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Lecture outline
▪ What are essential oils
▪ Functions
▪ Pain perception
▪ Ion channels
▪ TRPA1 antagonists
▪ Clinical Studies
▪ Summary
Biography of Kevin KF Ng, MD, PhD.
from adrenergic neuron blocker to ACE inhibitor, 150 clinical trials, and TRP pain blocker
Number of publications on “essential oils” on PubMed
from 1854 to 2023.
https://pubmed.ncbi.nlm.nih.gov/?term=essential+oils
Polls on use of Essential Oils
https://www.linkedin.com/in/kevin-kf-ng-
90543267/recent-activity/all/
24 votes 1,321 impressions 36 votes 2,956 impressions 46 votes 2,085 impressions
WHAT ARE ESSENTIAL OILS
Definition of an essential oil
▪ There are more than 3000 plants used for their
essential oils of which about 300 are used
commercially as flavors and fragrances
▪ Essential oils are volatile and concentrated liquids
extracted from different parts of plants.
▪ Essential oil is also known as essence oil or volatile oils
▪ The major bioactive compounds in essential oils are
terpenes and terpenoids.
▪ These compounds show anticancer, antimicrobial, anti-
inflammatory, antioxidant, and analgesic properties
https://in.pinterest.com/pin/642466703083349087/
Milestones in the history of the use of essential oils
Common uses of essential oils
Essential oil
• Aromatherapy
• Message
• Skin Care
• Hair Care
• First Aid
• Flavoring
agent
• Household
cleaning
• Insect
repellant
Central nervous
system
• Stress
• Anxiety
• Sleep
Pain
• Pain
• Headache
• Migraine
Symptom relief
• Respiratory
system
• Digestive
system
Pharmacological properties of essential oils
▪ Antimicrobial
▪ Antioxidant
▪ Anti-inflammatory
▪ Immuno-modulatory
▪ Analgesic
▪ Anticancer
▪ Anxiolytic
Analgesic properties of bioactive compounds in essential oils
ANATOMY OF PAIN
Here is what a fully dissected nervous system looks like:
2 to 3 miles of sensory nerves under the skin
Every square inch of skin contains > 1,000 nerve endings that sense touch, pain, temperature and pressure
3 types of sensory nerve fibers
https://www.mdpi.com/1424-8247/16/2/246
Sensory receptors
https://finwise.edu.vn/free-nerve-1693624453538041/
Pain, Touch, Temperature, Pressure Free nerve endings Varicosities, neuropeptides
Free nerve endings
Origin of the free penicillate nerve endings (1973)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271512/pdf/janat00313-0118.pdf
Sympathetic and sensory-motor nerves in
peripheral small arteries (2021)
A and B: almost 500 yr ago it was
known that the peripheral nerves follow
the blood vessels as illustrated by
Andreas Vesalius with these drawings
from 1546 in De Humani Corporis
Fabrica.
This is also nicely demonstrated in C,
where blood vessels (red) are seen
together with nerves (green) in the skin
of the forelimb of a mouse embryo
Scale bar = 100 μm.
https://journals.physiology.org/doi/full/10.1152/physrev.00007.2020
Vascular nerves in the wall of 1st-, 2nd-, and 3rd-order branches
of the rat mesenteric artery immunostained for
different neurotransmitters (2021)
A: vascular nerves in the wall of 1st-, 2nd-, and 3rd-order
branches of the rat mesenteric artery immunostained for
different neurotransmitters. Bars = 100 µm. Note the dense
network of nerves around the small arteries that is the focus
of this review. TH, tyrosine hydroxylase
B: immunostaining for calcitonin gene-related peptide
(CGRP) and neuropeptide Y (NPY) to assess the relation
between sensory-motor nerves (CGRP) and sympathetic
nerves (NPY) in rat mesenteric small arteries. Note that the
2 nerves run together and that there are more NPY
containing nerves than CGRP containing nerves.
C: vascular nerves in rat mesenteric small arteries loaded
with the Ca2+-sensitive fluorescent dye Oregon Green 488
BAPTA-1. Note the varicosities, which appear as pearls on a
string. nNOS, neuronal nitric oxide synthase. Bar = 1 µm
https://journals.physiology.org/doi/full/10.1152/physrev.00007.2020?rfr_dat=cr_pu
b++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
neurotransmitters
INFLAMMATION
Chemical mediators of Inflammation (2001)
https://sites.cns.utexas.edu/esenlab/research-interests
Actions of mediators on TRP pain receptors (nociceptors)
(TRP=Transient Receptor Potential)
https://www.rcemlearning.org/modules/pain-management-in-
adult-patients/lessons/the-pathophysiology-of-pain/
Inflammatory Mediators TRP Pain Receptors
https://www.news-medical.net/whitepaper/20190817/
on-Channels-Involved-in-Pain.aspx
ION CHANNELS AS PAIN RECEPTORS
What is an ion channel?
Adapted from https://www.genetex.com/Research/Overview/neuroscience/Ion-Channels
Ion channels are proteins located on the plasma membrane of the sensory nerve fiber
Classification of ion channels
https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=78
• 300 different ion channels
• 13 superfamilies
• 6 TRP subfamilies
• Only TRPV1 and TRPA1 are
widely studied for pain, cold,
and itch
6 TRP subfamilies
Pain
Pain
Cold
Pain receptors on 2 - 3 million sensory nerves in the skin
Activation of TRP ion channels by
inflammatory mediators
https://europepmc.org/article/med/33193423
Ion channels that converge onto TRPA1:
the final pathway for pain perception?
TRPM
Piezo Channels
ASIC
Nav
Kv
P2X Receptors
sensor for pain, cold, itch, chemicals
Capsaicin
AITC
TRPV1
TRPA1
TRPM8
Menthol
EVIDENCE
• Knockout mice
• Interactions with other
channels
• Knockout in specific
cell types
List of Pharmaceutical Companies that hold patents for
TRPA1 antagonists/blockers
▪ In the last three decades, 14 organizations published 28 patent
applications disclosing potential uses of TRPA1 antagonists.
▪ 5 have been evaluated by clinical trials.
▪ None had passed beyond Phase II trials.
▪ The major pharmaceutical companies are :
1. AstraZeneca
2. Pfizer
3. Merck & Co.
4. Sanofi
5. Novartis
6. GlaxoSmithKline (GSK)
7. Johnson & Johnson
8. AbbVie
9. Eli Lilly and Company
10. Boehringer Ingelheim
https://www.tandfonline.com/doi/abs/10.1080/13543776.2020.1797679?journalCode=ietp20
Synthetic and Natural TRP blockers
Synthetic TRPA1 blockers Natural TRPV1 and TRPA! blockers
Antinociceptive activity of TRPV1 and TRPA1
antagonists in essential oils
https://chat.openai.com/c/86ca8155-dc51-4d1a-a684-15e198d682f0
Topical pain relief by essential oil rub and balm
MECHANISM OF PAIN RELIEF
BY
BLOCKING TRPA1 ION CHANNEL
Dermal Nerve Plexus of Human Skin
https://www.sciencedirect.com/science/article/pii/S0022202X15305935#f0015
Biological functions of substance P (SP)
https://www.researchgate.net/figure/Scheme-of-biological-functions-of-
substance-P-Once-the-nerve-ending-catch-noxious_fig12_221917605
Neurogenic pain
Inflammatory pain
Proximity of afferent sensory nerve endings to blood vessels:
Neurogenic pain perception (axon reflex)
https://www.researchgate.net/figure/9-Events-occurring-around-a-muscle-
nociceptor-during-noxious-mechanical-stimulation-The_fig4_265425188
(Pain)
Neurogenic pain
• Migraine
• Trigeminal neuralgia
• Diabetic neuropathy
• Post-herpetic neuralgia
Antidromic axon reflexes induce the release of neuropeptides:
Inflammatory pain perception(2012)
https://www.researchgate.net/figure/Neuronal-factors-released-from-nociceptor-
sensory-neurons-directly-drive-leukocyte_fig4_230573679
Inflammatory Pain
• Arthritis
• Bursitis
• Tendinitis
• Fibromyalgia
Mechanism of Perception of pain caused by
intense exercise, infection, and chemicals
PAIN
©DRKKFNG
The current strategy to treat cociceptive pain:
anti-inflammatory drugs
PAIN
©DRKKFNG
Aspirin, NSADs, Anti-histamine
•
The future strategy of Topical Pain Management:
The rational use of topical phytochemicals as TRP Pain Blockers
PAIN
×
Inhibition of activation of ion channels renders a wide-spectrum blockade
©DRKKFNG
TRP Pain Blockers: phytochemicals
• Black pepper
• Ginger
• Turmeric
• Menthol
• Camphor
• Parthenolide
×
Summary of actions of inflammatory mediators and their
blockade by phytochemicals on nociceptive ion channel
Adapted from https://www.chemdiv.com/drug-discovery-services/discovery-biology/hts/Ion-channels/
Advantages of Topical TRPA1 antagonists/blocker
▪ Targeted pain relief
▪ Reduced systemic side effects
▪ Anti-inflammatory properties
▪ Brod spectrum of pain relief
▪ Non-addictive
▪ Complementary approach
In search of a more effective topical painkiller
Thank you
Q and A time
https://www.slideshare.net/ssusera9ba27

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Target pain receptors with essential oils

  • 1.
  • 2.
  • 3. Lecture outline ▪ What are essential oils ▪ Functions ▪ Pain perception ▪ Ion channels ▪ TRPA1 antagonists ▪ Clinical Studies ▪ Summary
  • 4. Biography of Kevin KF Ng, MD, PhD. from adrenergic neuron blocker to ACE inhibitor, 150 clinical trials, and TRP pain blocker
  • 5. Number of publications on “essential oils” on PubMed from 1854 to 2023. https://pubmed.ncbi.nlm.nih.gov/?term=essential+oils
  • 6. Polls on use of Essential Oils https://www.linkedin.com/in/kevin-kf-ng- 90543267/recent-activity/all/ 24 votes 1,321 impressions 36 votes 2,956 impressions 46 votes 2,085 impressions
  • 8. Definition of an essential oil ▪ There are more than 3000 plants used for their essential oils of which about 300 are used commercially as flavors and fragrances ▪ Essential oils are volatile and concentrated liquids extracted from different parts of plants. ▪ Essential oil is also known as essence oil or volatile oils ▪ The major bioactive compounds in essential oils are terpenes and terpenoids. ▪ These compounds show anticancer, antimicrobial, anti- inflammatory, antioxidant, and analgesic properties https://in.pinterest.com/pin/642466703083349087/
  • 9. Milestones in the history of the use of essential oils
  • 10. Common uses of essential oils Essential oil • Aromatherapy • Message • Skin Care • Hair Care • First Aid • Flavoring agent • Household cleaning • Insect repellant Central nervous system • Stress • Anxiety • Sleep Pain • Pain • Headache • Migraine Symptom relief • Respiratory system • Digestive system
  • 11. Pharmacological properties of essential oils ▪ Antimicrobial ▪ Antioxidant ▪ Anti-inflammatory ▪ Immuno-modulatory ▪ Analgesic ▪ Anticancer ▪ Anxiolytic
  • 12. Analgesic properties of bioactive compounds in essential oils
  • 14. Here is what a fully dissected nervous system looks like: 2 to 3 miles of sensory nerves under the skin Every square inch of skin contains > 1,000 nerve endings that sense touch, pain, temperature and pressure
  • 15. 3 types of sensory nerve fibers https://www.mdpi.com/1424-8247/16/2/246
  • 16. Sensory receptors https://finwise.edu.vn/free-nerve-1693624453538041/ Pain, Touch, Temperature, Pressure Free nerve endings Varicosities, neuropeptides Free nerve endings
  • 17. Origin of the free penicillate nerve endings (1973) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271512/pdf/janat00313-0118.pdf
  • 18. Sympathetic and sensory-motor nerves in peripheral small arteries (2021) A and B: almost 500 yr ago it was known that the peripheral nerves follow the blood vessels as illustrated by Andreas Vesalius with these drawings from 1546 in De Humani Corporis Fabrica. This is also nicely demonstrated in C, where blood vessels (red) are seen together with nerves (green) in the skin of the forelimb of a mouse embryo Scale bar = 100 μm. https://journals.physiology.org/doi/full/10.1152/physrev.00007.2020
  • 19. Vascular nerves in the wall of 1st-, 2nd-, and 3rd-order branches of the rat mesenteric artery immunostained for different neurotransmitters (2021) A: vascular nerves in the wall of 1st-, 2nd-, and 3rd-order branches of the rat mesenteric artery immunostained for different neurotransmitters. Bars = 100 µm. Note the dense network of nerves around the small arteries that is the focus of this review. TH, tyrosine hydroxylase B: immunostaining for calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) to assess the relation between sensory-motor nerves (CGRP) and sympathetic nerves (NPY) in rat mesenteric small arteries. Note that the 2 nerves run together and that there are more NPY containing nerves than CGRP containing nerves. C: vascular nerves in rat mesenteric small arteries loaded with the Ca2+-sensitive fluorescent dye Oregon Green 488 BAPTA-1. Note the varicosities, which appear as pearls on a string. nNOS, neuronal nitric oxide synthase. Bar = 1 µm https://journals.physiology.org/doi/full/10.1152/physrev.00007.2020?rfr_dat=cr_pu b++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org neurotransmitters
  • 21. Chemical mediators of Inflammation (2001) https://sites.cns.utexas.edu/esenlab/research-interests
  • 22. Actions of mediators on TRP pain receptors (nociceptors) (TRP=Transient Receptor Potential) https://www.rcemlearning.org/modules/pain-management-in- adult-patients/lessons/the-pathophysiology-of-pain/ Inflammatory Mediators TRP Pain Receptors https://www.news-medical.net/whitepaper/20190817/ on-Channels-Involved-in-Pain.aspx
  • 23. ION CHANNELS AS PAIN RECEPTORS
  • 24. What is an ion channel? Adapted from https://www.genetex.com/Research/Overview/neuroscience/Ion-Channels Ion channels are proteins located on the plasma membrane of the sensory nerve fiber
  • 25. Classification of ion channels https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=78 • 300 different ion channels • 13 superfamilies • 6 TRP subfamilies • Only TRPV1 and TRPA1 are widely studied for pain, cold, and itch 6 TRP subfamilies Pain Pain Cold
  • 26. Pain receptors on 2 - 3 million sensory nerves in the skin
  • 27. Activation of TRP ion channels by inflammatory mediators https://europepmc.org/article/med/33193423
  • 28. Ion channels that converge onto TRPA1: the final pathway for pain perception? TRPM Piezo Channels ASIC Nav Kv P2X Receptors sensor for pain, cold, itch, chemicals Capsaicin AITC TRPV1 TRPA1 TRPM8 Menthol EVIDENCE • Knockout mice • Interactions with other channels • Knockout in specific cell types
  • 29. List of Pharmaceutical Companies that hold patents for TRPA1 antagonists/blockers ▪ In the last three decades, 14 organizations published 28 patent applications disclosing potential uses of TRPA1 antagonists. ▪ 5 have been evaluated by clinical trials. ▪ None had passed beyond Phase II trials. ▪ The major pharmaceutical companies are : 1. AstraZeneca 2. Pfizer 3. Merck & Co. 4. Sanofi 5. Novartis 6. GlaxoSmithKline (GSK) 7. Johnson & Johnson 8. AbbVie 9. Eli Lilly and Company 10. Boehringer Ingelheim https://www.tandfonline.com/doi/abs/10.1080/13543776.2020.1797679?journalCode=ietp20
  • 30. Synthetic and Natural TRP blockers Synthetic TRPA1 blockers Natural TRPV1 and TRPA! blockers
  • 31. Antinociceptive activity of TRPV1 and TRPA1 antagonists in essential oils https://chat.openai.com/c/86ca8155-dc51-4d1a-a684-15e198d682f0
  • 32. Topical pain relief by essential oil rub and balm
  • 33. MECHANISM OF PAIN RELIEF BY BLOCKING TRPA1 ION CHANNEL
  • 34. Dermal Nerve Plexus of Human Skin https://www.sciencedirect.com/science/article/pii/S0022202X15305935#f0015
  • 35. Biological functions of substance P (SP) https://www.researchgate.net/figure/Scheme-of-biological-functions-of- substance-P-Once-the-nerve-ending-catch-noxious_fig12_221917605 Neurogenic pain Inflammatory pain
  • 36. Proximity of afferent sensory nerve endings to blood vessels: Neurogenic pain perception (axon reflex) https://www.researchgate.net/figure/9-Events-occurring-around-a-muscle- nociceptor-during-noxious-mechanical-stimulation-The_fig4_265425188 (Pain) Neurogenic pain • Migraine • Trigeminal neuralgia • Diabetic neuropathy • Post-herpetic neuralgia
  • 37. Antidromic axon reflexes induce the release of neuropeptides: Inflammatory pain perception(2012) https://www.researchgate.net/figure/Neuronal-factors-released-from-nociceptor- sensory-neurons-directly-drive-leukocyte_fig4_230573679 Inflammatory Pain • Arthritis • Bursitis • Tendinitis • Fibromyalgia
  • 38. Mechanism of Perception of pain caused by intense exercise, infection, and chemicals PAIN ©DRKKFNG
  • 39. The current strategy to treat cociceptive pain: anti-inflammatory drugs PAIN ©DRKKFNG Aspirin, NSADs, Anti-histamine •
  • 40. The future strategy of Topical Pain Management: The rational use of topical phytochemicals as TRP Pain Blockers PAIN × Inhibition of activation of ion channels renders a wide-spectrum blockade ©DRKKFNG TRP Pain Blockers: phytochemicals • Black pepper • Ginger • Turmeric • Menthol • Camphor • Parthenolide ×
  • 41. Summary of actions of inflammatory mediators and their blockade by phytochemicals on nociceptive ion channel Adapted from https://www.chemdiv.com/drug-discovery-services/discovery-biology/hts/Ion-channels/
  • 42. Advantages of Topical TRPA1 antagonists/blocker ▪ Targeted pain relief ▪ Reduced systemic side effects ▪ Anti-inflammatory properties ▪ Brod spectrum of pain relief ▪ Non-addictive ▪ Complementary approach
  • 43. In search of a more effective topical painkiller
  • 44. Thank you Q and A time https://www.slideshare.net/ssusera9ba27