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Printable Handouts
Navigable Slide Index
- Introduction
- Disclosure
- Hodgkin Huxley mechanism of generation of nerve impulses
- From H-H to the clinic
- Voltage-gated sodium (Na) channels
- Neuropathic pain: an unmet need (DM, PHN, chemotx, trauma)
- Hyper-excitability of pain-signaling nerve cells produces pain after nerve injury and SCI
- DRG neurons express multiple Na channel isoforms
- Molecular targets for pain
- Nav1.7 and Nav1.8 operate in tandem (1)
- Peripheral nerve injury
- Nav1.7 and Nav1.8 operate in tandem (2)
- NaV1.7 is preferentially expressed in peripheral neurons
- Why search throughout the world to find a rare genetic disorder?
- A model disease: inherited erythromelalgia (1)
- A model disease: inherited erythromelalgia (2)
- Molecular pathophysiology of a human hereditary pain syndrome: IEM
- Mutations in SCN9A (gene encoding Nav1.7) in two Chinese families
- IEM Nav1.7 gain-of-function mutations
- We surveille a population of ~3 billion to search for disease-causing genes
- IEM identifies over-activity of Nav1.7 as a cause of severe pain
- Nav1.7 loss-of-function
- DRG neuron from a human genetic model of neuropathic pain
- What’s next?
- Can we target Nav1.7 to alleviate pain in human subjects?
- iPSCs from IEM patients: pain in a dish
- Double-blind, placebo-controlled study: Nav1.7-blocker PF…771 in IEM
- Nav1.7 and Nav1.8 operate in tandem (3)
- Nav1.8: sensory neuron specific
- Nav1.8 mutations in painful peripheral neuropathy: a genetic link of Nav1.8 to pain
- Gain-of-function mutations of Nav1.8
- Nav1.8 as a driver of pain
- Nav1.8 powerfully confers hyperexcitability in depolarized peripheral neurons
- Can we capitalize on the molecular revolution? (1)
- Selective block of NaV1.8 attenuates acute pain
- Can we capitalize on the molecular revolution? (2)
- Genomically-guided, “precision” pain pharmacotherapy
- Atomic-level structural modeling and thermodynamic coupling
- In vitro studies
- Clinical study: pharmacotherapy for pain in inherited EM
- Carbamazepine attenuates pain driven by S241T-Nav1.7 IEM mutation
- Carbamazepine attenuates pain due to S241T-Nav1.7 mutation
- Can we capitalize on the molecular revolution? (3)
- Can we pinpoint pain resilience genes?
- Differences in excitability between iPSC-SNs from different subjects
- iPSC-SNs show differences in RMP and excitability that correlate with pain profiles
- Whole exome sequencing
- Dynamic-clamp
- Kv7 activator hyperpolarizes RMP and reduces excitability in human IEM iPSC-SNs
- Can we capitalize on the molecular revolution? (4)
- Nav channels are present in low densities within some “non-excitable” cells
- Na channel blockers attenuate some effector functions
- Nav1.7 is present and up-regulated in chondrocytes in osteoarthritis
- Chondrocyte-specific Nav1.7 deletion or pharmacological block
- Summary
Topics Covered
- Osteoarthritis
- Hodgkin-Huxley mechanism
- Neuropathic pain
- DRG neurons
- Inherited erythromelalgia
- Pain pharmacotherapy
- Sodium channels
- Pain genes and pain resilience genes
- Genomic pain therapy
Links
Series:
- Pain and the Control of Pain
- Periodic Reports: Advances in Clinical Interventions and Research Platforms
Categories:
Therapeutic Areas:
Talk Citation
Waxman, S. (2025, February 27). Huxley’s science fiction: ion channels in pain, pain resilience, and beyond [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved May 9, 2025, from https://doi.org/10.69645/JIRJ8358.Export Citation (RIS)
Publication History
- Published on February 27, 2025
Financial Disclosures
- Stephen Waxman has served as a consultant or advisor to: Amgen, Biogen, OliPass Biotechnology, Sangamo Therapeutics, ThirdRock Ventures, Medtronic, Population Health Partners, Chromocell Biotherapeutics, SiteOne Therapeutics and Navega Therapeutics.
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Transcript
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0:00
This is Steve Waxman at the
Yale School of Medicine.
My talk is entitled
Huxley's Science Fiction.
What I'm really going
to talk about is
ion channels and their
multiple roles in pain,
pain resilience, and the
spectrum of other disorders.
0:20
This is my disclosure slide.
0:24
This slide shows on
the top a diagram
that appears in virtually
every textbook of physiology.
It shows the
Hodgkin-Huxley mechanism
of generation of nerve
impulses action potentials.
They did this work in 1949.
It was published in 1952.
What it shows is an
action potential,
a nerve impulse from
the squid giant axon,
that's in blue.
It shows the crucial
dependence of
the action potential on the
opening of sodium channels,
those are in yellow.
It shows that termination,
the end of the action potential
depends on the opening
of potassium channels,
those is shown in pink.
This work as I said,
was done in 1952.
Molecular biology
was in its infancy,
modern microelectrodes
were not available,
modern computers didn't exist.
But despite that, Hodgkin and
Huxley were able to predict with
prescient precision
the properties of
sodium channels and they got
the Nobel Prize for
this work in 1963.
It remains one of the bastions
of modern electrophysiology.
Now, in 1995, I edited
a book called The Axon,
The Nerve Fiber and I
asked Andrew Huxley,
by then he was Sir
Andrew Huxley,
if he would write an
introductory chapter.
He very graciously did.
His last two sentences really
are I think very important.
What they said in
those last two sentences,
what he said was,
"When Hodgkin and I finished
the 1952 Nobel Prize papers,
we turned to other
lines of work,
any idea of analyzing
ion channels by
molecular genetics or
patch clamp would have seemed to
them to be science fiction."
I show this because almost
all of the listeners,
watchers of this lecture are
walking through the science
fiction of our forebears
and our job as we
learn new things
is to take our knowledge
and help society with it.
What this slide shows from 2023,
Hide