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

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.


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, 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.

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.

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).  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).

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, 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 endemic in the country, plants of the Cunila or Hedeoma genera have an endemism of up to 60% [35].

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, 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 endemic in the country, plants of the Cunila or Hedeoma genera have an endemism of up to 60% [35].

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][46][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].

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][46][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].  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.

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 involvement 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]. 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-HT 1A serotonin and CB1 cannabinoid receptors as the main mechanisms of action [99][100][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 gastrointestinal 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 inflammatory 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 associated 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 already 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 regarding 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].

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; however it was found that only a polar extract from ssp. mexicana produced spasmolytic-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 constituents [112]. In contrast, ssp. xolocotziana was associated with a spasmogenic response. The spasmolytic effects of A. mexicana were related to an activation of nicotinic receptors, 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].

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 modulate 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.

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 antiinflammatory activities are attributed to these compounds in various plant species [118]. Regarding the development of analgesics and anti-inflammatories, monoterpenes and sesquiterpenes have become a topic of interest with an increasing number of new patent applications [1,[119][120][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 antiinflammatory 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 αand 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, βcaryophylene, 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.
HO HO HO Reduction in leukocyte infiltration and TNF-α levels. [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 explored in pain and inflammation.
[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 explored in pain and inflammation.
[142] [143] Cannabinoid receptor type 2 agonist. Attenuation of Substance P and cytokines such as IL-1β, TNFα, and IL-6. [144] HO HO HO 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 explored in pain and inflammation.

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 reported 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 Marrubium 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 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.

Structure Mechanism of Action References
Tormentic acid

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 reported 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 Marrubium 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 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.

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]  [152] Increased activity of Superoxide dismutase, glutathione peroxidase and catalase.
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 blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter.
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 blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter.
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 blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter.
[  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 blocking PKC signaling and thereby the binding 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. [ 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 Ursolic acid 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 blocking PKC signaling and thereby the binding 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. [ 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.

Phenolic Compounds
Some species of the Lamiaceae family and their biological activities have been characterized 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][171][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 metabolites 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 depends 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

Phenolic Compounds
Some species of the Lamiaceae family and their biological activities have been characterized 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][171][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 metabolites 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 depends 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 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 barrier [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.

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.

Structure Mechanisms of Action References
Ferulic acid

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][171][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 phenolic 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 antiinflammatory 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. Table 5. Flavonoids commonly present in Lamiaceae and their molecular targets explored in pain and inflammation.

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.

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 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.  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.

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.

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 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.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.