**2. Pharmacology of bioactive compounds**

Bioactive compounds, produced by plants, are designated secondary metabolites. Metabolites can be divided into primary and secondary. Primary metabolites are those involved in growth and development, such as carbohydrates, amino acids, proteins, and lipids, while secondary metabolites, which often have unusual chemical structures, are not required for primary metabolic processes and are believed to support plant survival with respect to local challenges. Thus, the production of secondary metabolites of a given species will be related to their need for survival. Among the secondary metabolites, some compounds have an effect on biological systems, being considered bioactive, which defines them as secondary metabolites of plants that induce pharmacological or toxic effects in humans or animals [42].

Bioactive compounds can be extracted from various parts of the plant, such as the leaves, seeds, flowers, bark, roots, and fruits [43]. These compounds form the essential oil of the plant, resin, or other plant products, which can be extracted in a concentrated form (containing secondary metabolites) or by means of solvents, such as water, ethanol, methanol, chloroform, dichloromethane, ether, and acetone [42]. The best solvent or extraction procedure will depend on the botanical material to be used as well as of the type of secondary metabolites being obtained. In addition, various substances can be isolated from the essential oil or chemical extracts, such as terpenes, flavonoids, alkaloid, and steroids that already have some known property that can be used in the treatment of FM [43].

#### **2.1. Essential oils**

**Natural product Dose/route Type of study Sample Molecular** 

*Ginkgo biloba* 200 mg/day; po Clinical 25 subjects of

Linalool 25 mg/kg; po Preclinical Male Swiss mice

Citronellal 50 mg/kg; po Preclinical Male Swiss mice

400 mg/kg; ip Preclinical Male Wistar rats

(*n* = 5/group)

either sex

(*n* = 8/group)

(*n* = 7/group)

(*n* = 8/group)

(*n* = 8/group)

(*n* = 8/group)

Preclinical Male Swiss mice

Preclinical Male Swiss mice

Clinical 126 women and 4 men

*Note*: ATP, adenosine triphosphate; ip, intraperitoneal; po, oral administration; sc, subcutaneous; SP, substance P; to,

**Table 2.** Summary of studies involving bioatctive compounds aimed at the treatment of fibromyalgia and their main

20 mg/kg; po Preclinical Male Swiss mice

All preclinical studies used the chronic muscle pain model induced by acid saline.

**Plant extracts** *Phyllanthus amarus* and *Phyllanthus fraternus*

62 Discussions of Unusual Topics in Fibromyalgia

**Terpenes**

α-Terpineol 25, 50, and 100

β-Caryophyllene 10 and 20 mg/

Capsaicin 0.075% (3 times/

mechanisms of action.

day); to

topically; TRPV1, transient receptor potential vanilloid 1.

**Saponin** Hecogenin acetate

**Alkaloid**

\*

kg; po

mg/kg; po

**mechanism**

Opioid, glutamatergic, and blocking of neuronal excitability

Opioid, glutamatergic, SP pathway, TRPV1 receptor, involvement in the descending pain pathway, and blocking of sodium channels

Opioid, serotoninergic, glutamatergic, TRPV1, and reduction of SP, with involvement in the descending pain pathway

Opioid and cannabinoid

Opioid, SP, ATP-sensitive K (+) channel, with involvement in the descending pain pathway

TRPV1 and reduction of SP **References**

Sayyad [27]

Nascimento et al. [29]

Santos et al. [30]

Oliveira et al. [31]

Quintans-Júnior et al. [32]

Quintans et al.

Casanueva et al. [34]

[33]

Opioid Chopade and

Antioxidant Lister et al. [28]

Essential oils (EOs) are derived from the secondary metabolism of aromatic plants and are mainly terpene compounds. They are volatile and usually have a strong and characteristic smell. In nature, they perform plant protection functions against predators and help attract certain animals for pollination. In industry, they are used for numerous purposes including in perfume, as antiseptics, and food preservatives but also have numerous pharmacological properties [44]. They are mixtures and may contain 20–60 compounds (or more) in varying concentrations. Usually, each EO is characterized by its major components, which may be number two or three and usually be between 20 and 70% of the oil [45].

Although the biological effect of EOs are thought to be due to the major components which define their pharmacological profiles, synergism between the molecules present in each oil, even those that are in a smaller quantity, can modulate the effects of the major components [45].

#### **2.2. Plant extracts**

Based on non-pharmacological studies and holistic or alternative medicine with the use of medicinal plants (and related products), several researchers have sought to evaluate the effects of materials obtained through NPs in clinical and preclinical studies. This research has been based on the popular and potentially dangerous belief given the chemical diversity of NPs that "what is natural, cannot do you harm." The innovative pharmacological effects that these products are able to produce are promising but due to possible side effects remain challenging at the same time [50–52]. One way to evaluate possible pharmacological effects and examine their use in folk medicine is to study plant extracts obtained through the use of several solvents [53–55]. The extraction of biological products using solvents is mainly used with fragile or delicate flower materials, which do not tolerate the heat of steam distillation. Examples of solvents which may be used to produce plant extracts are acetone, hexane, ether, methanol, or ethanol [43]. These extracts, in turn, can have a limited use due to their high viscosity, facilitating aggregation and precipitation, or the presence of proteins that induce false results, causing better ways of obtaining and fractionating the crude extracts to be sought [54].

vanilloid receptors, resulting in increased sensitivity, which is perceived as pruritus, stinging, or burning. This happens due to selective activation of type C afferent fibers, release of substance P, and cutaneous vasodilation. Capsaicin-based topical creams have been used in the treatment of painful disorders such as musculoskeletal or neuropathic disorders, probably

Natural Products as Promising Pharmacological Tools for the Management...

http://dx.doi.org/10.5772/intechopen.70016

65

Recently, Quintans-Júnior et al. [24] evaluated pretreatment with the EO from *Hyptis pectinata* loaded in a nanoemulsion thermoreversible gel in an animal model of noninflammatory chronic muscular pain, an experimental model for FM. This pharmaceutical formulation containing EO and Pluronic F127-based hydrogel produced a long-lasting and consistent antihyperalgesic effect for 10 days after a single subcutaneous application, which was reversed by naloxone (opioid antagonist) and methysergide (serotoninergic antagonist). In addition, the formulation produced a significant reduction in substance P (SP) levels in the spinal cord. Moreover, it was also shown to increase neuron activation, by Fos protein expression, in the periaqueductal gray (PAG), the nucleus raphe magnus (NRM), and the locus coeruleus (LC), the CNS areas reported to be involved in the descending pathway of pain, so it appears that the formulation acts by improving the endogenous analgesia mechanism (**Figure 3**). Other studies have demonstrated that *H. pectinata* essential oil exhibits antinociceptive effects, prob-

Nascimento et al. [25] demonstrated in the same FM animal model that *Ocimum basilicum* essential oil, rich in monoterpenes such as linalool, has an important anti-hyperalgesic profile when complexed or noncomplexed with β-cyclodextrin (β-CD). Moreover, the complexed oil produced a long-lasting anti-hyperalgesic effect when compared to the oil alone, demonstrating that the complexation process allows greater stability and bioavailability of the oil or its main compounds, such as monoterpenes. In this paper, the authors also assessed Fos protein expression in the brains of mice and found that this oil promoted the activation of the PAG, NRM, and LC, which are encephalic regions that participate in the antinociceptive effect by

The results obtained for the *O. basilicum* essential oil may be due to its action on the inhibition of SP or through blocking the neurokinin-1 receptor and the vanilloid receptor (TRPV1). Indeed, this oil also acts by glutamatergic system inhibition or by the inhibition of inflammatory pathways, because it was able to produce a reduction in orofacial nociception when caused by formalin, capsaicin, and glutamate in mice [66]. Furthermore, when assessed using an electrophysiological approach, this oil was able to inhibit an orthodromic response in the dentate hippocampal gyrus, similar to DNQX (a glutamatergic drug), an AMPA and kainate receptor antagonist. In addition, another study carried out by Venâncio et al. [67] demonstrated that the peripheral and central antinociceptive effects of *O. basilicum* essential oil are related to the inhibition of the biosynthesis of pain mediators, such as prostaglandins and

functioning by depletion of substance P in the afferent nerve endings [34, 61–63].

ably mediated by the opioid and cholinergic receptors [64, 65].

the activation of the pain inhibitory descending pathway.

prostacyclins, and its ability to interact with opioid receptors.

**3. Preclinical studies**

#### **2.3. Terpenes**

Terpenes are the largest group of secondary metabolites obtained through natural products, being made from isoprene units (five carbons (C5)). They exhibit a wide variety of structures and are the most common class of chemical compounds found in essential oils [43, 46–48]. Essential oils contain mainly monoterpenes (C10) and sesquiterpenes (C15), which are generally hydrocarbons of the general formula (C5H8)n. At a lower concentration, they are present in essential oils as diterpenes (C20), triterpenes (C30), and tetraterpenes (C40), which are larger molecules. Terpenoids are oxygen compounds that can be derived from terpenes. These compounds may present predominantly as phenols, monoterpene alcohol, sesquiterpene alcohol, aldehydes, ketones, esters, oxides, lactones, and ethers [43].

Although monoterpenes are smaller molecules than sesquiterpenes, the structure and functional properties of these groups are similar [43, 49]. Most monoterpenes are colorless, volatile, and lipophilic, which promote greater penetration through the membrane [49]. Among the activities already described, the antinociceptive properties of these compounds have received a lot of attention [50–52].

#### **2.4. Saponin**

Triterpenoid or steroidal aglycones linked to portions of oligosaccharides are called saponins. Saponins are amphipathic because of the combination of the aglycone, having hydrophobic characteristics, and sugar molecules, with a hydrophilic profile. These compounds have been studied for use in the pharmaceutical, cosmetic, agronomic, and food industries [53]. Saponins present some therapeutic activities including powerful membrane-permeabilizing agents with hypocholesterolemic, immunostimulatory, anti-inflammatory, antimicrobial, anticarcinogenic, antiprotozoan, molluscicides, and antioxidant properties [54]. The majority of plant species-producing saponins are dicotyledonous and accumulate mainly triterpenoid saponins. The monocotyledon type mainly synthesizes saponins of the steroidal type [55].

#### **2.5. Alkaloids**

Alkaloids are complex compounds that contain nitrogen. These compounds have been used in the production of various drugs, such as metronidazole (derived from azomycin) and bedaquiline (derived from quinolone) [56–60]. Capsaicin is an alkaloid derived from hot chili peppers from the *Capsicum*. This alkaloid interacts with afferent nociceptors by means of the vanilloid receptors, resulting in increased sensitivity, which is perceived as pruritus, stinging, or burning. This happens due to selective activation of type C afferent fibers, release of substance P, and cutaneous vasodilation. Capsaicin-based topical creams have been used in the treatment of painful disorders such as musculoskeletal or neuropathic disorders, probably functioning by depletion of substance P in the afferent nerve endings [34, 61–63].
