Avraham Cooper
@avrahamcoopermd.bsky.social
Pulm/Crit physician, medical educator, The Curious Clinicians podcast
FORTHCOMING BOOK: WHY DOESN’T YOUR STOMACH DIGEST ITSELF? (W.W. Norton)
FORTHCOMING BOOK: WHY DOESN’T YOUR STOMACH DIGEST ITSELF? (W.W. Norton)
15/SUMMARY
Salt in wounds causes pain by multiple probable mechanisms.
These include:
🧂Increasing local osmolarity, which stimulates osmo-sensitive TRPV nociceptive neurons (the same neurons through which capsaicin signals)
🧂Osmotic stress leading to cellular injury/death
Salt in wounds causes pain by multiple probable mechanisms.
These include:
🧂Increasing local osmolarity, which stimulates osmo-sensitive TRPV nociceptive neurons (the same neurons through which capsaicin signals)
🧂Osmotic stress leading to cellular injury/death
April 18, 2025 at 3:52 PM
15/SUMMARY
Salt in wounds causes pain by multiple probable mechanisms.
These include:
🧂Increasing local osmolarity, which stimulates osmo-sensitive TRPV nociceptive neurons (the same neurons through which capsaicin signals)
🧂Osmotic stress leading to cellular injury/death
Salt in wounds causes pain by multiple probable mechanisms.
These include:
🧂Increasing local osmolarity, which stimulates osmo-sensitive TRPV nociceptive neurons (the same neurons through which capsaicin signals)
🧂Osmotic stress leading to cellular injury/death
14/
Another mechanism seems to be that the local hyperosmolar state induced by salt in wounds also creates osmotic stress on cells, leading to cellular injury and death.
This independently activates nociceptive neurons in the skin.
pubmed.ncbi.nlm.nih.gov/29675710/
Another mechanism seems to be that the local hyperosmolar state induced by salt in wounds also creates osmotic stress on cells, leading to cellular injury and death.
This independently activates nociceptive neurons in the skin.
pubmed.ncbi.nlm.nih.gov/29675710/
April 18, 2025 at 3:52 PM
14/
Another mechanism seems to be that the local hyperosmolar state induced by salt in wounds also creates osmotic stress on cells, leading to cellular injury and death.
This independently activates nociceptive neurons in the skin.
pubmed.ncbi.nlm.nih.gov/29675710/
Another mechanism seems to be that the local hyperosmolar state induced by salt in wounds also creates osmotic stress on cells, leading to cellular injury and death.
This independently activates nociceptive neurons in the skin.
pubmed.ncbi.nlm.nih.gov/29675710/
13/
TRPV/capsaicin signaling likely isn't the whole story, though, because in the same study as #11, TRPV4 knockout mice had equivalent (and intense) pain responses to a 10% saline solution.
pubmed.ncbi.nlm.nih.gov/16213085/
TRPV/capsaicin signaling likely isn't the whole story, though, because in the same study as #11, TRPV4 knockout mice had equivalent (and intense) pain responses to a 10% saline solution.
pubmed.ncbi.nlm.nih.gov/16213085/
April 18, 2025 at 3:52 PM
13/
TRPV/capsaicin signaling likely isn't the whole story, though, because in the same study as #11, TRPV4 knockout mice had equivalent (and intense) pain responses to a 10% saline solution.
pubmed.ncbi.nlm.nih.gov/16213085/
TRPV/capsaicin signaling likely isn't the whole story, though, because in the same study as #11, TRPV4 knockout mice had equivalent (and intense) pain responses to a 10% saline solution.
pubmed.ncbi.nlm.nih.gov/16213085/
12/
Glutamate may be a key mediator of salt-induced pain, as it is known to be released after TRPV 1 and 4 activation (pubmed.ncbi.nlm.nih.gov/39626870/), and injection of 5.8% hypertonic saline into the biceps muscle leads to spikes in glutamate production.
pubmed.ncbi.nlm.nih.gov/26485281/
Glutamate may be a key mediator of salt-induced pain, as it is known to be released after TRPV 1 and 4 activation (pubmed.ncbi.nlm.nih.gov/39626870/), and injection of 5.8% hypertonic saline into the biceps muscle leads to spikes in glutamate production.
pubmed.ncbi.nlm.nih.gov/26485281/
April 18, 2025 at 3:52 PM
12/
Glutamate may be a key mediator of salt-induced pain, as it is known to be released after TRPV 1 and 4 activation (pubmed.ncbi.nlm.nih.gov/39626870/), and injection of 5.8% hypertonic saline into the biceps muscle leads to spikes in glutamate production.
pubmed.ncbi.nlm.nih.gov/26485281/
Glutamate may be a key mediator of salt-induced pain, as it is known to be released after TRPV 1 and 4 activation (pubmed.ncbi.nlm.nih.gov/39626870/), and injection of 5.8% hypertonic saline into the biceps muscle leads to spikes in glutamate production.
pubmed.ncbi.nlm.nih.gov/26485281/
11/
In a mouse model, mild increases in osmolarity (eg w/ 2% saline) in paw wounds also activated a different nociceptive capsaicin-sensitive receptor from the same family called TRPV4.
pubmed.ncbi.nlm.nih.gov/16213085/
In a mouse model, mild increases in osmolarity (eg w/ 2% saline) in paw wounds also activated a different nociceptive capsaicin-sensitive receptor from the same family called TRPV4.
pubmed.ncbi.nlm.nih.gov/16213085/
April 18, 2025 at 3:52 PM
11/
In a mouse model, mild increases in osmolarity (eg w/ 2% saline) in paw wounds also activated a different nociceptive capsaicin-sensitive receptor from the same family called TRPV4.
pubmed.ncbi.nlm.nih.gov/16213085/
In a mouse model, mild increases in osmolarity (eg w/ 2% saline) in paw wounds also activated a different nociceptive capsaicin-sensitive receptor from the same family called TRPV4.
pubmed.ncbi.nlm.nih.gov/16213085/
10/
This dramatic ⬆️ in local osmolarity stimulates osmosensitive' cation pain receptor channels called TRPV (transient receptor potential vanilloid), similar to how these receptors respond to capsaicin.
Example of activation of TRPV1 is shown below.
pubmed.ncbi.nlm.nih.gov/21779403/
This dramatic ⬆️ in local osmolarity stimulates osmosensitive' cation pain receptor channels called TRPV (transient receptor potential vanilloid), similar to how these receptors respond to capsaicin.
Example of activation of TRPV1 is shown below.
pubmed.ncbi.nlm.nih.gov/21779403/
April 18, 2025 at 3:52 PM
10/
This dramatic ⬆️ in local osmolarity stimulates osmosensitive' cation pain receptor channels called TRPV (transient receptor potential vanilloid), similar to how these receptors respond to capsaicin.
Example of activation of TRPV1 is shown below.
pubmed.ncbi.nlm.nih.gov/21779403/
This dramatic ⬆️ in local osmolarity stimulates osmosensitive' cation pain receptor channels called TRPV (transient receptor potential vanilloid), similar to how these receptors respond to capsaicin.
Example of activation of TRPV1 is shown below.
pubmed.ncbi.nlm.nih.gov/21779403/
9/
So why does salt in a wound hurt so much?
One key clue is that salt in tissue causes significant increases in local osmolarity. For example, a 10% NaCl solution has an osmolarity of 3250 mOSM (>10x physiologic osmolarity).
pubmed.ncbi.nlm.nih.gov/16213085/
So why does salt in a wound hurt so much?
One key clue is that salt in tissue causes significant increases in local osmolarity. For example, a 10% NaCl solution has an osmolarity of 3250 mOSM (>10x physiologic osmolarity).
pubmed.ncbi.nlm.nih.gov/16213085/
TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator - PubMed
The ligand-gated ion channel, TRPV4, functions as a transducer of hypotonic stimuli in primary afferent nociceptive neurons and contributes to inflammatory and neuropathic pain. Hypertonic saline also...
pubmed.ncbi.nlm.nih.gov
April 18, 2025 at 3:52 PM
9/
So why does salt in a wound hurt so much?
One key clue is that salt in tissue causes significant increases in local osmolarity. For example, a 10% NaCl solution has an osmolarity of 3250 mOSM (>10x physiologic osmolarity).
pubmed.ncbi.nlm.nih.gov/16213085/
So why does salt in a wound hurt so much?
One key clue is that salt in tissue causes significant increases in local osmolarity. For example, a 10% NaCl solution has an osmolarity of 3250 mOSM (>10x physiologic osmolarity).
pubmed.ncbi.nlm.nih.gov/16213085/
8/
The degree to which NaCl can induce painful responses in the body has been studied in physiology experiments dating back to the 1930s.
In this 1997 study, infusing hypertonic saline into a muscle induced significantly more pain than normal saline.
pubmed.ncbi.nlm.nih.gov/9060024/
The degree to which NaCl can induce painful responses in the body has been studied in physiology experiments dating back to the 1930s.
In this 1997 study, infusing hypertonic saline into a muscle induced significantly more pain than normal saline.
pubmed.ncbi.nlm.nih.gov/9060024/
April 18, 2025 at 3:52 PM
8/
The degree to which NaCl can induce painful responses in the body has been studied in physiology experiments dating back to the 1930s.
In this 1997 study, infusing hypertonic saline into a muscle induced significantly more pain than normal saline.
pubmed.ncbi.nlm.nih.gov/9060024/
The degree to which NaCl can induce painful responses in the body has been studied in physiology experiments dating back to the 1930s.
In this 1997 study, infusing hypertonic saline into a muscle induced significantly more pain than normal saline.
pubmed.ncbi.nlm.nih.gov/9060024/
7/
One of the earliest references I came across for salt causing pain in wounds was from Pliny the Elder in the 1st century CE.
He recommended adding salt to beef fat to cure boils, but to avoid using salt if the combination caused pain.
www.perseus.tufts.edu/hopper/text?...
One of the earliest references I came across for salt causing pain in wounds was from Pliny the Elder in the 1st century CE.
He recommended adding salt to beef fat to cure boils, but to avoid using salt if the combination caused pain.
www.perseus.tufts.edu/hopper/text?...
April 18, 2025 at 3:52 PM
7/
One of the earliest references I came across for salt causing pain in wounds was from Pliny the Elder in the 1st century CE.
He recommended adding salt to beef fat to cure boils, but to avoid using salt if the combination caused pain.
www.perseus.tufts.edu/hopper/text?...
One of the earliest references I came across for salt causing pain in wounds was from Pliny the Elder in the 1st century CE.
He recommended adding salt to beef fat to cure boils, but to avoid using salt if the combination caused pain.
www.perseus.tufts.edu/hopper/text?...
6/
The Hippocratic authors in ancient Greece endorsed sea water as a wound healing treatment, observing that it helped heal wounds on the hands of fishermen.
A few centuries later, Galen similarly recommended salt to aid in wound healing.
pmc.ncbi.nlm.nih.gov/articles/PMC...
The Hippocratic authors in ancient Greece endorsed sea water as a wound healing treatment, observing that it helped heal wounds on the hands of fishermen.
A few centuries later, Galen similarly recommended salt to aid in wound healing.
pmc.ncbi.nlm.nih.gov/articles/PMC...
April 18, 2025 at 3:52 PM
6/
The Hippocratic authors in ancient Greece endorsed sea water as a wound healing treatment, observing that it helped heal wounds on the hands of fishermen.
A few centuries later, Galen similarly recommended salt to aid in wound healing.
pmc.ncbi.nlm.nih.gov/articles/PMC...
The Hippocratic authors in ancient Greece endorsed sea water as a wound healing treatment, observing that it helped heal wounds on the hands of fishermen.
A few centuries later, Galen similarly recommended salt to aid in wound healing.
pmc.ncbi.nlm.nih.gov/articles/PMC...