**5.4 Linalool**

*Pain Management - Practices, Novel Therapies and Bioactives*

and chemotherapeutic potentials [13, 52–54].

responses found in osteoarthritis [56].

**5.2 Myrcene**

**5.3** α**-Terpineol**

used as a sedative [50, 52].

antioxidant, anti-inflammatory, vasorelaxant, anticarcinogenic, chemopreventive,

The analgesic effect is helpful in relieving headaches and stomach ache, relaxing the muscles, and preventing muscle stiffness. It also helps to overcome fatigue and it plays a vital role in relaxing and stabilizing the nervous system and, therefore, is

Yoon et al. [55] carried out a study to verify the pharmacological and biological effects of limonene on the production of pro-inflammatory cytokines and inflammatory mediators in RAW 264.7 macrophages and concluded that limonene effectively inhibited lipopolysaccharide-induced nitric oxide (NO) and prostaglandin E2 production that included dose-dependent decreases in the expression of inducible nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. The same study also showed inhibition of macrophage-cytokine production [55]. A beneficial antioxidant effect via increased iNOS and COX-2 protein expression was found in ulcerative colitis rat models [53]. Moreover, systemic application of limonene reduced nociceptive behaviors via H2O2-induced TRPA1 activation, and this effect is related to the inflammatory pain [51]. Myrcene and limonene inhibit IL-1β-induced

In conclusion, D-Limonene presented significant antinociception in different models of nociception without opioid receptor stimulation [57]. Instead, it is more likely related to the appreciable anti-inflammatory activity of this compound [58].

Myrcene or β-myrcene is a monoterpene polyunsaturated acyclic found in nature, originally isolated from lemon grass oil (*Cymbopogon citratus*) [58]. Besides its effect on both central and peripheral sites through endogenous opioids and α2-adrenoreceptors, it was also shown to inhibit lipopolysaccharide [LPS]-induced inflammation including cell migration and production of NO, along with signifi-

α-Terpineol is a volatile monoterpene alcohol, relatively nontoxic, and one of the major components of the essential oils of various plant species, being a nonirritant at 1–15%, and non-phototoxic [13]. There are three isomers, α-, β-, and γ-terpene, with the latter two differing only by the location of the double bond [51]. It is the third most representative monoterpene in citrus species [60]. It has insecticidal, antimicrobial, antispasmodic, anticonvulsant [47], antinociceptive, and immunostimulant properties, and it increases the skin's permeability to soluble compounds [60].

Studies have found that α-terpineol possesses peripheral and central analgesic

properties [7]. A research conducted on mice, using carrageenan and TNF-α induced hypernociception, showed increase of the mechanical threshold of hypernociceptive behavior by α-terpineol, probably by the inhibition of inflammatory mediators (inhibiting the release of substance P and other inflammatory molecules such as serotonin, histamine, bradykinin, and prostaglandins) [60]. α-Terpineol showed an antioxidant activity as it was able to suppress the superoxide production by agonist-stimulated monocytes [7]. Moreover, α-terpineol showed higher COX-2 activity inhibition than aspirin, the most popular NSAID, and most potently inhibited the expression of pro-inflammatory cytokines and NF-κB activation [7, 61]. α-Terpineol also showed antinociceptive effect in the capsaicin (neurogenic origin), glutamate, and formalin-induced orofacial noci-

cant inhibition of c-interferon and IL-4 production [58, 59].

**278**

ception tests [51, 62, 63].

Linalool is an acyclic oxygenated monoterpene reported to be the major volatile component of the essential oils of several aromatic species, including the Rutaceae family, with sedative, antidepressant, anticancer, antifungal, and pesticidal properties [13]. It is the most studied monoterpene in various painful conditions [58]. A research on adult female Swiss mice treated with a single intraperitoneal injection of (−)-linalool (50 or 200 mg/kg) or multiple treatments given chronically (twice daily for 10 days; 50 mg/kg, i.p.) showed that (−)-linalool significantly reduced CFA-induced mechanical hypersensitivity (complete Freund's adjuvant) and produced effective reduction in CFA-induced paw edema following the acute treatment [61, 64]. Following intraperitoneal administration in mice, linalool was found to produce antinociceptive and antihyperalgesic effects in different animal models in addition to its anti-inflammatory properties [65]. (−)-Linalool acts as analgesic on several receptors, including opioids, adenosine A1 and A2, cholinergic M2, and produces changes in K+ channels, thus exerting analgesic-like activity [58, 66].

Some recent studies demonstrate that (−)-linalool inhibits transient receptor potential A1 (TRPA1) and N-Methyl-D-aspartate (NMDA) channels and decreases the nociception induced by cinnamaldehyde or capsaicin [58, 67].

It is neither toxic nor irritable to skin and presents an extremely low risk of skin sensitization [13]. However, due to poor oral availability, despite the biological properties of (−)-linalool, its use in the treatment of painful and inflammatory disorders is still limited [51]. Nascimento et al. [68] used pure 95% linalool, complexed and noncomplexed in β-cyclodextrin (used to increase aqueous solubility and bioavailability of monoterpenes), in an animal model of fibromyalgia. They found that both formulations had an anti-hyperalgesic effect, with the complexed form being more effective and producing a longer lasting effect (for 24 h after administration) [68]. Analgesic effect of linalool on acute central nociception (hot plate), visceral (acetic acid), and chronic pain models of neuropathic origin, and the opioid and glutamatergic systems are probably involved in this action [51, 62, 67, 69]. One preclinical trial showed that linalool from rosewood was able to reduce the action potential amplitude assessed using an isolated nerve in the single sucrose gap technique, showing it blocked neuronal excitability [70].

### **5.5 Pinene**

α-Pinene is an organic compound of the terpene class, one of two isomers of pinene, the other being β [30]. The effects of *Ugni myricoides* (Kunth) O. Berg essential oil and its major constituent, α-pinene [52.1%], were analyzed in inflammatory and neuropathic models of hypernociception in mice, and the results showed that the oil significantly prevented mechanical hypernociception induced by carrageenan or complete Freund's adjuvant (CFA), and those effects were attributed to α-pinene, which clearly has a potential role for the management of

inflammatory and neuropathic pain [61]. Furthermore, the effect on inflammatory processes were observed in studies performed *in vivo*, in which repeated treatments with α-pinene [5–50 mg/kg, p. o.] were able to abolish the mechanical sensitization induced by CFA or by the partial ligation of the sciatic nerve [58]. In addition, it has been shown that α-pinene has anti-inflammatory and anti-catabolic activities in human chondrocytes [56].

β-Pinene is present in high amounts [5.1–13.1%] in lime citrus oil [32]. In animal models, β-pinene showed to be effective only on acute central nociception, yet, it was able to reverse the antinociceptive effect of morphine in tests equivalent to the effect of naloxone [58].

#### **5.6 p-cymene**

Biological precursor of carvacrol, p-cymene occurs in oranges and tangerines [51, 71]. Different behavioral tests of nociception in animal models showed that it exerted both peripheral and central antinociceptive action [51]. A study investigated the antinociceptive potential of p-cymene in mice models of orofacial nociception induced by formalin, capsaicin, and glutamate, and results showed that the treatment with p-cymene at all doses reduced the nociceptive behavior in all nociception tests, suggesting an action in both neurogenic and inflammatory pain [71]. Moreover, tests conducted on Swiss mice showed decreased mechanical hypernociception, reduced leukocyte and neutrophils migration, and reduced TNF-α level [51]. Like other previously mentioned terpenic compounds, p-cymene has a relatively short pharmacological half-life and bioavailability; so, complexation with β-cyclodextrin has shown to improve its analgesic and anti-inflammatory effects through improved bioavailability [72].

#### **5.7 Nerol**

This acyclic monoterpene alcohol is found in many essential oils, *Citrus aurantium* among them [51]. In the oxazolone-induced colitis model, González-Ramírez et al. [73], observed antinociceptive effect of nerol [30 mg/kg], which led to a significant reduction on expression of some pro-inflammatory cytokines, like IL-13 and TNF-α, which are highly characteristic for gastrointestinal tract disorders [51].

#### **6. Analgesic potential of some essential oils**

All essential oils with high D-limonene content pose significant free radical scavenging effect, predominantly disabling production of reactive oxygen species (ROS) [13]. Essential oils of sweet orange, lemon, and bergamot are most widely used to test analgesic effects in animal models. More recently, some essential oil blends were tested in various human cell models and showed significant positive effects on inflammation, immune modulation, cell cycle regulation, and other cellular functions [8].

#### **7. Safety**

Bioactive compounds found in essential oils are quickly absorbed after dermal, oral, or pulmonary administration, and are excreted by the kidneys in the form of phase-II conjugates [66]. Only a small fraction is eliminated unchanged by the lungs [66]. Generally speaking, Citrus essential oils are nontoxic, non-mutagenic,

**281**

*Analgesic Potential of Monoterpenes from Citrus Essential Oils*

rabbits, and be carcinogenic and teratogenic [75].

and noncarcinogenic, meaning that sweet orange, bitter orange, neroli, petitgrain, lemon, lime (both distilled and expressed), bergamot, and grapefruit oils have

However, a mixture of two optic isomers of limonene present in the essential oils of citrus fruits was shown to be hepatotoxic, have a sedative muscular relaxing effect in mice and be nephrotoxic only in male rats, cause small-scale irritation in

The fast metabolism and short half-life of active compounds have led to the belief that there is a minimum risk of accumulation in body tissues [12]. In humans, ingestion of D-limonene resulted in an excretion of 52–83% of the dose in the urine within 48 hours [49]. However, limonene at 20 g caused diarrhea and transient proteinuria in healthy volunteers [75]. Vapor inhalation caused respiratory disorders coupled with a decrease in vital capacity [75]. No neurological disorders occurred, but chronic exposure can induce irritation and allergy; therefore, it must be mentioned in the list of "ingredients" of cosmetics [75]. It is not acutely toxic, nephrotoxic, or carcinogenic for humans, but the oxidized D-limonene may carry some toxicity, hence, citrus oils should be stored in dark at 4°C [13]. Nevertheless, unoxidized D-limonene is listed as an allergen by the EU, and moderately allergenic

All phytochemicals present in essential oils presented here may simultaneously target multiple mechanisms involved in chronic pain. Despite long history of therapeutic applications of essential oils for the treatment of pain, only recently more attention was given to their components and elucidating mechanisms behind their antioxidant, anti-inflammatory, and antinociceptive potential. Monoterpenes are key holders of analgesic potential in Citrus essential oils, especially D-limonene and linalool. Essential oils are generally considered as safe; however, due to low bioavailability and stability, monoterpenes are complexed with β-cyclodextrin to improve their analgesic activity [62, 69]. Further studies are encouraged to determine the analgesic potential of Citrus essential oils in managing daily activities of people

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of

*DOI: http://dx.doi.org/10.5772/intechopen.93265*

GRAS status [74].

in Germany [13].

**8. Conclusions**

with a long-term history of chronic pain.

**Conflict of interest**

interest.

#### *Analgesic Potential of Monoterpenes from Citrus Essential Oils DOI: http://dx.doi.org/10.5772/intechopen.93265*

and noncarcinogenic, meaning that sweet orange, bitter orange, neroli, petitgrain, lemon, lime (both distilled and expressed), bergamot, and grapefruit oils have GRAS status [74].

However, a mixture of two optic isomers of limonene present in the essential oils of citrus fruits was shown to be hepatotoxic, have a sedative muscular relaxing effect in mice and be nephrotoxic only in male rats, cause small-scale irritation in rabbits, and be carcinogenic and teratogenic [75].

The fast metabolism and short half-life of active compounds have led to the belief that there is a minimum risk of accumulation in body tissues [12]. In humans, ingestion of D-limonene resulted in an excretion of 52–83% of the dose in the urine within 48 hours [49]. However, limonene at 20 g caused diarrhea and transient proteinuria in healthy volunteers [75]. Vapor inhalation caused respiratory disorders coupled with a decrease in vital capacity [75]. No neurological disorders occurred, but chronic exposure can induce irritation and allergy; therefore, it must be mentioned in the list of "ingredients" of cosmetics [75]. It is not acutely toxic, nephrotoxic, or carcinogenic for humans, but the oxidized D-limonene may carry some toxicity, hence, citrus oils should be stored in dark at 4°C [13]. Nevertheless, unoxidized D-limonene is listed as an allergen by the EU, and moderately allergenic in Germany [13].
