Vincristine increases sensation/neuropathic pain by potentiating PIEZO2

[anacleta]

from a previous article: "PIEZO2 function is needed for triggering a touch-evoked erection reflex and successful mating in both male and female mice. Humans with complete loss of PIEZO2 function have genital hyposensitivity and experience no direct pleasure from gentle touch or vibration"


on the hypothetical idea that PIEZO2 might have something to do with the hypoesthesia of PSSD, this 2023 study from China is interesting:

Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity
Full text: https://www.sciencedirect.com/science/a ... 3523001569

says that vincristine, a widely used chemotherapeutic agent for treating different cancers, often induces severe peripheral neuropathic pain / mechanical hypersensitivity in a PIEZO2 channel-dependent manner, since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity.

vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.


more PIEZO2 = increased sensation of touch
less PIEZO2 = decreased sensation of touch


if a depotentiation of PIEZO2 were responsible for genital hypoesthesia in PSSD, Vincristine could increase excitability and sensations
conversely, in cases of PGAD where there is a burning and painful hyperexcitation in the genitals, a PIEZO2 inhibitor would reduce these neuropathic sensations.

but PIEZO2 is involved in myriad important things in the body if you look at the various studies and perhaps if there is a problem with PIEZO2 in PSSD it is a local one and does not involve the whole system.

could it also be involved with feelings of 'anaesthesia' to environmental stimuli underlying emotional numbness and anhedonia?

are there ways to locally potentiate and depotentiate PIEZO2, for example topically on the genitals or with targeted injections in rats?

[anacleta]

The Form and Function of PIEZO2 (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8794004/

"Given that PIEZO2 has several physiological roles, even if selective agonists and/or antagonists are identified, systemic drug delivery methods may not safely treat a single function in isolation. Incorporation of PIEZO2 drugs into a topical ointment is one strategy for targeting channel function in the skin without affecting internal organs, as has been suggested for treating mechanical allodynia (37, 38). It is important to test various drug vehicles and delivery routes to ensure that essential PIEZO2 functions, such as respiration and proprioception, are not affected."



The Mechanoreceptive Ion Channel PIEZO2 Plays a Critical Role in Sexual Function (2023)
https://www.nccih.nih.gov/research/rese ... l-function

"The investigators said the crucial role of PIEZO2 for perineal touch in mice and humans may hold therapeutic potential. Topical PIEZO2 inhibitors might be useful for targeted relief of genital hypersensitivity and pain, and agonists of PIEZO2 may help to alleviate genital hyposensitivity."

[Determined-Mind]

Thanks, that's interesting! It gives us hope!

That said, PIEZO2 might not be involved in the pleasure of sensations :

In clinical evaluations and surveys, three men and two women with PIEZO2-deficiency syndrome reported severe hyposensitivity in genital sensation. Despite their marked mechanosensory deficit, all described sexual activity as satisfying and rewarding. This finding reinforces prior research showing that other types of sensory input can compensate for deficits caused by loss of PIEZO2 function, and suggests that the same cellular, biomechanical, and neurological “work-arounds” occur in human sexual touch.

[anacleta]

Thanks, that's interesting! It gives us hope!

That said, PIEZO2 might not be involved in the pleasure of sensations :

In clinical evaluations and surveys, three men and two women with PIEZO2-deficiency syndrome reported severe hyposensitivity in genital sensation. Despite their marked mechanosensory deficit, all described sexual activity as satisfying and rewarding. This finding reinforces prior research showing that other types of sensory input can compensate for deficits caused by loss of PIEZO2 function, and suggests that the same cellular, biomechanical, and neurological “work-arounds” occur in human sexual touch.

this detail had escaped me, thank you

[pilha]

Thanks, that's interesting! It gives us hope!

That said, PIEZO2 might not be involved in the pleasure of sensations :

In clinical evaluations and surveys, three men and two women with PIEZO2-deficiency syndrome reported severe hyposensitivity in genital sensation. Despite their marked mechanosensory deficit, all described sexual activity as satisfying and rewarding. This finding reinforces prior research showing that other types of sensory input can compensate for deficits caused by loss of PIEZO2 function, and suggests that the same cellular, biomechanical, and neurological “work-arounds” occur in human sexual touch.

i also read this and i wondered did they born with this PIEZO2 deficiency? Because our brain and body is very powerfull and they can have adapted and take pleasure from a different mechanism. It's like blind people can "see" everything aroud them because somehow they perceive other things that we don't.

if they have a deficiency maybe they have a lack PIEZO of and maybe in our case we have it completely shut down

Maybe there are other "pleasure receptors". At least one - estrogen receptor - seems to be proved https://pubmed.ncbi.nlm.nih.gov/16267787/