Sensory Neuron Physiology & Pain Biology
PROJECT 3
Sensory neurons in the dorsal root ganglion are the origin of chronic itch and pain. We profile natural compounds and small molecules that suppress DRG neuron excitability across multiple ion channel targets simultaneously.
DRG Neurons
Chronic Pain
Chronic Itch
TRP Channels
K2P Channels
Nav Channels
Pain Has No Single Switch
THE PROBLEM
Each sensory neuron in the dorsal root ganglion expresses a diverse array of ion channels that work in concert to initiate and propagate pain signals. TRP channels detect the noxious stimulus. K2P channels set the resting membrane potential. Nav channels pull the trigger on the action potential. Blocking any one of these nodes leaves the rest of the system intact — and the neuron still fires.
This is not a theoretical concern — it has played out in the clinic. Selective Nav1.7 inhibitors, once among the most intensely pursued analgesic targets in the field, have largely failed to demonstrate efficacy in clinical trials despite compelling preclinical data. Nav1.8 inhibitors have only recently reached the market for acute pain, and their role in chronic pain remains uncertain. The pattern points to the same conclusion: suppressing a single channel is rarely enough. A new perspective on nociceptor-targeted drug discovery is needed.
The nociceptor is not a single lock. What we needed was a compound that changes the whole door.
OUR APPROACH
From Compound to Mechanism
We combine three methods to build a complete picture of how a candidate compound suppresses nociceptor firing — from single-cell population readouts down to individual channel currents.
METHOD 01
Multi-Target Natural Compound Profiling
We screen phytochemicals for simultaneous modulation of K2P, TRP, and Nav channels in DRG neurons — looking for compounds that stabilize the resting membrane potential and raise the action potential threshold in a single application.
METHOD 02
High-Content Calcium Imaging (APPOINT)
APPOINT combines automated liquid handling, single-cell segmentation, and calcium flux readouts across 8+ receptor types in primary DRG neurons — letting us profile a compound against the full nociceptor pharmacology in one experiment.
METHOD 03
Whole-Cell Patch-Clamp Electrophysiology
When calcium imaging tells us something is happening, patch-clamp tells us exactly what. We record action potential thresholds, individual channel currents, and time-dependent kinetics from small DRG neurons to establish mechanistic ground truth.
KEY RESULTS
What We Have Found
Three studies — two on DRG neuron pharmacology, one on sensory channelopathy — have established our multi-target framework for nociceptor suppression.
alpha-Mangostin · Phytomedicine 2023
One Compound, Three Channels
α-Mangostin activates TREK-1/2 and TRAAK more potently than arachidonic acid, inhibits TRPV1 with IC₅₀ 0.43 μM, and suppresses TTX-sensitive Nav — all at submicromolar concentrations. The net effect: DRG membrane hyperpolarization and a raised action potential threshold. Mode-specific TRPV1 inhibition (capsaicin-activated, not pH-activated) suggests it avoids the thermoregulation side effects of first-generation TRPV1 antagonists.
In collaboration with Prof. Sung Joon Kim, Seoul National University
Cannabidiol (CBD) · Pain 2024
CBD Silences the Whole Nociceptor Pharmacology
Using APPOINT, we showed that 10 μM CBD suppresses DRG neuron activation by 8 ionotropic and metabotropic agonists by 71.5%. At 250 nM, it progressively blocks Nav and Kv with unusually slow kinetics — implicating lipid raft interactions rather than direct channel binding. Most striking: 100 nM CBD completely eliminates vincristine-induced sensitization, relevant to chemotherapy-induced neuropathy.
In collaboration with Prof. Brian Wainger, MGH / Harvard Medical School
KCNQ4 · Exp Mol Med 2023
Matching the Variant to the Drug
In 21 KCNQ4 variants from Korean hearing loss patients and the general population, patch-clamp revealed distinct drug-response profiles. p.S185W and p.S691G responded to zinc pyrithione; p.R216H to retigabine. p.G435Afs*61 — a trafficking-deficient frameshift trapped in the ER — was partially rescued by sodium butyrate. Electrophysiology as precision medicine: not just 'does the channel work,' but 'which drug fixes it.'
In collaboration with Prof. Heon Young Gee, Yonsei University
REPRESENTATIVE PUBLICATIONS
Selected Work from This Program
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