The recent discoveries of nociceptive transient receptive ion channels as pain receptors and its blockade by phytochemicals opens a new era for topical pain research .

1. TOPICAL PAIN RELIEF
BY
PHYTOCHEMICALS
BLOCKING
NOCICEPTIVE ION CHANNELS
By
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine
University of Miami, FL., USA
Email: kevinng68@gmail.com
A slide presentation for “Integrative Medicine Today” Oct 19-20, 2023, Romania

2. Lecture Outline
 Definition of pain
 History of pain perception
 Milestones of topical pain relief
 Current concept of pain mechanism
 Inflammatory mediators
 Nociceptive ion channels
 Synthetic and natural ion channel (TRP) blockers
 Clinical applications of natural TRP pain blockers
 Summary

3. Biography of Kevin KF Ng, MD, PhD.
from adrenergic neuron blockade to ACE inhibitor and TRP pain blocker
1963 – 1977 University of Singapore 1966 – University of London 1981 – 2005 University of Miami 2008 – 2012 Private Practice

4. Definition of Pain by IASP
International Association on the Study of Pain (2020)
An aversive sensory and emotional experience typically caused by, or resembling that
caused by, actual or potential tissue injury.

5. Ideas of pain perception from ancient times to the modern
era
By
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine, , Division of Clinical Pharmacology
University of Miami, FL., USA
Email: kevinng68@gmail.com
©DRKEVINNG

6. In search of a more effective topical painkiller from
spices
By
Kevin KF Ng, MD, PhD
Former Associate Professor of Medicine. Division of Clinical Pharmacology
University of Miami, FL. USA
Email: kevinng68@gmail.com
©DRKEVINNG

7. ANATOMY OF PAIN

8. Here is what a fully dissected nervous system looks like:
2 to 3 miles of sensory nerves under the skin
https://www.linkedin.com/feed/ ©DRKEVINNG

9. 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

10. 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_pub++0p
ubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

11. Sensory nerves of the skin and transient receptor potential
cation channel, (TRPV1 and TRPA1) expression (2021)
https://www.researchgate.net/figure/Sensory-nerves-of-the-skin-and-
transient-receptor-potential-cation-channel-subfamily-V_fig1_352200793
Sensory nerves
• Aβ myelinated fiber
• Aδ myelinated fiber
• Unmyelinated Non-peptidergic C fiber
• Unmyelinated peptidergic C fiber

12. Emerging roles of keratinocytes in nociceptive
transduction and regulation (2022)
https://www.frontiersin.org/articles/10.3389/fnmol.2022.982202/full

13. Origin of the free penicillate Nerve endings (1973)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271512/pdf/janat00313-0118.pdf

14. Anatomy of sensory nerve endings with
nociceptive ion channels and neuropeptides

15. PHYTOCHEMICALS

16. What are phytochemicals?
 “Phyto” is a Greek name for plants.
 “Chemicals” are compounds that
occur naturally in plants.
 There are about 5,000 phytochemicals.
 Only 150 have been studied in depth.
https://www.breastcancer.org/tips/nutrition/reduce_risk/foods/phytochem

17. General classification of phytochemicals
There are > 5,000 phytochemicals
Salicylic acid
gingerol piperine
Terpenoids
menthol
Polyphenolic
curcumin

18. Functions of phytochemicals in humans
 Phytochemicals have not been shown to be essential nutrients.
 However, they have been shown to be beneficial for health by:
 Scavenging free radicals. ▪ Lowering high blood pressure
 Reducing inflammatory response ▪ Lowering high blood sugar
 Modulating cytokine release ▪ Lowering high blood cholesterol
 Reducing the risk of cancer ▪ Lowering the risk of obesity
 Preventing telomeres from shortening ▪ Lowering the risk of degenerative
diseases
 The discovery of ion channel TRPA1 in 2005 as a final pathway for
pain perception and its blockade by phytochemicals opens a new era
for pain research.

19. ION CHANNELS

20. 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

21. 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

22. TRP (Transient Receptor Potential) channels as
targets for novel analgesics(2023)
https://www.nature.com/articles/s41392-023-01464-x/figures/1
2008

23. Pain receptors on 2 - 3 million sensory nerves in the skin
©DRKEVINNG

24. Ion channels that converge onto TRPA1:
the final pathway for pain perception (2008)
TRPM
Piezo Channels
ASIC
Nav
Kv
P2X Receptors
©DRKEVINNG
Target

25. ▪ SEARCH FOR TRPA1 BLOCKER
▪ SIMPLE EXPERIMENTS
▪ CLINICAL STUDIES
● NOCICEPTIVE PAIN
INFLAMMATORY PAIN
●
● NEUROPATHIC PAIN

26. 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

27. Phytochemicals with antinociceptive compounds(2022)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9785912/

28. Phytochemicals with antinociceptive property
on TRP ion channels (2022)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9785912/
Black
pepper

29. Extraction of bioactive compounds in herbs and spices
Preparation of Liniments
Carrier oil Black pepper Turmeric Ginger Mint leaf

30. Effects of single and multiple phytochemical extracts on
my lower back pain due to a traumatized lumbar vertebra
©DRKEVINNG

31. Evaluation of phytochemical extracts on
nociceptive and inflammatory pains
 Nociceptive pain:
 Soft tissue injuries
 Post-surgical pain
 Radiation dermatitis
 Low back pain
 Inflammatory pain:
 Fire ant stings
 Wasp stings
 Yellow jacket stings
 Mosquito bites
 Medical conditions
 Itch in psoriasis
 Arthritis pain
 Diabetic neuropathy
 Gouty arthritis
 Migraine headache
 Menstrual cramps

32. Natural history of fire ant sting

33. Effect of Phytochemicals (4) on Fire Ant
Stings
Untreated for 36 hours Treated for 36 hours

34. Effect of black pepper extract on yellow jacket sting on lip:
my personal experience
2.43 PM Jul 29 2019
4.08 PM Jul 28 2019
Before After

35. Effect of black pepper extract on acute injury
brick wall abrasion
site of fall

36. Effect of black pepper extract on muscle soreness

37. 74 yr old Chinese female twisted her right ankle while going
down the staircase. She was unable to stand up because of the
severe pain. Physical examination showed a tender bruised
right ankle with a limited range of movement. Topical
application of oil extracts containing four ingredients were
applied three times a day followed by immobilization with an
ankle brace. The pain was reduced from10/10 to 2/10 within
15 minutes. She became pain-free after 1 day and ambulatory
after 2 days.
Effect of phytochemical extract (4) on Sprained Right Ankle

38. Effect of black pepper extract on
post-laparotomy cholecystectomy pain

39. 61 yr old Chinese male with 12 yr history
of Type2 Diabetes. VPT ? Complained of
Numbness, pain and swelling of both
legs. Meds: metformin 850 mg tid,
nifedipine 10 mg daily, Vit B complex.
Physical Examinations showed mycotic
nails, subnormal pedal pulse and
diminished sensation both legs
Topical treatment with L35 reduced
numbness, pain and swelling from 100%
to less than 5% within 10 to 60 minutes.
The relief lasted about 4 hours. Three
applications a day produced complete
relief in 1 week.
Effect of phytochemical extracts (4) on painful diabetic neuropathy
Before
After

40. MECHANISM OF PAIN RELIEF
BY
BLOCKING NOCICEPTIVE ION CHANNEL

41. Dermal Nerve Plexus of Human Skin
https://www.sciencedirect.com/science/article/pii/S0022202X15305935#f0015

42. Chemical mediators of inflammation released by
trauma, infection and chemicals
Stimuli
• Injury
• Infection
• Chemical
Source
• Tissue cells
• Immune cells
• Endothelium
• Nerves
• Fibroblasts
• Plasma
Mediators
• Histamine
• Serotonin
• Prostaglandins
• Leukotrienes
• Platelet activating
factor
• Nitric oxide
• Bradykinin
• Cytokines
• Chemokines
• Neuropeptides
• SP
• CGRP
©DRKEVINNG

43. Actions of Nociceptive Mediators on Intra-epidermal
free nerve endings (2020)
https://www.researchgate.net/figure/Epidermal-keratinocytes-modulate-nociceptive-
sensory-neuron-activity-Keratinocytes_fig2_338457032

44. Nociceptive activation in nerve endings triggers the release of
substance P (SP), calcitonin gene-related-peptide (CGRP), and neurokinin A (2006) ●
Adapted from https://www.nature.com/gimo/contents/pt1/fig_tab/gimo75_F9.html
●
●
●

45. 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)

46. 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

47. Substance P (SP) and Calcitonin gene-related peptide (CGRP)
TRP channels TRPV1 TRPA1
©DRKEVINNG

48. Mechanism of Perception of pain caused by
intense exercise, infection, and chemicals
PAIN
©DRKKFNG

49. The current strategy to treat nociceptive pain:
anti-inflammatory drugs
PAIN
©DRKKFNG
Aspirin, NSADs, Antihistamine
•

50. 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
×

51. 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/
Pain
Phytochemical Target

52. In search of a more effective topical painkiller
from 1971 to 2023
©DRKEVINNG

53. Thank you
Q and A time
https://www.slideshare.net/ssusera9ba27