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Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids (cell.com)
submitted 22d ago by Robert_Larsson
Robert_Larsson [OP] 4 points 22d ago
**Highlights**
* Penk (pro-enkephalin) is upregulated following induced removal of Nav1.7 in adult mice
* Penk upregulation in the DRG is specific for cLTMRs
* Analgesia observed after Nav1.7 removal is not driven by enkephalin overexpression
* Nav1.7 plays an essential role in the initiation of nociceptor action potentials
**Summary**
Loss-of-function mutations in Nav1.7, a voltage-gated sodium channel, cause congenital insensitivity to pain (CIP) in humans, demonstrating that Nav1.7 is essential for the perception of pain. However, the mechanism by which loss of Nav1.7 results in insensitivity to pain is not entirely clear. It has been suggested that loss of Nav1.7 induces overexpression of enkephalin, an endogenous opioid receptor agonist, leading to opioid-dependent analgesia. Using behavioral pharmacology and single-cell RNA-seq analysis, we find that overexpression of enkephalin occurs only in cLTMR neurons, a subclass of sensory neurons involved in low-threshold touch detection, and that this overexpression does not play a role in the analgesia observed following genetic removal of Nav1.7. Furthermore, we demonstrate using laser speckle contrast imaging (LSCI) and in vivo electrophysiology that Nav1.7 function is required for the initiation of C-fiber action potentials (APs), which explains the observed insensitivity to pain following genetic removal or inhibition of Nav1.7.
\-Not sure how you feel about a mouse model but for us interested in pain insensitivity especially related to sodium channels, this has been a headscratcher for years...
* Penk (pro-enkephalin) is upregulated following induced removal of Nav1.7 in adult mice
* Penk upregulation in the DRG is specific for cLTMRs
* Analgesia observed after Nav1.7 removal is not driven by enkephalin overexpression
* Nav1.7 plays an essential role in the initiation of nociceptor action potentials
**Summary**
Loss-of-function mutations in Nav1.7, a voltage-gated sodium channel, cause congenital insensitivity to pain (CIP) in humans, demonstrating that Nav1.7 is essential for the perception of pain. However, the mechanism by which loss of Nav1.7 results in insensitivity to pain is not entirely clear. It has been suggested that loss of Nav1.7 induces overexpression of enkephalin, an endogenous opioid receptor agonist, leading to opioid-dependent analgesia. Using behavioral pharmacology and single-cell RNA-seq analysis, we find that overexpression of enkephalin occurs only in cLTMR neurons, a subclass of sensory neurons involved in low-threshold touch detection, and that this overexpression does not play a role in the analgesia observed following genetic removal of Nav1.7. Furthermore, we demonstrate using laser speckle contrast imaging (LSCI) and in vivo electrophysiology that Nav1.7 function is required for the initiation of C-fiber action potentials (APs), which explains the observed insensitivity to pain following genetic removal or inhibition of Nav1.7.
\-Not sure how you feel about a mouse model but for us interested in pain insensitivity especially related to sodium channels, this has been a headscratcher for years...
SelfAwareMachine 2 points 20d ago
Mouse/rat models translate poorly because metabotropic mechanisms are significantly different (or at least different enough) in primates. See An independent regulator of global release pathways in astrocytes generates a subtype of extracellular vesicles required for postsynaptic function for an example.
Robert_Larsson [OP] 1 points 20d ago
In this case we have human knockouts however, in fact we have both up and downregulation of the same gene which causes the predicted phenotypes.
SelfAwareMachine 2 points 19d ago
I hope so! We've made a lot of progress over the last few years better understanding these mechanisms, but the fail rate between mouse->human trials is still kind of shocking. I found this book: Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions really illuminating, and it has a couple of chapters regarding the challenges of going from animal trials to human trials to successful product, and how rare it is for a candidate treatment to survive the transition between animal and human trials.
IMO a lot of work tends to way overemphasize ionotropic mechanics while the metabotropic side is where a lot of the differences lie.
IMO a lot of work tends to way overemphasize ionotropic mechanics while the metabotropic side is where a lot of the differences lie.
Robert_Larsson [OP] 2 points 19d ago
We have but the issues are specific as well. Sodium channels are well understood in this case both due to the over and under expression but also because of basic physiology which relies on them for excitability and the undeniably high efficacy of local anesthetics like lidocaine. Human animal models in this case aren't as informative for those reasons but in general yes there are issues in translation but that can also be explained specifically depending on the model and the purpose. Here the big issue I'd say is pharmacology. It is very hard to design a drug with specific properties, might say near impossible it is much more guesswork, screening and luck. Due to this function doesn't translate well and there are many effects of a bioavailable small molecule in many tissues. If you instead could control which cells get exposed to the treatment or target a specific protein much more precisely like through nucleic acids those issue mentioned above change dramatically. You see this especially in the rare conditions with single point mutations.
hutch_man0 1 points 21d ago
Can someone ILI5?
Robert_Larsson [OP] 2 points 21d ago
Sodium channels are necessary for the excitability and transmission of a signal that is obvious. However some of these sodium channels seem to be preferentially expressed on pain sensing nerve cells. In humans for example we know that people born without the sodium channel NaV1.7 can't feel any pain aka. congenital insensitivity to pain (CIP). Overexpression of the same protein NaV1.7 on the other hand leads to painful conditions, which means this sodium channel NaV1.7 seem to play a crucial part in pain signaling. By blocking or knocking it out we have been able to replicate pain insensitivity. It was observed however that that endogenous opioids called enkephalins increased in mice as a result of knocking out the gene coding for NaV1.7 as well, prompting the question what role these enkephalins might play in the painkilling. This paper shows that this overproduction of enkephalins only occurs in a subpopulation of low threshold touch neurons and that NaV1.7 is crucial to the initiation of the action potential in C-Fibers. That means that NaV1.7 does play a really important part in the painkilling itself.
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