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From the Townsend Letter
December 2016

Sniffing Out Pain
Part 2: The Multimodal Actions of Essential Oils on Pain Perception and Pain Relief
by Sarah A. LoBisco, ND
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One example of the mechanism of antinociception as determined by these pain models was described for Cymbopogon winterianus. The review authors state, "Since it has been reported that thermal and tonic tests elicit selective stimulation of A-γ fibers and C fibers, respectively [66], essential oil from the leaves of Cymbopogon winterianus may interfere with the transmission of both fibers, or a single common pathway." Other methods to determine analgesic effects of studying Citrus limon reported that "the acetic acid-induced writhings and hot plate tests was partially reversed by naloxone (1.5 mg/Kg, i.p.), an opioid antagonist." This indicated an opioid pathway of pain relief by this oil.66
A summary of the essential oils and their constituent(s) determined to have analgesic properties, along with their mechanism of action(s) (if specified), in this review are listed below:
1.   Bunium persicum (g-terpinene): Peripheral and central
2.   Citrus limon (limonene): Central mechanism
3.   Cymbopogon citrates (myrcene)
4.   Cymbopogon winterianus (geraniol): Peripheral and central
5.   Eucalyptus citriodora (citronellal)
6.   Eugenia carophyllata (eugenol): Opioid effect
7.   Heracleum pesicum (hexyl butyrate)
8.   Hofmeisteria schaffneri (hormeisterin III): Opioid effect
9.   Hyptis fruiticosa (1-8-cineole, a-pinene): Peripheral and central
10. Hyptis pectinata (ß-caryophyllene): Peripheral and central (opioid, nitrergic, and cholinergic)
11. Illicium lanceolatum (myristicin, thymol): Peripheral
12. Lippa gracilis (carvacrol): Peripheral and central (opioid, nitregic, and cholinergic)
13. Matricaria recutita (α-bisabolol oxide): Peripheral
14. Mentha x villosa (piperitenone oxide): Peripheral
15. Nepeta crispa
16. Ocimum basilicum (linalool): Peripheral and central (opioid)
17. Ocimum gratissimum (eugenol): Central (opioid)
18. Ocimum micranthum (€-methyl cinnamate): Peripheral
19. Peperomia serpens (€-nerolidol): Peripheral
20. Pimenta psuedocaryophyllus (neral, geranial): Peripheral
21. Piper alyreanum (carophyllene oxide): Peripheral
22. Satureja hortensis (γ-terpinene): Peripheral
23. Senecio rufinervis (germacrene): Peripheral and central
24. Tetradenia riparia (14-hydroxy-9-epi-carophyllene)
25. Teucrium stocksianum (g-cadinene)
26. Ugni myricoides (α-pinene)
27. Valeriana wallichii (g-guanene): Peripheral
28. Xylopia laevigata (γ-muurolene): Peripheral
29. Vanillosmopsis arborea (α-bisabolol): Peripheral and central (TRVP1 cholinergic, adrenergic, and serotonergic)
30. Zingiber officinale (zingiberene): Peripheral
31. Zingiber zerumbet (zerumbone): Peripheral and central (opioid)65
Another mechanistic review of essential oils constituents was reported on in an article describing the various phytotherapeutic agents in cannabis, rather than tetrahydrocannabinol (THC), which has been the primary focus in research. The author's goal for this review was to assess the pharmacology of these essential oil (EO) agents found in this plant and their possible therapeutic interactions with phytocannabinoids "that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus)." The cannabis terpenoids studied included limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol, and phytol, which are also present in various essential oils.
Phytocannabinoids and terpenoids are related in that they both synthesized from the same parent compound, geranyl pyrophosphate.67 The mevalonate pathway produces the terpenoid precursors isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2). In producing these compounds found in essential oils, geranyl pyrophosophate may then form limonene and other monoterpenoids in secretory cell plastids, or couple with isopentenyl pyrophosphate in the cytoplasm to form farnesyl pyrophosphate (FPP). FPP is synthesized into sesquiterpenoids.67-72 Interestingly, FPP was found to interact with transient receptor potential vanilloid receptor (TRPV) 1 in human and mice dorsal root ganglion, an endogenous ligand to date on the G-protein coupled receptor (GPR) 92. This suggests a role of this precursor compound in processing of noxious stimuli.67,73
Terpenoids are what are responsible for the aroma of cannabis and usually compromise approximately 1% of the yield in most cannabis assays. According to the article, "Terpenoids are pharmacologically versatile: they are lipophilic, interact with cell membranes, neuronal and muscle ion channels, neurotransmitter receptors, G-protein coupled (odorant) receptors, second messenger systems and enzymes. …"67
Among the terpenoids reviewed, the constituents that were found in vivo to be analgesic were myrcene, linalool, and β-caryophyllene, supporting the previous review discussed above of these compounds.65,67
In a third systematic review of essential oil constituents, the authors sought to determine what was known about the analgesic activity of monoterpenes. The authors began their search for fitting articles using the terms analgesia, anti-inflammatory, anesthetic, and antioxidant from studies published between 1990 and 2012. The authors used three databases (COPUS, PUBMED, and EMBASE). Within the 45 English-language articles selected, 27 monoterpenes were selected and explored for their potential pain-relieving properties. Studies that used the essential oils themselves were excluded.74
Similar to the review article relating the antinociceptive properties of essential oils and their active constituents in animal models, the mechanisms reported in this review were based on summaries of different testing methods and comparisons to agonist and antagonist analgesic drugs.65 Route, dosage, and animal sex were also taken into consideration. Impressively, this review also analyzed the different methodologies used, findings, and inconsistencies. In this way, the authors were able to determine the effects of dosage, animal species, sex, and study heterogeneity.
For example, when discussing myrcene, the authors reported:

In other studies, myrcene (5–405 mg/kg, p.o.) presented strong analgesic effect on the writhing induced by acetic acid or iloprost and on hyperalgesia induced by prostaglandin E2 or isoprenaline, a sympathomimetic beta adrenergic agonist. However, this monoterpene had no effect on DbcAMP [dibutyryl cyclic adenosine monophosphate]-induced hyperalgesia or in the hot-plate test (135 and 405 mg/kg, p.o.) and did not show any tolerance as compared with morphine after 5 days of consecutive oral dosing, suggesting a peripheral site of action for myrcene (Lorenzetti et al., 1991). This contradiction may be related to the administration route and hepatic first-pass effect present in the oral route (Buxton, 2006).74

The summary of the monoterpenes found to be antinociceptive, and mechanisms of action, if specified, in this review are listed by category below:74
Acyclic monoterpenes:
1.   Citral – peripheral
2.   Citronellal – opioid system and decreased nerve excitability
3.   Citronellol – peripheral (via inhibition of TNF-a and NO synthesis) and central (via opioids)
4.   (−)−Linalool – opioid, cholinergic, muscarinic, glutamatergic (iGLUr), and dopaminergic systems, adenosinergic system (A1 and A2A receptors), opening up KATP system, inhibition of TRPA1 and NMDA channels, and decreased neuronal excitability in the peripheral and central nervous system74,75
5.   Linalyl acetate
6.   Linalool – peripheral opioid receptors
7.   Myrcene – peripheral analgesic, arginine-NO-cGMP pathway stimulation, endogenous opioid release (alpha 2-adrenoceptor stimulation)

Monocyclic monoterpenes:
8.   Carvacrol – nonopioid peripheral mediators and central mechanisms inhibited, TNF-α inhibition and NO release
9.   (−)−Carvone – peripheral nerve excitability decreased (not opioid system related)
10. (+)−Carvone
11. p-Cymene – opioid, peripheral, and central mechanisms
12. Hydroxydihydrocarvone – supraspinal and spinal antinociception, non-opioid-mediated, central antinociception without tolerance
13. R-(+)−limonene – inflammation inhibition (nonopioid)
14. (−)−Menthol – selective activation of κ-opioid receptors
      Note: (+)−Menthol – without antinociceptive activity
15. α-Phellandrene – glutamatergic, opioid, nitrergic, cholinergic and adrenergic systems
16. (+)−Pulegone – nonopioid central mechanism
17. α-Terpineol – TNF-α production inhibition and NO release, central and peripheral action
18. Thymol (In this review, without mechanism, blockade of voltage-operated sodium channels was shown in an in vitro model.)76
19. Thymol acetate
20. Thymoquinone – indirect activation of the supraspinal μ1-opioid and κ-opioid receptor

Bicyclic monoterpenes
21. Carvone epoxide
22. 1,8-Cineol – spinal and supraspinal action, nonopioid
23. (−)−Fenchone
24. Limonene oxide
25. α-Pinene
26. β-Pinene – μ opioid receptors partial agonist
27. Rotundifolone – opioid and nonopioid mechanisms reported 74

The Macroscopic View of the Whole Oil
As noted above, analyzing the constituents of an essential oil can be helpful to determine how the constituents present modulate pain. However, the synergism of constituents of the essential oil itself can provide a more comprehensive healing response and have differing effects. In this section, I will review the studies that assessed essential oils themselves for pain relief. First, I will discuss single oils.
One in vivo study assessed the synergism of constituents found in three species of eucalyptus oil
Eucalyptus citriodora (EC), Eucalyptus tereticornis (ET), and Eucalyptus globulus (EG) in relation to their effects on inflammation and pain perception in rats exposed to acetic-acid and hot plates. EC, ET, and EG all induced analgesic effects, suggesting peripheral and central mechanisms. Furthermore, anti-inflammatory effects relating to carrageenan tests were also supported. However, there were some inconsistencies regarding parameters evaluated in terms of activity and dose-response relationships.77 This reflected the complexity of the essential oils makeup and may support how the environment affects their activity, even in rodents, as previously allotted to.41

In an article in Medical Hypotheses the authors theorized several mechanisms that could explain the mechanism of another essential oils, topical chamomile oil, for pain migraine headache as assessed in various studies. They concluded the following77:
1)  chamazulene and apigenin, which inhibit iNOS expression in activated macrophages and can lead to the prohibition of NO release and synthesis;77,78
2)  chamomile flavonoids, which have a strong inhibitory effect on endogenous prostaglandin E2 (PGE2) levels in RAW 264.7 macrophages and can play the role of selective COX-2 inhibitor;
3)  chamomile polyphenols, which possess anti-inflammatory effects due to the inhibition of pro-inflammatory biomarkers in THP1 macrophages and which can reduce inflammation in neurovascular units (NVU) at the site of migraine pain;
4)  chamomile, which has neuroprotective effects because of reduced NO levels;
5)  sesamin in sesame oil, which possesses an anti-inflammatory effect.78

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