. Anticancer, antimicrobial, antioxidant, antiviral, analgesic and anti-
inflammatory activities are attributed to these compounds in various plant species [
118
].
Regarding the development of analgesics and anti-inflammatories, monoterpenes and

Molecules 2021,26, 7632 11 of 27
sesquiterpenes have become a topic of interest with an increasing number of new patent
applications [
1
,
119
–
121
]. According to some studies, monoterpenes are promising in the
modulation of cytokines due to their lipophilic characteristics which favor their absorption
and rapid action [
121
], and they have been recognized as stimulating an increase in anti-
inflammatory cytokines, such as IL-10 [
122
,
123
]. Studies of Hyptis spicigera Lam. reported
the antinociceptive effects of the essential oil because of the presence of
α
- and
β
-pinene,
and 1,8-cineol associated to the participation of TRPV1, A1 and M8 receptors [
58
], whereas
in the case of the essential oil of Monarda fistulosa L., carvacrol, thymol and
β
-myrcene
were characterized as possible compounds responsible for the antinociceptive properties
mediated by TRPA1 receptors [
124
]. The presence of
δ
-cadinene,
α
-pinene, myrcene,
β
-
caryophylene, germacrene, and limonene in the essential oil of Teucrium stocksianum Boiss.
was characterized as a bioactive antinociceptive in the writhing test [
125
] but also in the
formalin test in the antinociceptive activity of Ocimum [126].
Table 2.
Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets
explored in pain and inflammation.
Compound Structure Mechanism of Action References
β-pinene
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Reduction in leukocyte infiltration and TNF-αlevels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]

Molecules 2021,26, 7632 12 of 27
Table 2. Cont.
Compound Structure Mechanism of Action References
α-humulene
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Inhibition of pro-inflammatory cytokines (TNF-αand IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Molecules 2021, 26, x FOR PEER REVIEW 12 of 29
Table 2. Monoterpenes and sesquiterpenes present in Lamiaceae with biological activity and their molecular targets ex-
plored in pain and inflammation.
Compound Structure Mechanism of action References
β-pinene
Decreased expression of IL-6, TNF-α, NO, iNOS and COX-2.
Down-regulation of MAPKs phosphorylation and the NF-κB
signaling pathway
[127]
Inhibition of COX-2 enzyme expression [128]
Limonene
Reduction in leukocyte infiltration and TNF-α levels. [129]
Decreased production of NO, PGE2 and Pro-inflammatory
cytokines [130]
Linalool
Inhibition of pro-inflammatory interleukins and modulation of
NMDA glutamatergic receptor. [131]
Reduction in oxidative stress and inflammation (NF-kB). [132]
Activation of opioid and muscarinic receptors [133]
Myrcene
Activation of opioid receptors and presynaptic α2
adrenoreceptor. [134]
Inhibition of IL-1β-induced NO production
Increased expression of TIMP-1 and TIMP-3. [135]
p-cymene
Reduced the production of pro-inflammatory cytokine TNF-α,
the migration of leukocytes, and the release of NO. Activation
of opioid receptors.
[136]
Reduced the calcium current density. [137]
Thymol
Voltage-operated sodium channel blocker [138]
TRPA1 channel presynaptic activation [139]
Carvacrol
Inhibition of expression TNF-α, IL-1β, and IL-6
Reduced the expression of NF-kB [140]
Modulation of opioid, vanilloid and glutamate systems [141]
α-humulene
Inhibition of pro-inflammatory cytokines (TNF-α and IL-1β)
and PGE2 generation.
Decreased expression of iNOS and COX-2.
Inhibition of Il-5, CCL11 and LTB4 levels and P-selectin
expression.
[142]
[143]
β-caryophyllene
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1β, TNF-
α, and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4;
MAPKs: Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA:
HO
HO
HO
HH
Cannabinoid receptor type 2 agonist.
Attenuation of Substance P and cytokines such as IL-1
β
, TNF-
α
,
and IL-6.
[144]
Agonist to opioid, benzodiazepine, 5HT1A receptors and NO. [145]
Abbreviations: COX-2: Cyclooxygenase-2; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; LTB4: Leukotriene B4; MAPKs:
Mitogen-activated protein kinase; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NMDA: N-methyl-D-aspartate
receptor; NO: Nitric oxide; PGE2: Prostaglandin E2; TIMP-: Tissue inhibitors of metalloproteinase-; TNF-
α
: Tumor necrosis factor-alpha;
TRPA1: Transient receptor potential cation channel, subfamily A, member 1.
Non-Volatile Terpenes
Non-volatile diterpenes (made up 20 carbon atoms) and triterpenes (made up
30 carbon atoms) are reported as the two main subclasses of components of species in
the Lamiaceae family [
146
]. Seven main types of non-volatile diterpenes have been re-
ported differing in the various arrangements of the 20-carbon atom structure in order to
form abietanes, clerodanes, ent-kauranes, iso-pimarans, labdanes and neo-clerodanes [
117
].
Some of these types are considered chemotaxonomic markers for specific subfamilies or
genera [147], although all of them can be indifferently evidenced in all Lamiaceae species.
Much attention has recently been paid to diterpenoids such as marrubiin, from Mar-
rubium vulgare L. assayed in experimental models of pain, such as writhing, formalin
and hot-plate tests, but also carnosol and carnosic acid [
148
], which suppress cyclooxyge-
nase (COX)-2, interleukin-1B, and TNF-alfa expression, as well as leukocyte infiltration in
inflamed tissues [149,150].
Regarding triterpenes, two main types have been reported: pentacyclic triterpenes and
phytoecdysteroids. The former is characterized by having an olean- and ursan-like base
structure [
151
], with oleanolic acid and ursolic acid being the most reported pentacyclic
triterpenes in species belonging to this family. Diterpenes and triterpenes within the
Lamiaceae have also been reported to produce antinociceptive and/or anti-inflammatory
effects. Their chemical structure and mechanism of action explored are listed in Table 3.
Table 3.
Diterpenes and triterpenes present in Lamiaceae with biological activity and their molecular targets explored in
pain and inflammation.
Compound Structure Mechanism of Action References
Tormentic acid
Molecules 2021, 26, x FOR PEER REVIEW 13 of 29
N-methyl-D-aspartate receptor; NO: Nitric oxide; PGE2: Prostaglandin E2; TIMP-: Tissue inhibitors of metalloproteinase-
; TNF-α: Tumor necrosis factor-alpha; TRPA1: Transient receptor potential cation channel, subfamily A, member 1.
Non-Volatile Terpenes
Non-volatile diterpenes (made up 20 carbon atoms) and triterpenes (made up 30 car-
bon atoms) are reported as the two main subclasses of components of species in the Lami-
aceae family [146]. Seven main types of non-volatile diterpenes have been reported differ-
ing in the various arrangements of the 20-carbon atom structure in order to form abi-
etanes, clerodanes, ent-kauranes, iso-pimarans, labdanes and neo-clerodanes [117]. Some
of these types are considered chemotaxonomic markers for specific subfamilies or genera
[147], although all of them can be indifferently evidenced in all Lamiaceae species.
Much attention has recently been paid to diterpenoids such as marrubiin, from Mar-
rubium vulgare L. assayed in experimental models of pain, such as writhing, formalin and
hot-plate tests, but also carnosol and carnosic acid [148], which suppress cyclooxygenase
(COX)-2, interleukin-1B, and TNF-alfa expression, as well as leukocyte infiltration in in-
flamed tissues [149,150].
Regarding triterpenes, two main types have been reported: pentacyclic triterpenes
and phytoecdysteroids. The former is characterized by having an olean- and ursan-like
base structure [151], with oleanolic acid and ursolic acid being the most reported penta-
cyclic triterpenes in species belonging to this family. Diterpenes and triterpenes within
the Lamiaceae have also been reported to produce antinociceptive and/or anti-inflamma-
tory effects. Their chemical structure and mechanism of action explored are listed in Table
3.
Table 3. Diterpenes and triterpenes present in Lamiaceae with biological activity and their molecular targets explored in
pain and inflammation.
Compound Structure Mechanism of Action References
Tormentic acid
Inhibition of NF-kB signaling pathway and
prevents the expressions of iNOS, COX-2, and
TNF-α.
[152]
Increased activity of Superoxide dismutase,
glutathione peroxidase and catalase. [153]
Andalusol
Inhibition of histamine [154]
Inhibition of iNOS expression by inactivation
of NF-kB [155]
Tanshinone IIA
TLR2/NF-kB signaling pathway blocker [156]
O
OH
HO
HO
HO
H
H
H
HO
OH
HO
H
O
O
O
Inhibition of NF-kB signaling pathway and
prevents the expressions of iNOS, COX-2, and
TNF-α.
[152]
Increased activity of Superoxide dismutase,
glutathione peroxidase and catalase. [153]

Molecules 2021,26, 7632 13 of 27
Table 3. Cont.
Compound Structure Mechanism of Action References
Andalusol
Molecules 2021, 26, x FOR PEER REVIEW 13 of 29
N-methyl-D-aspartate receptor; NO: Nitric oxide; PGE2: Prostaglandin E2; TIMP-: Tissue inhibitors of metalloproteinase-
; TNF-α: Tumor necrosis factor-alpha; TRPA1: Transient receptor potential cation channel, subfamily A, member 1.
Non-Volatile Terpenes
Non-volatile diterpenes (made up 20 carbon atoms) and triterpenes (made up 30 car-
bon atoms) are reported as the two main subclasses of components of species in the Lami-
aceae family [146]. Seven main types of non-volatile diterpenes have been reported differ-
ing in the various arrangements of the 20-carbon atom structure in order to form abi-
etanes, clerodanes, ent-kauranes, iso-pimarans, labdanes and neo-clerodanes [117]. Some
of these types are considered chemotaxonomic markers for specific subfamilies or genera
[147], although all of them can be indifferently evidenced in all Lamiaceae species.
Much attention has recently been paid to diterpenoids such as marrubiin, from Mar-
rubium vulgare L. assayed in experimental models of pain, such as writhing, formalin and
hot-plate tests, but also carnosol and carnosic acid [148], which suppress cyclooxygenase
(COX)-2, interleukin-1B, and TNF-alfa expression, as well as leukocyte infiltration in in-
flamed tissues [149,150].
Regarding triterpenes, two main types have been reported: pentacyclic triterpenes
and phytoecdysteroids. The former is characterized by having an olean- and ursan-like
base structure [151], with oleanolic acid and ursolic acid being the most reported penta-
cyclic triterpenes in species belonging to this family. Diterpenes and triterpenes within
the Lamiaceae have also been reported to produce antinociceptive and/or anti-inflamma-
tory effects. Their chemical structure and mechanism of action explored are listed in Table
3.
Table 3. Diterpenes and triterpenes present in Lamiaceae with biological activity and their molecular targets explored in
pain and inflammation.
Compound Structure Mechanism of Action References
Tormentic acid
Inhibition of NF-kB signaling pathway and
prevents the expressions of iNOS, COX-2, and
TNF-α.
[152]
Increased activity of Superoxide dismutase,
glutathione peroxidase and catalase. [153]
Andalusol
Inhibition of histamine [154]
Inhibition of iNOS expression by inactivation
of NF-kB [155]
Tanshinone IIA
TLR2/NF-kB signaling pathway blocker [156]
O
OH
HO
HO
HO
H
H
H
HO
OH
HO
H
O
O
O
Inhibition of histamine [154]
Inhibition of iNOS expression by inactivation of
NF-kB [155]
Tanshinone IIA
Molecules 2021, 26, x FOR PEER REVIEW 13 of 29
N-methyl-D-aspartate receptor; NO: Nitric oxide; PGE2: Prostaglandin E2; TIMP-: Tissue inhibitors of metalloproteinase-
; TNF-α: Tumor necrosis factor-alpha; TRPA1: Transient receptor potential cation channel, subfamily A, member 1.
Non-Volatile Terpenes
Non-volatile diterpenes (made up 20 carbon atoms) and triterpenes (made up 30 car-
bon atoms) are reported as the two main subclasses of components of species in the Lami-
aceae family [146]. Seven main types of non-volatile diterpenes have been reported differ-
ing in the various arrangements of the 20-carbon atom structure in order to form abi-
etanes, clerodanes, ent-kauranes, iso-pimarans, labdanes and neo-clerodanes [117]. Some
of these types are considered chemotaxonomic markers for specific subfamilies or genera
[147], although all of them can be indifferently evidenced in all Lamiaceae species.
Much attention has recently been paid to diterpenoids such as marrubiin, from Mar-
rubium vulgare L. assayed in experimental models of pain, such as writhing, formalin and
hot-plate tests, but also carnosol and carnosic acid [148], which suppress cyclooxygenase
(COX)-2, interleukin-1B, and TNF-alfa expression, as well as leukocyte infiltration in in-
flamed tissues [149,150].
Regarding triterpenes, two main types have been reported: pentacyclic triterpenes
and phytoecdysteroids. The former is characterized by having an olean- and ursan-like
base structure [151], with oleanolic acid and ursolic acid being the most reported penta-
cyclic triterpenes in species belonging to this family. Diterpenes and triterpenes within
the Lamiaceae have also been reported to produce antinociceptive and/or anti-inflamma-
tory effects. Their chemical structure and mechanism of action explored are listed in Table
3.
Table 3. Diterpenes and triterpenes present in Lamiaceae with biological activity and their molecular targets explored in
pain and inflammation.
Compound Structure Mechanism of Action References
Tormentic acid
Inhibition of NF-kB signaling pathway and
prevents the expressions of iNOS, COX-2, and
TNF-α.
[152]
Increased activity of Superoxide dismutase,
glutathione peroxidase and catalase. [153]
Andalusol
Inhibition of histamine [154]
Inhibition of iNOS expression by inactivation
of NF-kB [155]
Tanshinone IIA
TLR2/NF-kB signaling pathway blocker [156]
O
OH
HO
HO
HO
H
H
H
HO
OH
HO
H
O
O
O
TLR2/NF-kB signaling pathway blocker [156]
Salvinorin A
Molecules 2021, 26, x FOR PEER REVIEW 14 of 29
Salvinorin A
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Decreased levels of TNF-α and caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]
Carnosol
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the
inhibition of mPGES-1. [164]
Inhibition of the induction of COX-2 by
b
locking PKC signaling and thereby the
b
inding of AP-1 to the CRE of the COX-2
promoter.
[165]
Oleanolic acid
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+ channels.
[166]
Opioid and 5-HT agonist. [167]
O
OO
O
O
O
O
OH
H
OH
H
H
OH
H
H
HO
H
O
OH
H
H
H
OH
OH
OO
HO H
H
O
OH
H
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
Molecules 2021, 26, x FOR PEER REVIEW 14 of 29
Salvinorin A
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Decreased levels of TNF-α and caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]
Carnosol
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the
inhibition of mPGES-1. [164]
Inhibition of the induction of COX-2 by
b
locking PKC signaling and thereby the
b
inding of AP-1 to the CRE of the COX-2
promoter.
[165]
Oleanolic acid
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+ channels.
[166]
Opioid and 5-HT agonist. [167]
O
OO
O
O
O
O
OH
H
OH
H
H
OH
H
H
HO
H
O
OH
H
H
H
OH
OH
OO
HO H
H
O
OH
H
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Molecules 2021, 26, x FOR PEER REVIEW 14 of 29
Salvinorin A
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Decreased levels of TNF-α and caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]
Carnosol
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the
inhibition of mPGES-1. [164]
Inhibition of the induction of COX-2 by
b
locking PKC signaling and thereby the
b
inding of AP-1 to the CRE of the COX-2
promoter.
[165]
Oleanolic acid
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+ channels.
[166]
Opioid and 5-HT agonist. [167]
O
OO
O
O
O
O
OH
H
OH
H
H
OH
H
H
HO
H
O
OH
H
H
H
OH
OH
OO
HO H
H
O
OH
H
Decreased levels of TNF-αand caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
Molecules 2021, 26, x FOR PEER REVIEW 14 of 29
Salvinorin A
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Decreased levels of TNF-α and caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]
Carnosol
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the
inhibition of mPGES-1. [164]
Inhibition of the induction of COX-2 by
b
locking PKC signaling and thereby the
b
inding of AP-1 to the CRE of the COX-2
promoter.
[165]
Oleanolic acid
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+ channels.
[166]
Opioid and 5-HT agonist. [167]
O
OO
O
O
O
O
OH
H
OH
H
H
OH
H
H
HO
H
O
OH
H
H
H
OH
OH
OO
HO H
H
O
OH
H
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]

Molecules 2021,26, 7632 14 of 27
Table 3. Cont.
Compound Structure Mechanism of Action References
Carnosol
Molecules 2021, 26, x FOR PEER REVIEW 14 of 29
Salvinorin A
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Decreased levels of TNF-α and caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]
Carnosol
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the
inhibition of mPGES-1. [164]
Inhibition of the induction of COX-2 by
b
locking PKC signaling and thereby the
b
inding of AP-1 to the CRE of the COX-2
promoter.
[165]
Oleanolic acid
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+ channels.
[166]
Opioid and 5-HT agonist. [167]
O
OO
O
O
O
O
OH
H
OH
H
H
OH
H
H
HO
H
O
OH
H
H
H
OH
OH
OO
HO H
H
O
OH
H
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the inhibition
of mPGES-1. [164]
Inhibition of the induction of COX-2 by blocking
PKC signaling and thereby the binding of AP-1
to the CRE of the COX-2 promoter.
[165]
Oleanolic acid
Molecules 2021, 26, x FOR PEER REVIEW 14 of 29
Salvinorin A
KOR agonist. [157]
Inhibition of dopamine overflow mediated by
KOR. [158]
α-amyrenone
PKC and PKA activity blocker. [159]
Antioxidant activity. [160]
β-amyrenone
Decreased levels of TNF-α and caspase 3
Reduction in oxidative stress. [161]
Ursolic acid
NO, PGE2 inhibitor. [162]
TRPV1 antagonist.
Modulator of cGMP and serotonergic system. [115]
Carnosol
Suppression of iNOS by down-regulation of
NF-kB. [163]
Suppression of PGE2 synthesis by the
inhibition of mPGES-1. [164]
Inhibition of the induction of COX-2 by
b
locking PKC signaling and thereby the
b
inding of AP-1 to the CRE of the COX-2
promoter.
[165]
Oleanolic acid
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+ channels.
[166]
Opioid and 5-HT agonist. [167]
O
OO
O
O
O
O
OH
H
OH
H
H
OH
H
H
HO
H
O
OH
H
H
H
OH
OH
OO
HO H
H
O
OH
H
Opioid agonist.
NO inhibitor.
Activation of ATP-gated K+channels.
[166]
Opioid and 5-HT agonist. [167]
Betulinic acid
Molecules 2021, 26, x FOR PEER REVIEW 15 of 29
Betulinic acid
Reduction in TNF-α production.
Increase in IL-10 production. [168]
Reduction in the levels of COX-2, NO, TNF-α
and IL-1β.
Inhibition of MDA level via increasing the
activities of SOD, GPx, GRd.
[169]
Abbreviations: 5HT: 5-hydroxytryptamine; 5HT1A: Serotonin 1A receptor; AP-1: activator protein 1; ATP: Adenosine tri-
phosphate; CCL11: C-C motif chemokine 11; cGMP: Cyclic guanosine monophosphate; COX-2: Cyclooxygenase-2; CRE:
cyclic AMP response element; GPx: glutathione peroxidase; GRd: glutathione reductase; IL-: Interleukin-; iNOS: Inducible
nitric oxide synthase; KOR: κ-opioid receptor; LTB4: Leukotriene B4; MDA: Malondialdehyde; mPGES-1: Microsomal
prostaglandin E synthase-1; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NO: Nitric oxide;
PGE2: Prostaglandin E2; PKA: protein kinase A; PKC: protein kinase C; SOD: Superoxide dismutase; TLR2: Toll-like re-
ceptor 2; TNF-α: Tumor necrosis factor-alpha; TRPV1: Transient receptor potential cation channel subfamily V member 1.
2.7.2. Phenolic Compounds
Some species of the Lamiaceae family and their biological activities have been char-
acterized by the presence of phenolic compounds, even if only in minor quantities. Caffeic
acid and rosmarinic acid, together with their derivatives, are the most reported phenolic
acids in the family [170–172]. However, in recent studies, chemotaxonomic markers at the
genera level have also been found [121].
In general terms, phenols and polyphenols refer to a group of plant secondary me-
tabolites which carry at least one phenolic ring in their molecule; they are derived from
shikimic acid and phenylpropanoid metabolism pathways. A phenolic ring is made up of
a hydrophobic aromatic nucleus and a hydrophilic hydroxy group that can be involved
in hydrogen bond formation. As redox active compounds, plant phenols can also act as
antioxidants or pro-oxidants [173]. The antioxidant activity of phenolic compounds de-
pends on the number of hydroxy substituents, their position and the site of binding on the
aromatic ring [174].
All phenolic compounds of the plants in the Lamiaceae share significant antioxidant
activity which is attributed to the complete extracts [175]. Antioxidants protect plant cells
from damage caused by free radicals that develop with normal cellular metabolism or due
to stressful events, such as excessive UV radiation, exposure to soil or air pollutants, and
diseases [176]. The antioxidant properties of phenolic compounds can participate in the
uptake of reactive oxygen species and reactive nitrogen species (ROS/RNS), inhibiting
their formation by suppressing enzymes or metals associated with the production of free
radicals, and regulating or defending the plant antioxidant systems [177].
Lipid peroxidation processes which cause damage to fatty acids tend to decrease
membrane fluidity and lead to numerous pathological events [178], and could be reduced
by phenolic acids in plants due to their capacity to modulate different oxygen species
[121,175]. Furthermore, polyphenols have been demonstrated to protect the nervous sys-
tem against oxidative stress, to such an extent that regular dietary intake of flavonoids has
been associated with reduced dementia and delayed onset of Alzheimer’s and Parkinson’s
diseases [179]. Polyphenols have been considered potential neuroprotective and direct
neuromodulatory agents of the CNS because of their ability to cross the blood-brain bar-
rier [180]. Plants belonging to the genera Calamintha, Lavandula, Mentha, Melissa, Origanum,
Rosmarinus, Salvia, Teucrium or Thymus are used for the treatment of various nervous sys-
tem disorders, mainly thanks to the presence of polyphenols, particularly rosmarinic acid
[78].
Phenolic compounds present in the Lamiaceae and their corresponding structures,
which have shown antioxidant, anti-inflammatory and/or antinociceptive pharmacologi-
cal activity, related to the evaluated mechanisms of action, are shown in Table 4.
H
HO
H
H
H
O
OH
Reduction in TNF-αproduction.
Increase in IL-10 production. [168]
Reduction in the levels of COX-2, NO, TNF-α
and IL-1β.
Inhibition of MDA level via increasing the
activities of SOD, GPx, GRd.
[169]
Abbreviations: 5HT: 5-hydroxytryptamine; 5HT
1A:
Serotonin 1A receptor; AP-1: activator protein 1; ATP: Adenosine triphosphate; CCL11:
C-C motif chemokine 11; cGMP: Cyclic guanosine monophosphate; COX-2: Cyclooxygenase-2; CRE: cyclic AMP response element; GPx:
glutathione peroxidase; GRd: glutathione reductase; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; KOR:
κ
-opioid receptor; LTB4:
Leukotriene B4; MDA: Malondialdehyde; mPGES-1: Microsomal prostaglandin E synthase-1; NF-kB: Nuclear factor kappa-light-chain-
enhancer of activated B cells; NO: Nitric oxide; PGE2: Prostaglandin E2; PKA: protein kinase A; PKC: protein kinase C; SOD: Superoxide
dismutase; TLR2: Toll-like receptor 2; TNF-
α
: Tumor necrosis factor-alpha; TRPV1: Transient receptor potential cation channel subfamily V
member 1.
2.7.2. Phenolic Compounds
Some species of the Lamiaceae family and their biological activities have been charac-
terized by the presence of phenolic compounds, even if only in minor quantities. Caffeic
acid and rosmarinic acid, together with their derivatives, are the most reported phenolic
acids in the family [
170
–
172
]. However, in recent studies, chemotaxonomic markers at the
genera level have also been found [121].
In general terms, phenols and polyphenols refer to a group of plant secondary metabo-
lites which carry at least one phenolic ring in their molecule; they are derived from shikimic
acid and phenylpropanoid metabolism pathways. A phenolic ring is made up of a hy-
drophobic aromatic nucleus and a hydrophilic hydroxy group that can be involved in
hydrogen bond formation. As redox active compounds, plant phenols can also act as
antioxidants or pro-oxidants [
173
]. The antioxidant activity of phenolic compounds de-
pends on the number of hydroxy substituents, their position and the site of binding on the
aromatic ring [174].
All phenolic compounds of the plants in the Lamiaceae share significant antioxidant
activity which is attributed to the complete extracts [
175
]. Antioxidants protect plant cells
from damage caused by free radicals that develop with normal cellular metabolism or due
to stressful events, such as excessive UV radiation, exposure to soil or air pollutants, and
diseases [
176
]. The antioxidant properties of phenolic compounds can participate in the
uptake of reactive oxygen species and reactive nitrogen species (ROS/RNS), inhibiting

Molecules 2021,26, 7632 15 of 27
their formation by suppressing enzymes or metals associated with the production of free
radicals, and regulating or defending the plant antioxidant systems [177].
Lipid peroxidation processes which cause damage to fatty acids tend to decrease mem-
brane fluidity and lead to numerous pathological events [
178
], and could be reduced by
phenolic acids in plants due to their capacity to modulate different oxygen species [
121
,
175
].
Furthermore, polyphenols have been demonstrated to protect the nervous system against
oxidative stress, to such an extent that regular dietary intake of flavonoids has been
associated with reduced dementia and delayed onset of Alzheimer’s and Parkinson’s
diseases [
179
]. Polyphenols have been considered potential neuroprotective and direct
neuromodulatory agents of the CNS because of their ability to cross the blood-brain bar-
rier [
180
]. Plants belonging to the genera Calamintha,Lavandula,Mentha,Melissa,Origanum,
Rosmarinus,Salvia,Teucrium or Thymus are used for the treatment of various nervous system
disorders, mainly thanks to the presence of polyphenols, particularly rosmarinic acid [
78
].
Phenolic compounds present in the Lamiaceae and their corresponding structures,
which have shown antioxidant, anti-inflammatory and/or antinociceptive pharmacological
activity, related to the evaluated mechanisms of action, are shown in Table 4.
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α,
superoxide anion, and MPO activity levels; and
decreased GSH level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAAreceptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling
pathways. [187]
Vanillin
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.Suppresses
the expression of TNF-α, IL-6, IL-1βand plasma
AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
Reduction in the IκBαdegradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
α2-adrenoceptor agonist.5HT3and 5HT1receptor
agonist Interaction with TRPV1, TRPA1 and TRPM8
receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory
cytokine production, and NF-kB activation. [193]

Molecules 2021,26, 7632 16 of 27
Table 4. Cont.
Compound Structure Mechanisms of Action References
Ferulic acid
Molecules 2021, 26, x FOR PEER REVIEW 16 of 29
Table 4. Phenolic acids commonly found in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanisms of Action References
Rosmarinic
acid
Antioxidant activity. [75]
Suppression of TNF-α, iNOs, apoptotic factors (Bax,
caspases 3 and 9), Iba-1, TLR4 and GFAP levels. [181]
Gallic acid
ERK-Nrf2-Keap1-mediated antioxidant activity. [182]
Reduction in TBARS, total calcium, TNF-α, superoxide
anion, and MPO activity levels; and decreased GSH
level.
[183]
TRPA1 antagonist. [184]
Chlorogenic
acid
Inhibition of CD80/86 and Th1 cytokines. [185]
GABAA receptor agonist. [186]
Inhibition of NF-kB and JNK/AP-1 signaling pathways. [187]
Vanillin
Inhibition of protein and lipid oxidation processes.
Increased activity of GSH, SOD, catalase.
Suppresses the expression of TNF-α, IL-6, IL-1β and
plasma AST and ALT enzymes.
[188]
α2-adrenergic and opioid receptor agonist [189]
Caffeic acid
Reduction in the IκBα degradation and p65
phosphorylation in the NF-kB pathway. [190]
Inhibition of MPO, MDA and nitrite generation. [191]
Vanillic acid
α2-adrenoceptor agonist.
5HT3 and 5HT1 receptor agonist
Interaction with TRPV1, TRPA1 and TRPM8 receptors.
[192]
Inhibition of oxidative stress, pro-inflammatory cytokine
production, and NF-kB activation. [193]
Ferulic acid
The level/activity of elastase, lysosomal enzymes, nitric
oxide, lipid peroxidation, and pro-inflammatory
cytokines (TNF-α and IL-1β); and the mRNA expression
of NLRP3 inflammasomes, caspase-1, pro-inflammatory
cytokines, and NF-kB p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransfer-
ase; Bax: Bcl-2-associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellu-
lar-signal-regulated kinase; GABAA: γ-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glu-
tathione; Iba-1: Ionized calcium-binding adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkBα:
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1:
Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic
acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: Family pyrin domain containing 3;
NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD: Superoxide dis-
mutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-α: Tumor
OH
OH
O
O
HO
HO
OH
OH
OH
HO
HO
O
OH
OH
HO
O
HO
O
OH
O
OH
OH
HO
O
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OH
The level/activity of elastase, lysosomal enzymes,
nitric oxide, lipid peroxidation, and
pro-inflammatory cytokines (TNF-
α
and IL-1
β
); and
the mRNA expression of NLRP3 inflammasomes,
caspase-1, pro-inflammatory cytokines, and NF-kB
p65 were decreased.
[194]
Inhibition of xanthine oxidase and COX-2 enzyme. [195]
Abbreviations: 5HT: Serotonin; ALT: Alanine aminotransferase; AP-1: Activator protein 1; AST: Aspartate aminotransferase; Bax: Bcl-2-
associated X protein; CD80/86: CD28 receptor binds to the B7; COX-2: Cyclooxygenase-2; ERK: Extracellular-signal-regulated kinase;
GABA
A
:
γ
-aminobutyric acid type A receptor; GFAP: Glial fibrillary acidic protein; GSH: Glutathione; Iba-1: Ionized calcium-binding
adapter molecule 1; IL-: Interleukin-; iNOS: Inducible nitric oxide synthase; IkB
α
: Nuclear factor of kappa light polypeptide gene enhancer
in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinase; Keap1: Kelch-like ECH-associated protein 1; MDA: Malondialdehyde; MPO:
Myeloperoxidase; mRNA: Messenger Ribonucleic acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3:
Family pyrin domain containing 3; NRf2: nuclear factor erythroid 2–related factor 2; p65: Nuclear factor NF-kappa-B p65 subunit; SOD:
Superoxide dismutase; TBARS: Thiobarbituric acid reactive substances; Th1: T helper type 1; TLR4: Toll like receptor 4; TNF-
α
: Tumor
necrosis factor-alpha; TNF-
α
: Tumor necrosis factor-alpha; TRPA1: Transient receptor potential ankyrin 1; TRPA1: Transient receptor
potential cation channel, subfamily A, member 1; TRPM8: Transient receptor potential cation channel subfamily M (melastatin), member 8;
TRPV1: Transient receptor potential cation channel subfamily V member 1.
Phenolic Acids
Phenolic acids have been characterized as being responsible for the biological activity
of several Lamiaceae species, such as antioxidant, anti-inflammatory and antinociceptive
activities, exploring not only their pharmacological activity but also the possible mechanism
of action involved (Table 4). As redox active compounds, phenolic acids can also act
as antioxidants or pro-oxidants [
173
]. The antioxidant activity of phenolic compounds
depends on the number of hydroxy substituents, their position and the site of binding on
the aromatic ring [
174
]. Caffeic acid and rosmarinic acid and their derivatives have been
part of the most common phenolic acids described [
170
–
172
]. Nevertheless, recent studies
have found and established chemotaxonomic markers at the genera level [121].
Rosmarinic acid is among the main phenolic compounds contained in the tissues of
various plant species belonging to this family. The genotype of the plant, but also physiological
or environmental factors, such as phenology, climate, growth technique and stress conditions,
strongly influence the amounts of phenolic compounds in the plant [121,196].
High levels of rosmarinic acid are commonly found only within the Nepetoideae
subfamily. In the genus Stachys, in the Lamioideae subfamily [
197
], several species belonging
to the Lamiaceae can accumulate high levels of different phenolic compounds, such as
phenolic acids, flavonoids, or phenolic terpenes. Only in the Lamiaceae family are some
phenolic compounds present, such as carnosic acid, which prevents the oxidative damage
of the chloroplast and shows highly antioxidant properties
in vitro
[
198
]. Another phe-
nolic acid exclusive to Lamiaceae species is clerodendranoic acid, which was found in
Clerodendranthus spicatus (Thunb.) C.Y. Wu ex H.W. Li [199].
Flavonoids
A few compounds from flavonoid nature in Lamiaceae with antinociceptive and anti-
inflammatory activities have been reported. This is the case of a standardized mixture of
baicaline and catequine from Scutellaria baicalensis Georgi, which was evaluated using the
writhing, formalin and carragennan tests in rodents [
200
]. Salvigenina was isolated from S.
officinalis as the responsible flavonoid for the antinociceptive effects in writhing, hot-plate
and carragennan tests [
201
]. Other flavonoids including pedalitin from S. amarissima have
been explored in writhing test in mice [
102
], while tilianin and acacetin were identified
in Agastache mexicana and reported in several experimental models of acute and chronic
pain [
113
]. Examples of these flavonoids commonly present in species of the Lamiaceae
family with antioxidant, antinociceptive and anti-inflammatory activity are listed in Table 5.

Molecules 2021,26, 7632 17 of 27
Table 5. Flavonoids commonly present in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanism of Action References
Pedalitin
Molecules 2021, 26, x FOR PEER REVIEW 17 of 29
necrosis factor-alpha; TNF-α: Tumor necrosis factor-alpha; TRPA1: Transient receptor potential ankyrin 1; TRPA1: Tran-
sient receptor potential cation channel, subfamily A, member 1; TRPM8: Transient receptor potential cation channel sub-
family M (melastatin), member 8; TRPV1: Transient receptor potential cation channel subfamily V member 1.
Phenolic Acids
Phenolic acids have been characterized as being responsible for the biological activity
of several Lamiaceae species, such as antioxidant, anti-inflammatory and antinociceptive
activities, exploring not only their pharmacological activity but also the possible mecha-
nism of action involved (Table 4). As redox active compounds, phenolic acids can also act
as antioxidants or pro-oxidants [173]. The antioxidant activity of phenolic compounds de-
pends on the number of hydroxy substituents, their position and the site of binding on the
aromatic ring [174]. Caffeic acid and rosmarinic acid and their derivatives have been part
of the most common phenolic acids described [170–172]. Nevertheless, recent studies have
found and established chemotaxonomic markers at the genera level [121].
Rosmarinic acid is among the main phenolic compounds contained in the tissues of
various plant species belonging to this family. The genotype of the plant, but also physi-
ological or environmental factors, such as phenology, climate, growth technique and
stress conditions, strongly influence the amounts of phenolic compounds in the plant
[121,196].
High levels of rosmarinic acid are commonly found only within the Nepetoideae sub-
family. In the genus Stachys, in the Lamioideae subfamily [197], several species belonging
to the Lamiaceae can accumulate high levels of different phenolic compounds, such as
phenolic acids, flavonoids, or phenolic terpenes. Only in the Lamiaceae family are some
phenolic compounds present, such as carnosic acid, which prevents the oxidative damage
of the chloroplast and shows highly antioxidant properties in vitro [198]. Another phe-
nolic acid exclusive to Lamiaceae species is clerodendranoic acid, which was found in
Clerodendranthus spicatus (Thunb.) C.Y. Wu ex H.W. Li [199].
Flavonoids
A few compounds from flavonoid nature in Lamiaceae with antinociceptive and anti-
inflammatory activities have been reported. This is the case of a standardized mixture of
baicaline and catequine from Scutellaria baicalensis Georgi, which was evaluated using the
writhing, formalin and carragennan tests in rodents [200]. Salvigenina was isolated from
S. officinalis as the responsible flavonoid for the antinociceptive effects in writhing, hot-
plate and carragennan tests [201]. Other flavonoids including pedalitin from S. amarissima
have been explored in writhing test in mice [102], while tilianin and acacetin were identi-
fied in Agastache mexicana and reported in several experimental models of acute and
chronic pain [113]. Examples of these flavonoids commonly present in species of the La-
miaceae family with antioxidant, antinociceptive and anti-inflammatory activity are listed
in Table 5.
Table 5. Flavonoids commonly present in Lamiaceae and their molecular targets explored in pain and inflammation.
Compound Structure Mechanism of Action References
Pedalitin
Inhibitory effects against NO, TNF-α and IL-12. [202]
Rutin Increased activity of GPx, GRd, CAT, SOD and GSH. [203]
O
OO
HO
OH
OH
OH
Inhibitory effects against NO, TNF-αand IL-12. [202]
Rutin
Molecules 2021, 26, x FOR PEER REVIEW 18 of 29
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.
Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6 decreased.
Increased sensory nerve conduction velocity.
[204]
Apigenin
Increased expression levels of Nrf2 and HO-1.
Inhibition of TNF-α, IL-1β, IL-6, MPO and MDA
content.
[24]
Inhibition of CD40, TNF-α and IL-6 [205]
Quercetin
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker
Modulation of PGF2α pathway [207]
5HT1A agonist [208]
Luteolin
Inhibition of IL-1β, TNF-α and histamine release. [209]
Decreased neutrophil infiltration.
Inhibition of TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/
TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-α and IL-6 [205]
Hesperidin
Modulation of D2, GABAA and opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Inhibition of oxido-nitrosative strees, TNF-α, IL’s and
NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
OOH
HO O
OH
OH
OOH
HO O OH
OH
O
O
HO
OH
OH
OH
O
O
OO
OO
HO
OH
OH
HO
OH
OH
O
OH
OH
OO
HO
HO
HO
O
O
O
O
OH
OH
OH
OH
HO
Increased activity of GPx, GRd, CAT, SOD and GSH.
[203]
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6
decreased.Increased sensory nerve conduction
velocity.
[204]
Apigenin
Molecules 2021, 26, x FOR PEER REVIEW 18 of 29
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.
Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6 decreased.
Increased sensory nerve conduction velocity.
[204]
Apigenin
Increased expression levels of Nrf2 and HO-1.
Inhibition of TNF-α, IL-1β, IL-6, MPO and MDA
content.
[24]
Inhibition of CD40, TNF-α and IL-6 [205]
Quercetin
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker
Modulation of PGF2α pathway [207]
5HT1A agonist [208]
Luteolin
Inhibition of IL-1β, TNF-α and histamine release. [209]
Decreased neutrophil infiltration.
Inhibition of TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/
TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-α and IL-6 [205]
Hesperidin
Modulation of D2, GABAA and opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Inhibition of oxido-nitrosative strees, TNF-α, IL’s and
NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
OOH
HO O
OH
OH
OOH
HO O OH
OH
O
O
HO
OH
OH
OH
O
O
OO
OO
HO
OH
OH
HO
OH
OH
O
OH
OH
OO
HO
HO
HO
O
O
O
O
OH
OH
OH
OH
HO
Increased expression levels of Nrf2 and
HO-1.Inhibition of TNF-α, IL-1β, IL-6, MPO and
MDA content.
[24]
Inhibition of CD40, TNF-αand IL-6 [205]
Quercetin
Molecules 2021, 26, x FOR PEER REVIEW 18 of 29
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.
Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6 decreased.
Increased sensory nerve conduction velocity.
[204]
Apigenin
Increased expression levels of Nrf2 and HO-1.
Inhibition of TNF-α, IL-1β, IL-6, MPO and MDA
content.
[24]
Inhibition of CD40, TNF-α and IL-6 [205]
Quercetin
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker
Modulation of PGF2α pathway [207]
5HT1A agonist [208]
Luteolin
Inhibition of IL-1β, TNF-α and histamine release. [209]
Decreased neutrophil infiltration.
Inhibition of TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/
TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-α and IL-6 [205]
Hesperidin
Modulation of D2, GABAA and opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Inhibition of oxido-nitrosative strees, TNF-α, IL’s and
NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
OOH
HO O
OH
OH
OOH
HO O OH
OH
O
O
HO
OH
OH
OH
O
O
OO
OO
HO
OH
OH
HO
OH
OH
O
OH
OH
OO
HO
HO
HO
O
O
O
O
OH
OH
OH
OH
HO
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker Modulation of PGF2α
pathway [207]
5HT1A agonist [208]
Luteolin
Molecules 2021, 26, x FOR PEER REVIEW 18 of 29
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.
Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6 decreased.
Increased sensory nerve conduction velocity.
[204]
Apigenin
Increased expression levels of Nrf2 and HO-1.
Inhibition of TNF-α, IL-1β, IL-6, MPO and MDA
content.
[24]
Inhibition of CD40, TNF-α and IL-6 [205]
Quercetin
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker
Modulation of PGF2α pathway [207]
5HT1A agonist [208]
Luteolin
Inhibition of IL-1β, TNF-α and histamine release. [209]
Decreased neutrophil infiltration.
Inhibition of TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/
TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-α and IL-6 [205]
Hesperidin
Modulation of D2, GABAA and opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Inhibition of oxido-nitrosative strees, TNF-α, IL’s and
NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
OOH
HO O
OH
OH
OOH
HO O OH
OH
O
O
HO
OH
OH
OH
O
O
OO
OO
HO
OH
OH
HO
OH
OH
O
OH
OH
OO
HO
HO
HO
O
O
O
O
OH
OH
OH
OH
HO
Inhibition of IL-1β, TNF-αand histamine release. [209]
Decreased neutrophil infiltration.Inhibition of
TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-αand IL-6 [205]
Hesperidin
Molecules 2021, 26, x FOR PEER REVIEW 18 of 29
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.
Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6 decreased.
Increased sensory nerve conduction velocity.
[204]
Apigenin
Increased expression levels of Nrf2 and HO-1.
Inhibition of TNF-α, IL-1β, IL-6, MPO and MDA
content.
[24]
Inhibition of CD40, TNF-α and IL-6 [205]
Quercetin
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker
Modulation of PGF2α pathway [207]
5HT1A agonist [208]
Luteolin
Inhibition of IL-1β, TNF-α and histamine release. [209]
Decreased neutrophil infiltration.
Inhibition of TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/
TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-α and IL-6 [205]
Hesperidin
Modulation of D2, GABAA and opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Inhibition of oxido-nitrosative strees, TNF-α, IL’s and
NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
OOH
HO O
OH
OH
OOH
HO O OH
OH
O
O
HO
OH
OH
OH
O
O
OO
OO
HO
OH
OH
HO
OH
OH
O
OH
OH
OO
HO
HO
HO
O
O
O
O
OH
OH
OH
OH
HO
Modulation of D2, GABAAand opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Molecules 2021, 26, x FOR PEER REVIEW 18 of 29
Central modulation of the vlPAG descending circuit
partly mediated by an opioidergic mechanism. [106]
Increased H2S level.
Modulation of Nrf2 pathway.
Caspase 3 and, NF-kB, TNF-α, IL-6 decreased.
Increased sensory nerve conduction velocity.
[204]
Apigenin
Increased expression levels of Nrf2 and HO-1.
Inhibition of TNF-α, IL-1β, IL-6, MPO and MDA
content.
[24]
Inhibition of CD40, TNF-α and IL-6 [205]
Quercetin
Interaction with L-arginine-nitric oxide, serotonin,
and GABAergic systems. [206]
ROCs and VOCs Blocker
Modulation of PGF2α pathway [207]
5HT1A agonist [208]
Luteolin
Inhibition of IL-1β, TNF-α and histamine release. [209]
Decreased neutrophil infiltration.
Inhibition of TNF-α, IL-1β, IL-6. [210]
Downregulation of TLR4/
TRAF6/NF-kB pathway [211]
Inhibition of CD40, TNF-α and IL-6 [205]
Hesperidin
Modulation of D2, GABAA and opioid receptors. [212]
Agonist of opioid receptors. [213]
Modulation of TRPV1 receptor. [189]
Naringin
Inhibition of oxido-nitrosative strees, TNF-α, IL’s and
NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]
O
O
O
O
OO
HO
OH
OH OH
OH
OH
HO
OH
OH
OH
OOH
HO O
OH
OH
OOH
HO O OH
OH
O
O
HO
OH
OH
OH
O
O
OO
OO
HO
OH
OH
HO
OH
OH
O
OH
OH
OO
HO
HO
HO
O
O
O
O
OH
OH
OH
OH
HO
Inhibition of oxido-nitrosative strees, TNF-α, IL’s
and NF-kB mRNA levels. [214]
Inhibition of PGE2, NO, IL-6 and TNF-α. [215]

Molecules 2021,26, 7632 18 of 27
Table 5. Cont.
Compound Structure Mechanism of Action References
Naringenin
Molecules 2021, 26, x FOR PEER REVIEW 19 of 29
Naringenin
Inhibition of NF-kB and activation of NO-Cyclic
GMP-PKG-ATP sensitive K+ channel pathway [216]
Inhibition of IL-6, TNF-α and NO release, by
interfering MAPK signal pathway and suppressing
the activation of NF-kB.
[217]
Abbreviations: 5HT1A: Serotonin 1A receptor; ATP: Adenosine triphosphate; CAT: Catalase; CD40: Cluster of differentia-
tion 40; GABA: γ aminobutyric acid; GMP: Cyclic guanosine monophosphate; GPx: glutathione peroxidase; GRd: gluta-
thione; reductase; GSH: Glutathione; H2S: Hydrogen sulfide; HO-1: Heme oxygenase-1; IL-: Interleukin-; MAPK: Mitogen-
activated protein kinase; MDA: Malondialdehyde; MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic acid; NF-kB:
Nuclear factor kappa-light-chain-enhancer of activated B cells; NF-kB: Nuclear factor kappa-light-chain-enhancer of acti-
vated B cells; NO: Nitric oxide; Nrf2: Nuclear factor erythroid 2–related factor 2; PGE2: Prostaglandin E2; PGF2α: Prosta-
glandin F2α: PKG: cGMP-dependent protein kinase ROCs: Receptor-operated channels; SOD: Superoxide dismutase;
TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-alpha; TRAF6: TNF receptor associated factor 6; TRPV1: Transi-
ent receptor potential cation channel subfamily V member 1; VOCs: Voltage-operated channels.
3. Materials and Methods
Literature Survey Databases
This literature review was carried out based on an electronic search in the Sciencedi-
rect, Pubmed and Springer link databases in 2020. The keywords used were “Lamiaceae”
“antinociceptive” “pain”, “analgesic” and “anti-inflammatory”. Almost 1200 articles were
found, and after an extensive survey, 217 articles were selected, which described the an-
tinociceptive and/or anti-inflammatory potential of natural compounds to relieve pain.
4. Conclusions
The chemical characteristics and the pharmacological properties of the Lamiaceae
constituents are of interest to researchers, laboratories, and pharmaceutical companies.
During the last few decades, the mechanisms of action of the different secondary metab-
olites of the Lamiaceae family have been broadly investigated by means of in vivo and in
vitro assays to confirm their participation in the modulation of pain and in the cascade of
inflammation mediators. This work summarizes part of the reported scientific knowledge
regarding the secondary metabolites of some specific Mexican species of the Lamiaceae
that have shown activity for pain relief, highlighting the participation of terpenes, flavo-
noids, and phenolic acids as potential alternatives for new drug therapies. As a result of
this review, it is important to mention that few studies have been reported regarding Mex-
ican genera of this family; for example, Calosphace is one of the largest subgenera of Salvia
in all the world, mainly found in Mexico, but it has barely been investigated regarding its
potential biological activities and their bioactive constituents. The scientific evidence re-
garding the different bioactive constituents found in species of the Lamiaceae family
demonstrates that several species of this family require further investigation in preclinical
studies, but also in controlled clinical trials to evaluate the efficacy and safety of these
natural products to support their therapeutic potential in pain relief and/or inflammation,
along with other health conditions.
Author Contributions: Conceptualization: M.E.G.-T., G.F.M.-P. and A.H.-L.; methodology, M.E.G.-
T., G.F.M.-P., A.H.-L., M.G.V.-D., M.M.-G., E.A.-H. and M.I.D.-R.; validation, M.E.G.-T., G.F.M.-P.,
A.H.-L., M.M.-G., E.A.-H., M.I.D.-R. and F.P.; formal analysis, M.E.G.-T., G.F.M.-P., A.H.-L., M.M.-
G. and E.A.-H.; investigation, M.E.G.-T., G.F.M.-P., A.H.-L., M.G.V.-D., M.M.-G., E.A.-H., M.I.D.-R.
and F.P.; resources, M.E.G.-T., G.F.M.-P., A.H.-L., M.M.-G., E.A.-H. and F.P.; writing—original draft
preparation, M.E.G.-T., G.F.M.-P., A.H.-L., M.G.V.-D., M.M.-G., E.A.-H., M.I.D.-R. and F.P.; writ-
ing—review and editing, M.E.G.-T., G.F.M.-P. and A.H.-L.; visualization, M.E.G.-T. and A.H.-L.;
project administration, M.E.G.-T. and F.P. All authors have read and agreed to the published version
of the manuscript.
OOH
HO O
OH
Inhibition of NF-kB and activation of NO-Cyclic
GMP-PKG-ATP sensitive K+channel pathway [216]
Inhibition of IL-6, TNF-αand NO release, by
interfering MAPK signal pathway and suppressing
the activation of NF-kB.
[217]
Abbreviations: 5HT
1A
: Serotonin 1A receptor; ATP: Adenosine triphosphate; CAT: Catalase; CD40: Cluster of differentiation 40; GABA:
γ
aminobutyric acid; GMP: Cyclic guanosine monophosphate; GPx: glutathione peroxidase; GRd: glutathione; reductase; GSH: Glutathione;
H
2
S: Hydrogen sulfide; HO-1: Heme oxygenase-1; IL-: Interleukin-; MAPK: Mitogen-activated protein kinase; MDA: Malondialdehyde;
MPO: Myeloperoxidase; mRNA: Messenger Ribonucleic acid; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NF-kB:
Nuclear factor kappa-light-chain-enhancer of activated B cells; NO: Nitric oxide; Nrf2: Nuclear factor erythroid 2–related factor 2; PGE2:
Prostaglandin E2; PGF2
α
: Prostaglandin F2
α
: PKG: cGMP-dependent protein kinase ROCs: Receptor-operated channels; SOD: Superoxide
dismutase; TLR4: Toll-like receptor 4; TNF-
α
: Tumor necrosis factor-alpha; TRAF6: TNF receptor associated factor 6; TRPV1: Transient
receptor potential cation channel subfamily V member 1; VOCs: Voltage-operated channels.
3. Materials and Methods
Literature Survey Databases
This literature review was carried out based on an electronic search in the Sciencedirect,
Pubmed and Springer link databases in 2020. The keywords used were “Lamiaceae”
“antinociceptive” “pain”, “analgesic” and “anti-inflammatory”. Almost 1200 articles were
found, and after an extensive survey, 217 articles were selected, which described the
antinociceptive and/or anti-inflammatory potential of natural compounds to relieve pain.
4. Conclusions
The chemical characteristics and the pharmacological properties of the Lamiaceae con-
stituents are of interest to researchers, laboratories, and pharmaceutical companies. During
the last few decades, the mechanisms of action of the different secondary metabolites of the
Lamiaceae family have been broadly investigated by means of
in vivo
and
in vitro
assays
to confirm their participation in the modulation of pain and in the cascade of inflammation
mediators. This work summarizes part of the reported scientific knowledge regarding
the secondary metabolites of some specific Mexican species of the Lamiaceae that have
shown activity for pain relief, highlighting the participation of terpenes, flavonoids, and
phenolic acids as potential alternatives for new drug therapies. As a result of this review, it
is important to mention that few studies have been reported regarding Mexican genera
of this family; for example, Calosphace is one of the largest subgenera of Salvia in all the
world, mainly found in Mexico, but it has barely been investigated regarding its potential
biological activities and their bioactive constituents. The scientific evidence regarding the
different bioactive constituents found in species of the Lamiaceae family demonstrates that
several species of this family require further investigation in preclinical studies, but also
in controlled clinical trials to evaluate the efficacy and safety of these natural products to
support their therapeutic potential in pain relief and/or inflammation, along with other
health conditions.
Author Contributions:
Conceptualization: M.E.G.-T., G.F.M.-P. and A.H.-L.; methodology, M.E.G.-T.,
G.F.M.-P., A.H.-L., M.G.V.-D., M.M.-G., E.A.-H. and M.I.D.-R.; validation, M.E.G.-T., G.F.M.-P., A.H.-L.,
M.M.-G., E.A.-H., M.I.D.-R. and F.P.; formal analysis, M.E.G.-T., G.F.M.-P., A.H.-L., M.M.-G. and E.A.-H.;
investigation, M.E.G.-T., G.F.M.-P., A.H.-L., M.G.V.-D., M.M.-G., E.A.-H., M.I.D.-R. and F.P.; resources,
M.E.G.-T., G.F.M.-P., A.H.-L., M.M.-G., E.A.-H. and F.P.; writing—original draft preparation, M.E.G.-T.,
G.F.M.-P., A.H.-L., M.G.V.-D., M.M.-G., E.A.-H., M.I.D.-R. and F.P.; writing—reviewand editing, M.E.G.-T.,
G.F.M.-P. and A.H.-L.; visualization, M.E.G.-T. and A.H.-L.; project administration, M.E.G.-T. and F.P. All
authors have read and agreed to the published version of the manuscript.

Molecules 2021,26, 7632 19 of 27
Funding:
This work was partially supported by Consejo Nacional de Ciencia y Tecnología (CONA-
CYT) grant numbers 226454 and 256448 and Institutional projects numbers INP-NC123280.0 and
INP-NC17073.0. G.F.M.-P thanks academic training and CONACYT Fellowship number 631351.
Data Availability Statement:
The data presented in this study are available on request from the
corresponding author.
Acknowledgments:
We thank to Psych. Marissa González for proof-reading the English version of
this manuscript.
Conflicts of Interest: The authors declared no conflict of interest.
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