Serotonin (5-HT), TRPV1, and Thermal Hyperalgesia

Over the past month or so I have been focusing on researching the transient receptor potential cation channel subfamily, specifically the TRPV1 and TRPV3 variants, for a paper I am putting together on EM. It seems as though there is a subgroup of EM sufferers whose symptoms started after an injury and respond to serotonin based medications (specifically myself). This group has the potential to respond strongly to capsaicin based treatment (which has shown full remission in a couple of publications). I will try to summarize the paper below in a progression pathway for those who don’t care to read it all.

injury (noxious stimuli) > release of proinflammatory mediators that sensitize nociceptors > serotonin (5-HT) is one of these prominent inflammatory neuromodulators > serotonin leads to an increase in TRPV1 sensitization during inflammation (thermal hyperalgesia) > depleting 5-HT via antagonists (cyproheptadine, pizotifen, feverfew, white willow) reduces afferent transmission of painful, burning stimuli by reducing TRPV1 activation > capsaicin also reduces TRPV1 activation, however, with repeated applications and introduction to the stimuli it can completely desensitize the overactive TRPV1 channels rather than just reducing activity like 5-HT antagonists.

I think this is exciting information, however, a very similar TRP variant (TRPV3) is also active in reported cases of thermal hyperalgesia seen in erythromelalgia. TRPV3, unlike its sibling TRPV1, is sensitized by capsaicin and repeated exposure to stimuli. Only one paper to date has documented a case of erythromelalgia caused by a TRPV3 mutation. TRPV1 overactivity is by far the more common of the two and is also seen in migraine disorders, however, TRPV3 overactivity is a possible explanation as to why some worsen with capsaicin and Bob’s protocol and do not return to the baseline pre-treatment. TRPV1 could explain why some improve greatly with Bob’s protocol or capsaicin treatment. When I say improve in this case I am referring to a decrease in redness and burning sensation, not just a built up tolerance to the stimuli.

Unfortunately there is no treatment currently for TRPV3 overactivity and mutations but research is being done and is linked below. I thought this information might be interesting to some and potentially helpful. I am meeting with a geneticist at Northwestern next week to discuss testing to TRPV1 and TRPV3 mutations to continue to rule out causes. As I am doing well currently, capsaicin treatment isn’t something I’m pushing to do, however, if a mutation is found or anything along those lines, I would consider it.

Paper about erythromelalgia and capsaicin treatment after surgery (injury response): https://pmj.bmj.com/content/postgradmedj/70/829/841.full.pdf

Papers about 5-HT and TRPV1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104492/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183408/

Papers about TRPV3: https://jamanetwork.com/journals/jamadermatology/fullarticle/1813224
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039508/

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I have thought about TRPV1 and other TRP’s as well (I should say I have migraines and pain along the trigeminal nerve) What prompted this direction for me is, that mexiletine and other local anesthetics (sodium channel blockers) feel like they bite/electrocute my nerves - the only thing I know is that it is a very consistent result. I can tolerate very small doses of sodium channel blockers or else a huge amount (lidocaine iv). The only explanation I can find (I’ve asked several neurologists and they just say neuroanatomy knowledge is lagging way behind general anatomy knowledge) is that local anesthetics can irritate the TRP’s. And maybe for me my problem lies more with TRP’s than overactive sodium channels in terms of SFN pain.

I have applied to center for undiagnosed diseases hoping to get whole exome sequencing in biopsy taken from affected areas.

I’ve poked around in clinical trials - there is coming out soon, a topical TRPV1 antagonist used in eczema [ https://onlinelibrary.wiley.com/doi/full/10.1111/bjd.17455 ]. I asked my derm if it could reach the sensory nerves, and he said yes, and seemed to think it would be worth a shot for me. At the very least, maybe it would help me tolerate sodium channel blockers better (or do nothing). There are some other anti - TRPV1 migraine meds I’ve found in clinical trials that I’ve emailed (and my pain doc has emailed), but haven’t heard back.

I’ve only just skimmed your post and will read it more thoroughly later. But was excited to see someone else talking about TRP’s, I guess, ha! Btw here is a paper saying some people with EM have TRP genetic variants -

Do you respond to imitrex/triptans? (just curious)
(edit to include -



basically imitrex can modulate TRPV1)

Take care

I do not take any triptans but I do take two serotonin antagonists (cyproheptadine and feverfew). I also take mexiletine which helps modestly I think, but I do not have a known sodium channelopathy but very well could have an undiscovered one. The cyproheptadine and feverfew help me the most and since returning to working out about 6 months ago it seems as though my flares lessen with repeated exercise which also points towards TRP issues due to TRPV1 overactivity desensitizing to repeated activation via either heat or an increased body temperature (exercise). If I don’t see further improvement in the coming months before I start medical school I will probably look into trying OTC capsaicin under the guidance of my doc.

God bless you, joeshmoe for posting this. I have not participated in this EM conversation very much lately. I’ve been discouraged by my MD’s lack of interest in helping with solutions. I’ve live in California, USA and have recently been using cannaboid cream during flares, which reduces pain, but the redness and swelling remain. And I’ve been taking cbd sublingual, which seems to give me a sense of whole body calmness. I am encouraged by your paper and I would like to try the capsaicin topically on my feet. How is it suggested to be used. I know about using gloves and not applying it after showering, but how often is it applied? And when? During flare? Between flares? Any info appreciated. Thank you!

I would try the capsaicin under the guidance of your doctor to do a controlled test. It can make your symptoms worse so I would talk to your doctor about it and see what they think, it has a narrow range of success, like many treatments for EM, but it can be very helpful in some cases. From my understanding is that it needs to be applied at least twice daily to desensitize properly in addition to removing cooling methods and walking more, wearing shoes, etc. If it works, it should eventually not need to be used anymore. Again, I would ask your doctor about it, it was a pretty popular treatment about 10 years ago for pain relief so he or she should know about it.

Again, thank you so much! I appreciate the information. Kimr

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Hi Joe, I am wondering if you ended up testing for these mutations?

I did but the results are not back yet. Northwestern is sequencing my entire exom so they are testing for any know genetic anomalies in sodium channels, TRPV channels, and lots more. I submitted my samples in April so I should know back relatively soon. Thankfully my insurance covered nearly all of it, I paid $30, without it its nearly a $5000 test. In the meantime, they tested my serum serotonin levels due to serotonin antagonists helping me so much and they were normal (which is good, high levels can be indicative of carcinoid syndrome).

I am happy to hear your serotonin levels were normal! What an expensive test, yes thank goodness for insurance! Please keep us posted on your results.

I stumbled on

and some similar articles.

“Together, the findings showed that a GABA receptor agonist [like baclofen] could counteract TRPV1 sensitization.”

I was playing around with a CBD topical (CBD is thought to activate + desensitize TRP’s channels, but also do some other things … used for pain + inflammation) and felt it was similar to my experience with (oral) THC - like it flattened small triggers (baseline tingles) while exacerbated big triggers (showering). In addition, It felt like I’d float in and out between numb and feeling like there was acid on my skin (otherwise an unusual sensation), like it was just confusing my nerves. Anyway it was interesting. I wish I could capture what it was doing to cause the numbing, and do it all the time!

Wanted to share that under my allergist’s guidance I “attempted” a .075% prescription capsaicin cream. This is a no go for me! Went on fine, nothing, then about 7 hours after application I experienced a burn like no other. I used a face wash that rids of oils to finally get the burn to stop. Thankfully I only applied to one foot. Tonight that foot is burning yet again, though not as bad as yesterday.

I am sorry to hear that. It is supposed to burn though. The theory is that it activates the heat sensitive receptors and then after repeated applications (weeks) it permanently desensitizes the area to heat.

So I decided to test out the capsaicin cream 0.1% strength. My EM has been improving with the medications I have been taking but I wanted to try one last thing prior to starting school in August and give myself a few weeks after the test to recover.

I have been using it for two days on my feet. It took a day or so for any burning to start. The burning seems to be aggravated by an increase in skin wetness (shower/sweating) or obviously heat. It is a different burning than my EM in that it is a different sensation and is only on the surface of the skin. The best analogy I can think of is when you eat spicy food and your lips burn after eating, that is exactly how it feels on your skin. My EM has not seen any changes or worsening with it. The burning is different than the EM so I think I will keep giving it a go for the next few weeks and put up with the burning to finish the experiment since it is not worsening my EM. I have been working out with the cream on. I lifted weights today and then did a 30 minutes run outside in the hot sun and it was tolerable but did burn a little. The whole idea of it is that it takes repeated uses to desensitize so I figured I am already a few days in so I might as well finish.

I hope this provides additional relief and adds on to your progressive improvement! I’m still working so I don’t feel I can tolerate this burn on top of the EM burn while at work. I struggle as is. Please do keep us informed! Best wishes!

It has been one week since I started applying the high potency capsaicin cream to all areas of both of my feet. I have been trying to be as active as possible to allow the nerves to reset to an active lifestyle. I have been running 20-30 minutes each day in addition to an hour of weightlifting and on fridays I play 2-3 hours of basketball in a men’s league (my feet burned a lot last Friday during playing but toughed through it). This burning that I experienced was worse than it was before I started using the cream. For the first 4 days or so I would get pretty intense burning during any exercise that caused my feet to sweat.

The burning, however, has gradually decreased day by day. As of yesterday, I no longer experience any burning or blood pooling during and after running in the hot sun. That held today as well. This was improving previously but the improvement over the past 3-4 days has been more than I’ve seen in the past 2 months on my medication regiment. I ran at 6pm yesterday and at 10am today so late afternoon running seems to be viable for me now. I also walked around town today for about 45 minutes to run errands and had no color changes or hotness present in my feet and it’s nearly 90 degrees today. The baseline temperature of my feet seems to have increased as they are warm when I’m resting as opposed to the very cold baseline temperature that has been present since my EM started. I will update again in a few weeks if improvement continues and will consider applying the capsaicin to my knees as well (especially my surgical knee where this all started). It seems as though I may have been onto something months ago with the relationship between serotonin, TRPV1 channels and their desensitization with capsaicin, and the thermal hyperalgesia in EM.

Here’s my late take on this. But I’m just a caregiver.

This is a theory that no doctor has verified and one doctor our MD said, if this was the case why would there not be more areas where you’re mom would have burning. Why just the feet? (My response was being mute, I could not explain how it would only affect the feet for the most part in her case.)

Here’s the premise of my theory or list of reasons, but keep in mind I’m not a doctor and a neurologist would who know a lot more than I would could easily tear down or perhaps validate a bit my theory. First in my mom’s case she developed EM from Risperdal. She was taking it and while taking it her feet became more and more worse over the course of 6 weeks and we refused to take the drug anymore, but ironically it was prescribed twice more by doctors and we rejected those prescriptions as well. She had level 10 pain flares and went to the hospital ER five times for extreme pain in the first year (2002).
Let’s look at some of the side effects of Risperdal and I’ll stop with the important one for my mom’s case, or what destroyed the lives of three adults since 2002.

Risperdal Side Effects Center

Risperdal is available as a generic drug. Common side effects of Risperdal include:

  • extrapyramidal effects (sudden, often jerky, [involuntary] motions of the head, neck, arms, body, or eyes),
  • [dizziness],
  • tiredness,
  • drowsiness,
  • [fatigue]
  • [fever]
  • feeling hot or cold

And the list goes on an on.

Now when we look at Risperdal on Wikepedia we can see how it affects 7 Seretonin (5HT) receptors that control vascular function or thermal regulation. It’s an antagonists, which means it locks it’s molecules into “key hole” receptors of nerve receptors related to 7 types of 5HT nerve pathways that control thermo-regulation or blood flow and pain and of course other things can be a result. It’s an antagonist, which means it cuts back on the receptor activity to sense, how each one senses and controls the autonomic nerves and bodies ability to control itself is not clear for a layman reading the wikepedia. But we know that antagonists will stop the use of a receptor, so it’s cutting back on Seretonin signals which control those things. Now I have not heard anyone else, ever say they received EM from Risperdal, but thermal regulation issues is listed as a side effect, so perhaps a rare group of people have had EM from that drug. But there’s another clue that it may be from the 5HT or Seretonin antagonistic effects of Risperdol. That would be a kind of thin piece of proof I’d say comes from one study which used .5% Ketamine and 1% Amitriptyline cream to “treat” burning foot syndrome. In that study, some who applied the cream on their feet had a “burning sensation” on their feet, from the Amitriptyline which was a slight burning that happened until the Ketamine action started to happen to reduce pain. In other words in the study, patients said they felt a warming of the feet from the amitriptyline component of a compound cream which was used in a study to treat their EM. A trip to Wikepedia to look at the actions of the Amitriptyline shows 6 of the seven neurotransmitter sites which is affected with “antagonistic side effects” is affected by Amitriptyline. This means Amitriptyline, could be thought of as Risperdal-lite perhaps. Almost as bad as Risperdal. Why would I guess that to be the case. Because Risperdal has 7 neurotransmitter sites that it can antagonize but Amitriptyline has only 6. But also one of those sites has an “irreversable” antagonistic effect. Think of an antagonist as being a key that slips into a lock, and each lock being a different kind of lock for each channel. Risperdal can put keys in 7 kinds of 5HT sites, but Amitriptyline can put keys into only 6 of them. But Risperdal will not only put a key in the receptors of the nerves, it does something akin to super-gluing and breaking off the key into the site of one of the receptors and that antagonistic effect never is removed. It’s irreversible nerve damage. So in my opinion, based on what I’ve seen and experienced Risperdal is worse and a much greater threat. Now perhaps the Amitriptyline can wear off and nerve sensing can return to normal for many people, but in the case of Risperdal I don’t think it’s ever reversible. As my mom still has flares which are basically as bad as when she first had this problem since 2002, we are still waiting for her nerves to be released from the effects of Risperdal. Of course we live in Michigan and in 1996 the wonderful state Republicans and our Republican governor signed a bill into effect saying drug companies cannot be sued for side effects they cause. So unless you can prove that they committed fraud, they are shielded from any persecution. Doctors have the power to prescribe any drug they want for any reason and they can experiment in their practice on their patients. If the drug companies push drugs and use incentives to make them pushed, they profit and the consumer or patient in Michigan becomes a drug test dummy for the drug companies. So if you’re living in the State of Michigan you can sue the drug companies for side effects that ruin your life, but you can’t win.

But aside from the little rant about lack of protection in Michigan. The antagonistic effects are limiting the nerves ability to send normal signals. Do those normal signals warm or cool the feet? Difficult for a layman to say and it’s probably not easy for a perhaps even a doctor to tell us. There are two kinds of processes that a chemical can have on a nerve receptor. They can reduce signals or stop them which means they are antagonists. Or they can excite and perhaps enhance a signal which means they are agonists. One could think as a layman, if antagonistic effects are causing my EM, maybe if I took an agonist for the same nerve receptor it would reverse the effect. That sounds like it makes sense at a very simplistic level. If you’re using something that makes your feet warm by causing more agonist reactions, you might be using something that is causing some receptors to warm up as well, or maybe chill them. In any case, the effect would be throwing nerve signals on more frequently. Drugs that are agonists for 5HT are in the class of “speed” drugs that makes peoples nerves go crazy and gives them “high” feelings and trips. So there’s not much legally or medically that a doctor would likely want to do to give people “speed” to excite and try to reverse the effects of an antagonist on a nerve. With an irreversable antagonistic effect not more keys to stimulate the nerve receptor can be put into the lock because the irreversable side effect of putting the Risperdal key into that lock has stayed there, and that nerve receptor is dead for the rest of your life. So even if an agonist could trigger the reverse effect it will never be plugged into that keyhole, to cause the effect to happen.

Now that I’ve given you some basics of the smoking gun as I can see it, we also know that some people on this board have reported that they had EM symptoms happen or get worse taking Amitriptyline. This is a further piece of possible evidence that the 5HT antagonism will cause burning feet syndrome to happen to some people. Maybe they experience some kind of mutation from the effect and the receptor sites are permanently damaged. Amitriptyline is also something that can cross the brain blood barrier and the peripheral nerves are protected much like the “brain blood barrier” and less susceptible to the effect of nerve medication unless it can pass the brain blood barrier. So Amitriptyline and Risperdal being designed as nerve medications for the brain, can perhaps have a greater effect on the nerves in your hands and feet.

Now regarding my thought process on how this is working and why the body flares up more and is more sensitive to heat than a normal human being. First I want to point out that one process I talked with a neurologist about was the numbing of the nerves by injections of numbing agents by a foot doctor, as if he was performing surgery. This being a shot into the Tibial Nerve, but they may use a different nerve bundle on the foot as well. And they might numb the foot and do diagnostic blocks. Which by the way won’t be covered by most insurance for “neuropathy” but in the case of EM, the foot doctor may be able to classify this different than for general nueropathy kinds of use and get it approved. So we tested and tried having mom’s nerves numbed as if she was having a foot operation. This is a short term numbing so she might have a few hours or perhaps up to six hours of pain relieve far better than Opiods can give her. And the thought was “if the diagnostic” numbing works, we can decide if the foot doctor will do a permanent numbing of the nerves either in part or wholly numb it by injecting alchohol solution into the nerve area to kill the nerve outright, without cutting it. When we asked the neurologist about this “hail mary” approach of how we might make her feet become like a diabetic foot condition. The Neurologist said that is a very bad idea. He stated that the foot would grow black and require amputation as the side effect of that. He was pretty adamant that it would be a way to cause her to loose her feet. The foot surgeon that suggested this “hail mary” (5% chance) thought, said it might not work when he suggested it. He said it might make things worse as well. So we didn’t do the kill the nerve route, but we have a different foot doctor who does give mom temporary nerve block injections in her feet, about once every two weeks.

The Neurologist told me that if nerves are cut the default autonomic response by the body is to “send blood” to the injury. So if you’re nerves die or are killed off on the way to the foot, you’re body will think an injury occur and the default response is “send blood to the injury”. Hence we get edema and flares from nerves that are missing or lost their function.

So with that in mind, we can see why diabetics can have edema in their feet, their body is trying to cure it by sending blood down there. And it tries to send blood down there and they’ll feel pain and have EM flares at first, when the nerves are working enough to not have the feet become numb. Later as their nerves die more and more from small fiber neuropathy perhaps, they have a numb foot. So they have swelling and horribly bad looking feet, but they don’t feel pain, because their feet are numb.

When you put your feet in a cold ice water bath what are you doing? You’re making you’re foot numb from the cold environment. You are as an early EM suffering person in effect giving you’re foot a temporary case of diabetic loss of feeling and less pain sensations are going to the brain. So to me, getting a nerve block with a shot of lidocaine is the same thing medically as putting you’re feet into an ice bath to freeze out the pain.

The threshhold of pain and heat sensitivity is thrown way off. Why? My theory would be because some of the nerves are gone, they are like broken wires on a volume control of a speaker or radio. And when you turn the volume control on those old style pots that had maybe a hundred resister settings, well now only maybe 10 percent of them are left. So you’re radio goes from a volume of 1 to 10 instantly because there is no granularity of signals. What I think happens to people like my mom, is they have lost many of their nerve signals and the brain doesn’t know how to remap the pain volume controls for the fewer signals and fewer nerves that are left. So when a “flare happens” the person has maybe 1/10th the sensors operating and when you trigger only one of them with perhaps a light touch on the skin for Small Fiber Neuropathy like symptoms, sensitive to light touch, or heat for EM. . . you have one nerve acting like it’s ten nerves and the brain thinks ten nerves are getting warm instead of one and the granularity of the numbers is not remapped properly inside the brain. Thus the temperature scale has lost precision and may interpret lower temperatures as much higher. So 85 degree water may seem temperate to my feet, but would cause a flare to my mom and she wants her feet to be in a range from 60 degrees to perhaps 80 degrees, but no warmer. For her 85 degrees is like 120 to me. This is because she has lost nerve sensations and the brain has either remapped the remaining ones to a scale which is way outside the normal body range that we are used to, or the body will say there’s an injury I’m sending blood to heal the foot. Which of course is not injured at all, but the blood flow causes pain, especially with someone with fewer nerve receptors, left. Because of nerve damage.

The further away you are from the brain, the longer the distance, so more nerve damage will affect signals which are further away and if the damage isn’t to great along the pathway, it may only affect the far extremes of the body. Thus it affects the feet and hands first. If mom kept taking those pills that caused her EM, the pain would move further and further toward her brain throughout her body as more and more nerves would be damaged and degrade the entire signal network closer.

Some of my theory is based on a belief that signals are being accumulated in mass by numbers of nerve sensors, which is a digital concept from computer processing approaches to the body. The body may not act that way, so my programming background may be coloring my thought process in my theory or thinking.

If the brain cannot be remapped and make up properly for lost nerves and the brain will mess up the remap, you’ll have problems. Phantom pain, jolts and fake signals may be triggered as the few remaining signals have more “pain weight” or sensation weight than they should have. So this would be my theory.

Now if you can “train the body” by making nerves hot and tell yourself this is not bad and get the body used to higher temperatures, you can “train” yourself out of the flare state. This it what the “hot pepper” on the nerves approach is saying. They are saying you can exercise you’re mind and remap it. I don’t think that is possible and before I read the entire thread I felt it would not work. And I think CRPS advanced therapy approach videos have said it doesn’t work for CRPS type 2 ailments either. So the training idea probably won’t work for most folks. It will probably make it worse. Things like "firing off signals randomly with electric shocks to “test you’re nerves” may trigger flares as well. So I would not say TENs is a good idea either, but this based on my limited experience as a caregiver. As usual it’s good to validate any approach and get the opinion of medical experts and take most of our comments with a grain of salt.

Excuse me but that was the farthest thing from a little rant.

I was hoping you would have put a summary at the end so that I would at least be able to reply to something you said. I am not sure where you are getting your information from for your theories as they don’t seem to be backed by tangible evidence but I am symptom free now with the therapies that I talk about in a few of my posts (all of which were attempted based on published research). I am not sure if that is of help to you or not but it might provide some closure on this specific topic.