How Do Nerve Cells Signal Pain?

Some of the speakers from the conference are here with us, including David Julius, from the University of California, San Francisco; he studies the part of our nervous system we're probably most consciously aware of, our pain receptors.

Chris - David, you're very interested in how the nervous system signals pain and looking at your resume, this pot of bright red chillies I have in front of me is something which is featured very much in your work over the years. How does the nervous system signal pain?  If I eat one of these, why does it make me feel I've got a pain in my mouth?

David - Well, the nervous system signals pain in the way that Fran has already described that there are ion channels and other molecules that are activated by different stimuli, be it a hot chilli pepper which we'll talk about in a second or temperature or pressure. And that induces the opening and closing of ion channels to change the flow of ions across the membrane when that happens.  You activate the cell, excite the nerve fibres, say, a sensory fibre in your lips when you eat a hot chilli pepper. That sends an action potential or message to the brain that you eventually receive as a noxious or painful stimulus. So, the reason that chilli peppers are painful and sometimes people think of this as a taste response, a gustatory response, but it's really a pain response and you would know that if rather than eating the chilli pepper, you chopped one up and then stuck your finger in your eye and there would obviously be a pain response and not a taste response.  There's a main pungent ingredient in chilli peppers of the Capsicum family called Capsaicin. The plant has over evolutionary time, developed this compound to fit very nicely into a pocket of an ion channel called the Vanilloid receptor TRPV1 which is pretty highly expressed particularly on nerve fibres that are involved in sensing painful stimuli as it turns out, mostly specified for detecting heat and inflammatory agents. When Capsaicin binds to this channel, it opens up in a way that Fran described. It's like a little doughnut that opens up and ions flow through the membrane and this activates the nerve fibre and then you perceive this is a pain response.

Chris - So, in my nervous system, I've got lots of different sensory nerve fibres which supply my skin and my eyes, and my mouth.  Do different nerve fibres detect different sorts of stimuli? So, we're talking about chillies here and if I eat these, I get a stinging painful sensation, but I also would describe it as hot. If I suck on a Polo mint, I get a sensation of coolness in my mouth or if I put my hand in ice, I feel cold. So, are they different nerve cells that are doing those senses?

David - They are to a large extent different nerve cells. So, there was for many years a big debate in the pain area as to whether nerve fibres that detect noxious or pain producing stimuli - of course, these are stimuli that have a capacity to cause tissue damage.  That's why we perceive them as being painful.  There is a debate as to whether they're all the same functionally or whether there are distinct subsets. And now, we know really through molecular studies that not all pain sensing nerve fibres are the same. They're specifically tuned to detect different things. And so, the subset of nerve fibres that detect cold are to a large extent distinct from those that detect heat. You can tell that because the molecules that are involved in detecting say, Capsaicin from a hot chilli pepper or menthol from mint leaf are the same molecules that are involved in detecting heat versus cold. If you'd look at where those genes are expressed, they're expressed in largely non-overlapping subsets of nerve fibres. So, that's kind of like in what we would say, a labelled line to some extent that you have these different circuits coming in from the periphery that inform you about different sorts of perceptions.

Chris - Just ignoring the effects of chilli for a second, when I'm feeling heat or sensing cold, how are my nerve cells detecting those stimuli? What's going on in the nerve cell to enable it to tell what the temperature is?

David - Well, pretty much the same ways that we just described through these chemical mimics, if you want to say that. For these compounds, these chemicals that illicit these sensations. They're acting on some of the same molecules that are involved, that are actually activated by heat versus cold. And so, they do the same things. They're activating an ion channel that allows ions to flow into the cell. So, when you touch a stove or if you eat a chilli pepper, or put a mint in your mouth, it's basically the same thing.  Really, what these compounds from these different plants do is to act on the same ion channels that are involved in sensing heat or cold. What they're really doing is just, they're acting as what we would call allosteric modulators of the channel which basically means that when you eat a mint and when menthol from a mint comes in contact with these channels, they change the temperature at which the channel now must respond to be active.

Chris - So, it sort of fools the channel into thinking it's cooler than it is so it discharges.

David - Enables it to be activated at a higher temperature than it normally would be activated at and that might be for example the temperature of the nerve fibre in your mouth. And so now, the nerve fibre thinks that it just interacted with a cold substance, but instead, it's just being sort of fooled in a sense. In some ways similar to some of the things we'll hear about from Karl in terms of how light can mimic the actions of different things.

Chris - And if I'm unlucky enough to be bitten by a snake or a tarantula or something and this elicits pain, are the venom molecules in these animals also effectively binding to these same targets such as the chilli pepper does in order to elicit the sensation of pain?

David - Yeah, there are some. So, venoms as you may are very complex mixtures of all kinds of toxins, but we found in fact that there are some toxins in say, tarantula venoms that target the same channel that Capsaicin targets from the chilli pepper. So, it's a really beautiful example of convergent evolution. Here, you have these two organisms. One is a plant and one is an animal namely, the chilli pepper and the spider. They have both evolved chemical defence mechanisms that activate your pain sensing nerve fibres basically to say, "Stay away from me."  But they do so by very different chemical strategies because the molecule of a chilli pepper is a small organic molecule. The toxin in the spider that activates the same channel is a large peptide or small protein. And so, they've converged on the same mechanism, but they do it through a somewhat different chemical armamentarium.

Chris - Now, if I eat a lot of chillies and Hannah picked me up on Friday because she fed me some chillies she had in the office and she said I wouldn't eat those, but I did.  I thought they were refreshingly spicy, but not over the top. Hannah said she thought they were really hot.  I eat a lot of chilli though. So, if I keep on eating the chilli, does this have any kind of damaging effect on my sensory nerves?

David - Yeah, probably reversible, but people who eat a lot of chilli peppers - probably, if you're a kid growing in Korea eating a lot of kimchi for breakfast, you would have a much higher threshold.

Chris - But what's actually happening?  Are you damaging nerve cells or are you just losing the receptor?

David - Well, you're probably doing both. So, you're probably what we call, 'desensitising' the receptor, the channel, which means it sort of goes to quiescent state. But if you put Capsaicin at very high concentrations on say, an area of your skin - your forearm or whatever, you will cause those nerve fibres to sort of wither and retract from that area. So, there is some damage fortunately, peripheral nerve fibres will grow back and re-innervate those areas. But there is a decrease in their presence or their activity there. In fact, this just sort of underlies the paradoxical use of Capsaicin as an analgesic because if you get these balms with Capsaicin and rub it on, it will use to de-sensitise the nerve fibre or cause it to actually regress from that area. As a result, you've sort of de-nervated in a sense functionally or physically de-nervated that region.

Chris - Because I think I've seen people use that for pain caused by shingles for example, haven't they?

David - That's right and can be used in very high concentration for example for things like that or what we call neuropathic pain associated with viral infection, things like that.

Chris - David, thank you very much. David Julius from the University of California, San Francisco.