1, Lázaro Gomes do Nascimento 1, Cícero Francisco Bezerra Felipe
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(0.24%) as the main constituents of the oil. Initially, mice were subjected to the formalin pain model. In this test, animals treated with the essential oils eugenol and myrcene showed reduced licking times of the paw in the first (5–10 min) and second (15–30 min) phases of nociception. On the other hand, in the hot-plate test, the essential oil increased the latency of paw withdrawal from the hot plate, even after 4 h of administration. Animals that received 5 or 10 mg/Kg of eugenol or 5 or 10 mg/kg of myrcene exhibited a significant increased latency to either lick the paw(s), or to jump from the hot plate. Pre-treatment with naloxone (1 mg/Kg, i.p.) significantly reversed the antinociceptive effects of the oil, eugenol and myrcene in the hot plate test. These data suggest that the opioid system is involved in the mediation of the antinociceptive effects of Ocimum gratissimum essential oil and its isolated active principles, eugenol and myrcene. Opioid receptors (m, κ and d) are located in several steps of the pain transmission pathway and are responsible for the direct and indirect antinociceptive activities of opioid agonists [ 122 ]. Substances that can also activate these receptors should be of great pharmacological and therapeutic importance [ 123
]. Antinociceptive effects of Ocimum micranthum essential oil (15, 25, 50 and 100 mg/Kg, p.o.) were studied by Pinho et al. [ 42 ] in mice subjected to the following pain models: acid-induced writhing, formalin and hot-plate tests. Chemical analyses of the essential oil revealed the following composition: (E)-methyl cinnamate (33.6%), limonene (12.9%), carvone (9.6%), β-caryophyllene (8.03%), linalool (7.2%), (Z)-methyl cinnamate (5.92%), β-selinene (3.95%), α-selinene (2.82%), α-humulene (2.7%) and trans-α-bergamotene (2.68%). Initially, Ocimum micranthum essential oil significantly reduced the acetic acid-induced writhing responses. Under formalin-induced nociception, only the second phase was significantly inhibited. No effect was observed in mice subjected to the hot-plate test. Based on the lack of significant results in the first phase of the formalin test and in the hot plate model Pinho et al. [ 42 ] conclude that the essential oil inhibits nociception of inflammatory origin acting at the peripheral rather than supraspinal and/or spinal level. However, as β-caryophyllene is found in the composition of the essential oil, early studies showing that β-caryophyllene has both antinociceptive and anti-inflammatory actions [ 124 –
] may be due to its cannabinoid receptor 2 (CB2) activating properties [ 127
]. The formalin model of nociception may not be a reliable model to reveal the actions of substances outside of certain pharmacological profiles. 3.15. Peperomia serpens (Sw.) Loud Essential Oil The genus Peperomia, belonging to Piperaceae, comprises an estimated 1500–1700 species [ 128
]. Peperomia serpens (Sw.) Loud. In the Amazon rainforest it is known as “carrapatinho” or “carapitinha” growing wild on differing host trees. The decoction of its leaves is recommended for anti-inflammatory and analgesic properties, particularly against flu, asthma, cough, earache and irritation provoked by ant bites [ 129
]. Other oils of Peperomia contain mono- and sesquiterpenes, as in the case of Peperomia serpens, whose main constituents were α-humulene, (E)-caryophyllene, (E)-nerolidol and (Z)-nerolidol acetate [ 130
]. Pinheiro et al. [ 43 ] evaluated the antinociceptive effect of the essential oil from the whole plant (31.25, 62.5, 125, 250 and 500 mg/Kg, p.o.) in mice subjected to the acetic acid-induced writhing, formalin and hot plate tests. GC-MS analysis indicated the presence of the following major constituents: (E)-Nerolidol (38.0%), ledol (27.1%), α-humulene (11.5%), (E)-caryophyllene (4.0%) and α-eudesmol (2.7%). Oral pretreatment with Peperomia serpens (Sw.) Loud essential oil evoked dose-dependent inhibition of acetic acid-induced abdominal writhes in mice. The writhing test induced by acetic acid in mice is described as a typical model of study of inflammatory pain, used to screen when evaluating analgesics or anti-inflammatory drugs [ 131
]. The local irritation provoked by intraperitoneal injection of acetic acid triggers the liberation a variety of mediators such bradykinin, substance P and prostaglandins, and especially PGI2, as well as some cytokines such as IL-1β, TNF-α and IL-8 [ 132 ]. Such mediators activate chemosensitive nociceptors that contribute to the development of this type of inflammatory pain, which is known to be sensitive to non-steroidal anti-inflammatory drugs (NSAIDs). Like indomethacin (10 mg/Kg, p.o.), the essential oil was able to reduce dose-dependent acetic acid-induced writhing response,
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suggesting a mechanism resulting in peripheral antinociceptive effect. Pretreatment of animals with the essential oil showed no antinociceptive effect in mice subjected to the hot-plate test. Such results indicate non-participation in thermal stimulation associated with central neurotransmission where heat activates nociceptors (Aδ, and C fibers), driving the momentum to the dorsal horn of the spinal cord subsequently to cortical centers. Finally, in the formalin test, the oil inhibited both first (neurogenic pain), and second (inflammatory pain) phases of the test. Such effect was not altered by naloxone pretreatment [ 43 ]. The formalin test is a very useful method for not only assessing antinociceptive drugs but also for helping to elucidate their action mechanism. Centrally acting drugs such as narcotics inhibited both phases equally. Peripheral acting drugs such as NSAIDs and corticoids inhibited mainly the second phase [ 60 ]. According to Pinheiro et al. [ 43 ], Peperomia serpens (Sw.) Loud essential oil induces its antinociceptive action by direct action on nociceptive afferent fibers not interacting with the opioid system. In addition, the oil was effective in the second phase of the formalin test indicating anti-inflammatory activity. These results suggest that the antinociceptive action of Peperomia serpens (Sw.) Loud essential oil is more related to a peripheral mechanism than a central one. 3.16. Pimenta pseudocaryophyllus (Gomes) L.R. Landrum Essential Oil Pimenta pseudocaryophyllus (Gomes) L.R. Landrum (Myrtaceae) is a plant popularly known in Brazil as pau-cravo, louro-cravo, louro, craveiro, craveiro-do-mato, chá-de-bugre and cataia [ 133 –
]. In folk medicine, the leaves have been used to produce a refreshing drink with calming, diuretic and aphrodisiac properties, as well as to treat colds with their complications, and digestive and menstrual problems [ 133 –
]. De Paula et al. [ 44 ] studied the antinociceptive effect of the essential oil obtained from leaves of Pimenta pseudocaryophyllus in mice subjected to the acetic acid-induced writhing test. GC-MS analysis indicated the presence of oxygenated mono- and sesquiterpenes (69.65% and 13.7%, respectively), and monoterpene aldehydes neral and geranial were the major components (27.59% and 36.49%, respectively), which are referred to as citral when their isomers are mixed [ 44 ]. The essential oil at doses of 60, 200 and 600 mg/Kg, p.o., showed significant dose-dependent inhibitory effects on abdominal contortions induced by intraperitoneal acetic acid in mice. De Paula et al. [ 44 ] suggest that inhibition by Pimenta pseudocaryophyllus essential oil of the contortions induced by chemical stimulation in mice in this study may be due to both peripheral and central mechanisms. However, more investigations are needed to reinforce their case. 3.17. Piper alyreanum C.DC Essential Oil Piper alyreanum C.DC, a member of the Piperaceae family, is a small tree that is widely distributed in tropical and subtropical regions, and greatly in North and South America. In Brazil, it is found in the North, mainly in the Amazon forest and is popularly known as “João brandinho”, “pimenta longa”, “pimenta longa da mata”, “pimenta de cobra” and “pani-nixpu”. Moreover, this plant has been used as an immunomodulator, analgesic and antidepressant in folk medicine [ 45 ].
aleyreanum was evaluated. The essential oil (30, 100, 300 and 1000 mg/Kg, p.o.) was tested in mice subjected to the formalin test. GC-MS analysis indicated the presence of caryophyllene oxide (11.5%), β -pinene (9%), spathulenol (6.7%), camphene (5.2%), β-elemene (4.7%), myrtenal (4.2%), verbenone (3.3%) and pinocarvone (3.1%) as the major constituents [ 45 ]. The results indicated that the essential oil significantly inhibited both the neurogenic and inflammatory phases of formalin-induced licking. However, its antinociceptive effects were significantly more pronounced in the second phase of this pain model. Also, it was noted that pre-treatment with the non-selective opioid receptor antagonist naloxone (1 and 5 mg/Kg, i.p.) did not reverse the antinociception caused by the essential oil [ 45 ].
such as acetylsalicylic acid, indomethacin, paracetamol and diclofenac. However, these drugs can dose-dependently attenuate the second phase of formalin-induced licking [ 25 ,
, 137
]. Moreover, it Molecules 2016, 21, 20 13 of 29
has also been reported that morphine, some tachykinin receptor antagonists, non-selective excitatory amino acid antagonists and both B1 and B2 bradykinin receptor antagonists are able to inhibit both phases of the formalin test [ 138
, 139
]. Lima et al. [ 45 ] suggest that the opioid system is unlikely to be involved in the antinociceptive action of Piper alyreanum essential oil. This is inferred by the fact that pre-treatment of animals with naloxone, a nonselective opioid receptor antagonist, did not inhibit the antinociceptive effect of morphine in the formalin model. 3.18. Satureja hortensis L. Essential Oil Satureja hortensis L. belongs to the Lamiaceae family and is a well-known medicinal herb in Iran. Aerial parts of this plant are frequently used as a food additive and also as a traditional remedy to treat various disorders including cramps, muscle pain, nausea, indigestion, diarrhea and infectious diseases, based on the antispasmodic, antidiarrheal, antibacterial and antifungal properties of their constituents [ 140
– 142
]. The essential oil (100 and 200 µL/Kg) from the seeds of Satureja hortensis in mice subjected to the acetic acid-induced writhing and formalin tests was tested [ 143 ]. A chemical analysis indicated the presence of γ-terpinene (50.5%) and thymol (32.7%) as the main constituents. In the acetic acid-induced writhing test, the essential oil significantly inhibited abdominal writhes. In the formalin test, the essential oil presented antinociceptive activity only in the late phase. Acetic acid-induced abdominal pain is not a specific model, but because of its similarity to the signs of human visceral disorders it has been extensively used for the screening of analgesic drugs [ 78 , 144 ]. In this test, many drugs including opioids, nonsteroidal anti-inflammatory drugs, antispasmodics, calcium channel blockers and antihistamines show analgesic activity [ 57 , 78 ]. Pain in the early phase is predominantly caused by the activation of C-fibers, while in the late phase, a combination of an inflammatory reaction in peripheral tissue and functional changes in the dorsal horn of the spinal cord are involved [ 65 ]. Finally, the authors suggested that the antinociceptive effect of the essential oil is dependent upon peripheral mechanisms. 3.19. Senecio rufinervis D.C. Essential Oil Senecio rufinervis D.C. (Asteraceae) is a tall aromatic herb, leaves are shortly stalked, ovate, long pointed, sharply toothed; the lower surface is white and tomentose except for the nerves. The flowers are yellow and present as small rounded corymbs [ 145
]. The plant grows in Uttarakhand, India at an altitude of 1800–3000 m and has no traditional or commercial use. Senecio rufinervis is an aromatic plant containing essential oil which is produced by many plants and confirms analgesic and antiinflammatory activities [ 146 –
]. It was studied the antinociceptive effect of the essential oil from the dried leaves of Senecio rufinervis (25, 50 and 75 mg/Kg, i.p.) in mice subjected to the acetic acid-induced writhing and hot-plate tests [ 46 ]. A chemical analisys of the essential oil showed the presence of germacrene (40.19%) as the major constituent, followed by β-pinene (12.23%), β -caryophyllene (6.21%) and β-longipinene (4.15%). In the acetic acid-induced writhing test, the essential oil significantly and dose-dependently inhibited the acetic acid-induced abdominal twitches. Similarly, the essential oil significantly increased the latency of reaction time 15 and 30 min after the administration of drug. Therefore, Mishra et al. [ 46 ] demonstrated significant analgesic activity in both pain models. The acetic acid-induced writhing reaction in mice, described as a typical model for inflammatory pain, has long been used as a screening tool for the assessment of analgesic or anti-inflammatory properties of new agents [ 152
]. The hot-plate method is considered to be selective for screening of the compound acting through the opioid receptor, but other centrally acting drugs, including sedatives and muscle relaxants, have also shown activity in this test [ 153
]. From the above results the authors affirm that the oil possesses both peripheral and central analgesic effect. Yet, the peripheral analgesic effect produced by oil was more pronounced than the central analgesic effect.
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3.20. Tetradenia riparia (Hochst.) Codd Essential Oil Tetradenia riparia (Hochst.) Codd (Lamiaceae) is an herbaceous shrub that occurs throughout tropical Africa [ 154
, 155
]. T. riparia possesses a variety of medicinal properties. In South Africa, T. riparia has traditionally been used in the treatment of cough, dropsy, diarrhea, fever, headaches, malaria and toothache [ 154
]. In Brazil, Tetradenia riparia was introduced as an exotic ornamental plant and is grown in parks, home gardens and orchards in the state of São Paulo. In Brazil, it is popularly known as incenso, lavândula, limonete, pluma-de-névoa, or falsa mirra and is mainly used as an ornamental [ 155 ]. The antinociceptive effect of the essential oil obtained from the leaves of Tetradenia riparia (10 mg/Kg, p.o.), collected in different seasons, was investigated by Gazim et al. [ 47 ] in mice subjected to the acetic acid-induced writhing test. GC-MS analysis indicated that oxygenated sesquiterpenes were the dominant compounds, such as 14-hydroxy-9-epi-caryophyllene (18.27%–24.36%), cis-muurolol-5-en-4-α-ol (7.06%–13.78%), α-cadinol (5.36%–8.33%) and ledol (4.39%–8.74%). The content of the essential oil varied significantly by season. The oxygenated sesquiterpenes that varied most by season were 14-hydroxy-9-epi-caryophyllene (maximum 24.36% in spring, and absent in winter) and cis-muurolol-5-en-4-α-ol with a maximum of 13.78% in autumn and a minimum of 7.06% in winter. In the acetic acid-induced writhing test, the essential oil inhibited constrictions and this activity was not affected by seasonal variation. However, no additional information about the mechanism of action is given by the authors. 3.21. Teucrium stocksianum Essential Oil The Lamiaceae family is rich in essential oils. The main components of the essential oil reported from the genus Teucrium are alpha pinene, linalool, carophyllene oxide, germacrene D, beta-carophyllene and delta-cadinene. Teucrium stocksianum is a species found in North Western Pakistan. It is a perennial aromatic herb of 10–30 cm height having grayish-white leaves and sessile flowers. It grows in the shades of the mountains. This plant is used in folk medicine for treating diarrhea, cough, jaundice and abdominal pain [ 156
]. In the work developed by Shah et al. [ 48 ], a GC-MS analysis of the essential oil obtained from the aerial parts of Teucrium stocksianum revealed the presence of δ-cadinene (12.92%), α-pinene (10.3%), myrcene (8.64%), β-caryophyllene (8.23%), germacrene D (5.18%), limonene (2.36%), elemol (2.13%) and γ-cadinene (1.86%) as the main compounds. The antinociceptive activity of the essential oil (20, 40, 80 and 160 mg/Kg, i.p.) was assessed in mice subjected to the acetic acid induced writhing test. In this model of pain, the oil decreased the number of writhings. The acetic acid induced writhing protocol is most commonly used for evaluating antinociceptive activity of medicinal plants. In this model, prostaglandins, initially PGE2 and then PGF2α and free arachidonic acid are released from tissue phospholipids and, consequently, their levels in the peritoneal fluids increase due to intraperitoneal administration of the irritant, acetic acid. This results in localized inflammatory response and pain sensation due to increases in capillary permeability. Substances which counteract this phenomenon exert antinociceptive effects and reduce pain sensations [ 64 ]. Despite reporting these effects, more investigations are needed in order to elucidate the mechanism of action of the material. 3.22. Ugni myricoides (Kunth) O. Berg Essential Oil The Myrtaceae family comprises a large number of plants, including at least 138 genera and approximately 3800 species [ 157 ,
]. Several experimental studies have demonstrated the biological activity of extracts, essential oils, or fractions obtained from different species of this family, such as Psidium guajava L., Syzygium jambos (L.) Alston, and Plinia glomerata (O. Berg) Amshoff [ 3 – 6 ]. Ugni myricoides (Kunth) O. Berg (syn. Myrtus myricoides Kunth), one of the four members of this genus, is found in Brazil, Southern Mexico, Central America, Colombia, Venezuela, Guyana, Ecuador and Peru [ 159 ]. The plant can be recognized by its small (1–1.5 cm long), opposite, coriaceous, dark green, aromatic, obovate to elliptic leaves and by its solitary white or pink flowers. The spherical Molecules 2016, 21, 20 15 of 29
fruits, of about 1 cm in diameter, are edible, fleshy and purple to black in color. Quintão et al. [ 49 ] studied the antinociceptive effect of essential oil from the leaves of Ugni myricoides (Kunth) O. Berg (5, 10, 12.5, 25 and 50 mg/kg, p.o.) in mice subjected to the following pain models: carrageenan- and CFA (complete Freund’s adjuvant)-induced mechanical hypernociception (evaluated by Von Frey hairs-induced hindpaw withdrawal response method), and used partial ligation of sciatic nerve tests. A GC-MS analysis of the essential oil indicated the presence of α-pinene (52.1%), 1,8-cineole (11.9%), α-humulene (4.6%), caryophyllene oxide + globulol (4.5%), humulene epoxide II (4.2%) and β -caryophyllene (2.9%) as the main components. In the first test, oral treatment with the essential oil was able to significantly inhibit the mechanical hypernociceptive response induced by carrageenan. This effect was observed for up to 48 h after treatment with the essential oil. Similar results were obtained with animals injected with CFA, in which Ugni myricoides (Kunth) O. Berg essential oil postponed the onset of hypernociceptive threshold for up to 24 h after CFA paw injection [ 49 ].
reduced by the pretreatment of animals with the pure monoterpene compound present as the major constituent in the oil, α-pinene (5–50 mg/Kg, p.o.), given 24 h before the injection of CFA. In the partial ligation of sciatic nerve tests, the essential oil was capable of diminishing the hipernociceptive response induced by this chronic constriction injury. This effect was observed for up to two days after the end of the treatment, and α-pinene administration was also capable of abolishing the hypernociceptive response in this model of pain. Quintão et al. [ 49 ] suggest that oral treatment with Ugni myricoides essential oil presents important effects in preventing and also reverting mechanical sensitization caused by inflammatory and neuropathic states. This conclusion is supported by results showing that the mechanical hypernociception induced by i.pl. injection of carrageenan or CFA in mice was strikingly reduced by both the essential oil and its major constituent. The injection of carrageenan into the hindpaws of mice induces a local inflammatory response, characterized by paw edema, neutrophil migration, and the release of several mediators such as cytokines, which precedes inflammatory hypernociception [ 160
]. Additionally, CFA produces an inflammatory response that is associated with a striking modification in the activity of superficial (I and II), and deep (V and VI) laminal dorsal horn neurons receiving noxious inputs [ 161
]. Also, chronic constriction nerve injury (such as partial ligation of the sciatic nerve) produces an inflammatory response that is associated with modification of the spinal cord neurons, culminating in altered neuronal excitability and conduction during evoked and spontaneous activity [ 162 ,
]. Quintão et al. [ 49 ] conclude that the essential oil obtained from the leaves of Ugni myricoides has relevant oral anti-hypernociceptive properties for persistent models of inflammatory and neuropathic pain in mice. However, the mechanism through which Ugni myricoides essential oil exerts its anti-hypernociceptive actions remains unclear and requires further investigation. 3.23. Valeriana wallichii DC Essential Oil Valeriana (Valerianaceae) originated from the Latin word “valere” meaning “to be in good health”, as a source of important phytomedicines, has been used for curing nervous unrest, emotional troubles, epilepsy, insanity, snake-poisoning, eye-trouble and skin diseases [ 164 ]. Valeriana wallichii DC grows wild in the temperate Himalaya at an altitude of 1500–3000 m and is an ingredient of herbal medicines in Indian systems of medicine. Sah et al. [ 50 ] evaluated the antinociceptive effect of the essential oil isolated from the roots and rhizomes of Valeriana wallichii DC chemotype (patchouli alcohol) (20, 40 and 80 mg/Kg, p.o.) in mice subjected to the acetic acid induced writhing and tail-flick tests. GC-MS analysis of the essential oil revealed the presence of δ-guaiene (10%), seychellene (8%), acetoxyl patchouli alcohol (5%) and virdifloral (5%). Initially, the administration of the essential oil produced a significant inhibition of writhings. The effect was potentiated in the presence of aspirin (5 mg/Kg, i.p.). The writhing test induced by acetic acid in mice is described as a typical model of study of inflammatory pain, being used as a screening for evaluation of analgesics or anti-inflammatory drugs [ 131 ]. The local irritation provoked by intraperitoneal injection of acetic Molecules 2016, 21, 20 16 of 29
acid triggers liberation of a variety of mediators such bradykinin, substance P and prostaglandins, (especially PGI2), as well as certain cytokines such as IL-1β, TNF-α and IL-8 [ 132 ]. Such mediators activate chemosensitive nociceptors that contribute to the development of this type of inflammatory pain, which is known to be sensitive to non-steroidal anti-inflammatory drugs (NSAIDs). However, the essential oil failed to prolong the latency time in the tail-flick model. This pain model is reported to be a useful test to discriminate analgesic agents acting primarily at the spinal medulla level and at the higher central nervous system levels, from those acting by peripheral mechanisms, (positive results indicating central action [ 3 ]. Based on the results, Sah et al. [ 50 ] suggest that Valeriana wallichii DC essential oil possesses peripheral analgesic action and the effect is comparable to aspirin. 3.24. Xylopia laevigata (Mart.) R.E.Fries Essential Oil The Annonaceae is a large family of tropical and subtropical trees and shrubs, comprising about 135 genera and more than 2500 species [ 165 ,
]. This family is known for its edible fruits and the medicinal properties of many of its species [ 167 ]. In the Brazilian Northeast, Xylopia laevigata (Mart.) R.E. Fries (Annonaceae) is commonly called “meiú” or “pindaíba”, a plant (leaves and flowers) used popularly to treat painful disorders, heart disease and inflammatory conditions [ 51 ].
51 ] evaluated the antinociceptive effect of Xylopia laevigata essential oil in mice subjected to the acetic acid-induced writhings and formalin tests. Chemical analysis indicated the presence of the following sesquiterpenes: γ-muurolene (17.78%), δ-cadinene (12.23%), bicyclogermacrene (7.77%), α-copaene (7.17%), germacrene D (6.54%), (E)-caryophyllene (5.87%), γ-cadinene (4.72%), aromadendrene (4.66%) and γ-amorphene (4.39%). When tested, the essential oil significantly inhibited the acetic acid-induced writhings, and the two phases of formalin. It is important to stress that the antinociceptive effect of the oil was not reversed by naloxone (1.5 mg/Kg, i.p.) in the formalin test. The acetic acid-induced abdominal constriction test is a standard, simple and sensitive model for measuring analgesia induced by both opioids and peripherally acting analgesics [ 168
]. According to Le Bars et al. [ 3 ], in the acetic acid test, pain is elicited by the injection of an irritant, such as acetic acid into the peritoneal cavity, which produces episodes of characteristic stretching (writhing) movements; those behavioral changes are probably in relation to the inhibition in the peritoneal fluid levels of prostaglandin and cytokines. This information supports the authors’ conclusion that the essential oil may also participate in the inhibition of prostaglandin synthesis, since nociceptive mechanisms involve the processing or release of arachidonic acid metabolites via COX and prostaglandin biosynthesis [ 169
]. In addition, the formalin test is sensitive to various classes of analgesic drugs [ 24 ]; and is characterized by the first phase (neurogenic), which is evoked by direct formalin stimulation of the sensorial C-fibers followed by substance P release [ 60 ], and the second phase (inflammatory) mainly due to a subsequent inflammatory reaction in the peripheral tissue mediated by the release of various inflammatory mediators associated with the increased level of prostaglandin, induction of COX and release of nitric oxide (NO) [ 3 ]. It is important to note that the essential oil reduced the production of nitrite, showing it to have a potential role as a NO scavenging agent, and since NO plays an important role in various types of inflammatory processes, it is thus possible that the reduction of NO is involved in a potential antinociceptive action of the Xylopia laevigata essential oil [ 51 ].
Vanillosmopsis arborea Baker is native to the Araripe National Forest, in the Northeast of Brazil in the state of Ceará. There are few studies concerning the traditional use of this plant. However, biological and pharmacological studies have shown that its essential oil presents antimicrobial, antiinflammatory and gastroprotective activities [ 170 ]. The topical antinociceptive effect of Vanillosmopsis arborea Baker essential oil (25, 50, 100 and 200 mg/Kg, p.o. or topical) was studied by Leite et al. [ 52 ] in mice subjected to formalin and eye wiping (corneal nociception) tests. The composition (w/w) of Vanillosmopsis arborea Baker essential oil revealed the presence of Molecules 2016, 21, 20 17 of 29
α -bisabolol (70%). Other identified compounds were α-cadinol (8.4%), elemicin (6.21%), β-bisabolene (4.46%), δ-guaiene (2.31%), β-cubebene (1.76%) and estragole (1.08%). In the formalin test, pretreatment with the essential oil (oral and topical) caused significant reductions of both first phase (neurogenic) and second phase (inflammatory) nociception responses. Such effect may be related, at least in part, to release of leukotrienes, which decrease the production of inflammatory eicosanoids and influence the production of arachidonic acid metabolites [ 171
]. This antinociceptive effect may also be related to the high α-bisabolol content in the essential oil, since α-bisabolol possesses visceral antinociceptive activity [ 172
], and is able to reduce neuronal excitability in a concentration-dependent manner [
107 ]. The topically administered essential oil decreased the number of eye wipes induced through local application of 5 M NaCl solution on the corneal surface. Oral treatment with the oil also reduced the number of eye wipes. In addition, the antinociceptive effect induced by the essential oil was significantly inhibited by ondansetron (0.5 mg/Kg, i.p.), PCPA (a tryptophan hydroxylase inhibitor—100 mg/Kg, i.p.), prazosin (0.15 mg/Kg, i.p.), atropine (0.1 mg/Kg, i.p.) and capsazepine (5 mg/Kg, i.p.). On the other hand, the administration of glibenclamide (2 mg/Kg, i.p.), naloxone (2 mg/Kg, i.p.), ruthenium red (5 mg/Kg, s.c.), yohimbine (2 mg/Kg, i.p.), L-NAME (2 mg/Kg, i.p.) or theophylline (5 mg/Kg, i.p.) did not prevent the essential oil-induced antinociception. The cornea is used for nociception studies on the trigeminal system [ 173 ], since corneal nociceptive receptors have large representation in the trigeminal ganglion through the ophthalmic branch of the trigeminal nerve [ 174 ]. Thin myelinated fibres [ 175 ] as well as unmyelinated fibers in the cornea respond to chemical, mechanical and thermal noxious stimuli [ 176
]. The application of hypertonic saline to the tongue and cornea transiently activates nociceptive neurons with wide dynamic range properties in the trigeminal subnucleus caudalis [ 177
]. Moreover, infusion of hypertonic saline into the masseter muscle produces hind paw shaking and activates c-Fos positive neurons in the ipsilateral trigeminal subnucleus caudalis [ 178
]. Taken together, the results indicate that the essential oil of Vanillosmopsis arborea Baker exerts antinociceptive activity by peripheral and central mechanisms, possibly mediated by 5-HT, α1, muscarinic and TRPV1 receptors. 3.26. Zingiber oficinalle and Zingiber zerumbet Essential Oils The Zingiberaceae family is among the most prolific plants in tropical rainforests. Ginger, the rhizome of Zingiber officinale Roscoe, is one of the most widely used spices and a traditional remedies in Indian, Chinese and Oriental medicine against pain, inflammation and gastrointestinal disorders. Ginger oil is produced from fresh rhizomes of Zingiber officinale. It possesses the aroma and flavor of the spice but lacks the pungency. The essential oil of ginger has been found to possess antibacterial, antiviral and antifungal properties [ 179 ,
]. Zingiber zerumbet (L.) Smith, locally known in Malaysia as “lempoyang” is one of the commonly used wild ginger species in Malay traditional medicine. The concoction of Zingiber zerumbet rhizomes is normally drunk to treat indigestion, stomach ache, fever, and worm infestation. The young stems, rhizomes and inflorescence are also used as a poultice for topical applications to treat muscle sprain and as a curative for swelling sores. The juice extracted from the rhizomes or the cooked rhizomes are usually taken by women post-partum or post-surgical patients to improve appetite, enhance recovery or healing as well as to alleviate pain [ 181 ,
]. Jeena et al. [ 53 ] studied the antinociceptive effect of the essential oil of ginger (100, 500 and 1000 mg/Kg, i.p.) in mice subjected to the acetic acid-induced writhing test. The principal constituent of ginger oil was found to be zingiberene (31.08%), a sesquiterpene hydrocarbon, followed by arcurcumene (15.4%) and α-sesquiphellandrene (14.02%). Other compounds include bisabolene (13.80%) and sabinene (8.27%). Ginger oil showed marked and significant reduction in the number of writhings induced by acetic acid. The analgesic activity at all tested doses indicated a dose dependent relationship. Jeena et al. [ 53 ] affirm that acetic acid induces pain in the peritoneal cavity by enhancing levels of endogenous substances like: PGE2 and PGF2 [ 63 ]. This indicates that acetic acid acts indirectly in the stimulation of nociceptive neurons by releasing endogenous mediators and suggests that ginger oil has strong antinociceptive activity. Its mode of action
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might involve inhibition of arachidonic acid synthesis, a metabolite mediated by COX inhibition. Sulaiman et al. [ 54 ] investigated the antinociceptive effect of essential oil from the rhizome of Zingiber zerumbet (30, 100 and 300 mg/Kg, i.p. and p.o.) in mice subjected to the following pain models: acetic acid-induced abdominal writhing, formalin and hot-plate tests. GC/MS analyses indicated the presence of zerumbone (36.12%) was the most abundant constituent among the sesquiterpenes, followed by humulene (10.03%), humulene oxide I (4.08%), humulene oxide II (2.14%), caryophyllene oxide II (1.66%) and caryophyllene oxide I (1.43%). Among the monoterpenes we found: camphene (14.29%), borneol (4.78%), camphor (4.18%), eucalyptol (3.85%), α-pinene (3.71%), γ-terpinene (2.00%), β-phellandrene (1.63%), 1-terpen-4-ol (1.44%), β-myrcene (1.22%) and linalool (1.06%). Intraperitoneal administration of the essential oil caused dose-dependent inhibition of the writhing response induced by acetic acid. The oral administration caused a partial but significant inhibition of the acetic acid-induced pain. This method is very sensitive and able to detect antinociceptive effects of compounds and dose levels that may appear inactive in other methods like the tail-flick test [ 183
]. It has been suggested that acetic acid acts indirectly by releasing endogenous mediators, such as PGE2 and PGF2α as well as increasing lipoxygenase production in the peritoneum that stimulate the nociceptive neurons sensitive to nonsteroidal anti-inflammatory drugs [ 184 ]. Therefore, the results of the acetic acid-induced abdominal constriction test strongly suggest that the mechanism of action of the oil may be mediated by lipoxygenases and/or cyclooxygenases’ activity inhibition. In the formalin test, intraperitoneal pretreatment with different doses of Zingiber zerumbet essential oil had significant and dose-dependent effects on the duration of licking activity in both early and late phases of the test. Such effect was reversed significantly by naloxone (5 mg/Kg, i.p.). It is well known that centrally acting drugs such as narcotics inhibit both nociception phases equally, while peripherally acting drugs such as acetylsalicylic acid, which block prostaglandin synthesis, only inhibit the second phase [
60 ]. Taken together, Sulaiman et al. [ 54 ] affirm that the antinociceptive effects of the essential oil in the writhing test and in both phases of the formalin test strongly suggested that they contained active analgesic principles acting both centrally and peripherally, it was also implied that the extract possessed not only antinociceptive but also antiinflammatory activity. This finding is supported, at least in part, by the results of the hot plate test. In this pain model, the intraperitoneal administration of the oil increased the latency time to the nociceptive response in the hot plate test significantly. This effect began early, 30 min after intraperitoneal administration of the essential oil, and persisted until the fifth hour. The antinociceptive effect was also reversed by naloxone. In a later study, Khalid et al. [ 55 ] suggested a mechanism of antinociceptive action for Zingiber zerumbet essential oil (50, 100, 200 and 300 mg/Kg, i.p. and p.o.). Acetic acid-induced abdominal constriction, capsaicin-, glutamate- and phorbol 12-myristate 13-acetate-induced paw licking tests in mice were employed in the study. The essential oil exhibited significant dose-dependent inhibition on abdominal writhing when administered intraperitoneally. Similar dose dependent inhibition was also observed in mice administered orally. Likewise, intraperitoneal administration of Zingiber zerumbet essential oil at similar doses produced significant dose dependent inhibition of neurogenic pain induced by intraplantar injection of capsaicine (1.6 µg/paw). It is believed that capsaicin directly activates a non-selective ionotropic channel in primary sensory neurons, the capsaicin receptor, also known as the transient receptor potential vanilloid 1 (TRPV1) [ 185 ]. Therefore, this finding indicates that the effect of the essential oil may involve, at least in part, TRPV1 receptor inhibition. Similarly, the essential oil also inhibited pain induced by intraplantar injection of glutamate (10 µM/paw). It was reported that this nociceptive response caused by glutamate involves peripheral, spinal and supraspinal sites of action with glutamate receptors (AMPA, kainate and NMDA receptors), which play an important role in modulating the nociceptive response [ 186
]. A similar result was observed with intraplantar administration of phorbol 12-myristate 13-acetate (a PKC activator at 1.6 µg/paw). PKC activation is an essential step for the nociceptive effects of numerous stimuli, including those that are caused by inflammatory mediators. PKC phosphorylates many cellular components, including membrane bound receptors, ion channels and enzymes, which are known to regulate the excitation
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of nociceptors [ 187
]. Peripheral introduction of PMA produces nociception, thermal hyperalgesia and mechanical allodynia in mice and rats. PMA, acting on PKC can directly stimulate TRPV1 channels leading to the propagation of nociceptive impulses [ 188
]. This finding can be linked to earlier findings discussed above. It was also demonstrated that pretreatment with L -arginine (100 mg/Kg, i.p.) significantly reversed the antinociceptive activity induced by the oil. Previous studies have reported that NOS inhibitors reduced nociception caused by acetic acid [ 189 ]. NO is a diffusible gas that permeates cell membranes and is not stored in vesicles. NMDA receptor activation increases intracellular calcium, which in turn stimulates NOS to catalyze the substrate L -arginine to NO and to L -citrulline [ 190 ]. NO seems to be involved in all three levels of the pain pathway, which are the peripheral, spinal cord dorsal horn and the cerebral cortex where perception of pain is processed [ 191 ]. In addition, pre-treatment with methylene blue (20 mg/Kg, i.p.) significantly enhanced antinociception produced by the essential oil. It has been suggested that methylene blue promotes antinociception by sequentially inhibiting peripheral NOS and guanylyl cyclase, resulting in NO interference [ 192
]. The activation or deactivation of noci-responsive neurons is dependent on the availability of cGMP. Intracellular cGMP concentrations are regulated by the action of guanylyl cyclase and also by the rate of degradation by cGMP-specific phosphodiesterases [ 193
]. Therefore, cGMP is very important for the functioning of nociceptors. Nitric oxide activates guanylyl cyclase, which in turn catalyses the formation of cGMP from guanosine triphosphate, whereas cyclic GMP-specific phosphodiesterase catalyzes the hydrolysis of cGMP to GMP, thus consequently ending the signal transduction [ 194
]. Finally, the administration of glibenclamide (10 mg/Kg, i.p.), an ATP-sensitive K + channel antagonist, significantly reversed antinociceptive activity induced by the essential oil. This finding suggests that the oil exerted its antinociceptive activity through the opening of ATP sensitive K + channel that allows the efflux of K + ions, thus leading to membrane repolarization and/or a hyperpolarization state which reduces the membrane excitability [ 195
]. Taken together, the results indicate that the antinociceptive action of Zingiber zerumbet essential oil involves, at least in part, the activation of the L -arginine/NO/cGMP/ATP-sensitive K + channel pathway, apart from its ability to interact and inactivate the TRPV1 receptor, inactivation of protein kinase C, and also inhibition of the glutamatergic system. Kataloq: pdf pdf -> Fakültə İxtisas qrup Kurs fənn tarix baslanma vaxti otaq pdf -> Flukofast kapsullar flucofast beynəlxalq patentləşdirilməmiş adı Yüklə 298,7 Kb. Dostları ilə paylaş:
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