Researchers at Arizona State University are trying to come up with a new way to make pain medication that would be less addictive than opioids and would also not make patients feel cold. And, they’re using a specific protein to try to do that.
Wade Van Horn is a professor in Arizona State University’s School of Molecular Sciences and Biodesign Center for Personalized Diagnostics and spoke more about it with The Show.
Full conversation
WADE VAN HORN: So, so I've been fascinated for a number of years. So you and I, we interact with our environment and we need to know, kind of are things hot or cold. And that has a lot of implications in in both, you know, are, are we cold and do we need to warm up or are we hot and do we need to cool down?
But so my lab has been studying the cold sensing protein in humans, which has a funny name called TRPM8 for a number of years now and we were really interested in, could we understand a way that maybe we could turn this into a, a drug target for new kinds of pain therapies.
MARK BRODIE: What led you to think that was even something that you should be thinking about.?
VAN HORN: Well, so, so many kinds of pain are associated with this receptor, this protein TRPM8, this cold receptor. And so, for example, if you know, if you touch something really cold, it, it feels like it's burning and it hurts, but there's a number of other kinds of pains that are known to be associated with it.
And, and they, they vary widely from things like migraine headaches to neuropathic pain, you know, where maybe you get injured and then you have kind of pains for long term or, or things like, diabetics often have neuropathic pain. And so it's been known that that TRPM8 is involved in pain for a number of years. And so we wanted to see if we could help understand how and maybe come up with ideas to, to target it more effectively.
BRODIE: Well, so what might that look like in terms of trying to target more effectively and maybe use it to, to our advantage?
VAN HORN: Yeah. So, so one of the things that's made targeting TRPM8 difficult is that it's sensitive to both cold but also to chemicals. And so if you think about say the mint plant, it has a, a chemical called menthol, and menthol actually induces the same kind of cold feeling that cold does through this exact same receptor.
And so some drug companies have tried to target TRPM8 for pain and they found that it, it's very effective at inhibiting certain kinds of pain. But there's a side effect and that side effect often is that you feel cold and patients don't tolerate that well. So we wanted to see if we could understand the side effect and maybe come up with a new way to screen new kinds of drugs.
BRODIE: So, does that mean that for at least some patients, if they are on some of these medications aimed at helping dull their pain as a side effect, they might end up feeling cold?
VAN HORN: Yeah. So, so, you know, most commonly people are taking, you know, for chronic pain, things like opioids, right? Which have, you know, tremendous side effects. So people are on the lookout for new kinds of pain targets that don't have the same kinds of side effects as opioids like addiction. So in theory, if one were to be able to target TRPM8, it wouldn't be addictive. And so then that would alleviate a lot of societal problems that, that are, you know, surround opioids and opioid addiction.
BRODIE: So I guess that means the big question is how do you actually do that? How do you develop an effective pain medication that does that?
VAN HORN: Yeah. So, so one of the things that's known is like I said, when you target TRPM8 it might cause you not to feel cold. Both just, you know, if you stuck your hand in an ice bucket kind of thing, but also it could change your body temperature, both of which could be dangerous. And so we wanted to see, could we use modern science to, to decouple, or separate, these kinds of features of TRPM8? And so how we went about doing it is using a funny technique called ancestral protein reconstruction.
BRODIE: And what does that mean?
VAN HORN: So, yeah, I think the easiest way to think about it is, is imagine that, you know, you have your great-great-great-grandmother's chocolate chip cookie recipe. And it's changed over time perhaps. So, what you did is you got all the recipes from all your cousins and aunts and uncles and maybe with all of those, you could kind of recapitulate what the original chocolate chip cookie recipe was.
So that's kind of what we did for TRPM8, is we looked at sequences for humans and rats and monkeys and kind of every organism we could find and we could use then mathematics to predict what ancestral TRPM8 sequences were and we could, we could study those so we could resurrect those and study those. And we found effectively that we could separate out the cold sensing aspect of TRPM8 from the chemical sensing aspect of TRPM8.
BRODIE: So it sounds like what you came up with was kind of an amalgam of all sorts of different TRPM8s?
VAN HORN: Yeah. Well, so what we came up with was yeah, a predecessor TRPM8. So that's right. So the, the way, you know, it's a funny bit of biochemistry and mathematics and evolutionary theory. But based on that, we can kind of track back along evolution and then say, what was TRPM8 like back then? And then we can study that and we can go back further or closer and with those kinds of studies, we can then try and understand, you know, is this cold sensitive? Is this menthol sensitive? Is it both?
And, and accordingly, we were able to kind of say, hey, look, here's a, here's an ancestral TRPM8 that's sensitive to cold. Oh, and here's one that's sensitive to menthol or chemicals. And now that puts us in a position where in theory, we should be able to screen drugs against both of these and find one that can inhibit the chemical activation but leave the cold activation alone.
BRODIE: Well, so you mentioned that you can do that in theory. In practice how easy or difficult might that be to achieve, do you think?
VAN HORN: Well, so I think it depends on, on at what level. So, you know, my lab is set up with instruments that we can assess this in a very high throughput way. And so it, it should be straightforward to, you know, identify candidate drugs that will be selective for one activation mode over the other. Of course, that's just the start of the drug discovery pathway. Right. And so then it's, it's many years to make sure it's safe, that it's effective, you know, in the clinic.
So, you know, I think that the starting point it's obvious what to do and it's pretty straightforward, but again, it's, it's a time-consuming process to eventually get something in the clinic.
BRODIE: Well, and as you referenced, it sounds like the goal here is to be able to develop a medication that treats pain without being addictive and without some of the side effects, for example, making patients feel like they're cold.
VAN HORN: That's what we hope we can do. Yeah. Is that, you know, and this is a funny, using this so-called ancestral sequence reconstruction as a really different way to do it. But yeah, I think, you know, we'll start now finding different kinds of drug candidates and, and looking for ones that have the right properties and, you know, I if we're successful, then we should be able to come up with, you know, alternatives to opioids and things that, you know, are non-addictive but, but effectively treat pain.