Why pain sets in, chronically

Chances are, almost half of you listening to this programme right now are feeling pain you’ve been enduring for 3 months or more, and that means you’re experiencing “chronic pain”. And as Alan told us earlier, this seems to be associated with some kind of change in the way parts of the nervous system’s pain network behave. And our next guest, Kings College London neuropharmacologist Peter McNaughton, thinks he knows why: he’s discovered that chronic pain signals are triggered by a special ion channel or “pore” on the affected nerve cells. This turns on in chronic pain states and activates the affected nerve, producing incessant pain signals. The good news is that if he blocks it, at least in experimental animals, the pain is blocked too. He told Chris how it works…

Peter - Now, something that I often tell my students is they can conduct an experiment on pain and the only equipment they need is a brick and their toe. If they drop the brick on their toe, that's acute pain. The next day their toe is red, swollen, and throbbing. And that is inflammatory pain with a lot of inflammatory mediators having been released to make the pain worse. And if after three months their pain is still present, then that's chronic pain.

Chris - And looking at what underpins each of those different elements with the acute pain that's physically activating pain nerve cells, because you've done damage with the brick and the intermediate inflammatory pain is because you've done damage to tissue, which has now released loads of chemicals, which are winding up the nerve cells. And then three months later, if you've done serious damage, that's when something's rewired because everything else has got better or gone away. But something physically has to be rewired to keep that pain state running.

Peter - Yes, acute pain, we made some large advances in that in the last 20 years or so, you activate these ion channels as they are in the membranes of the nerve cells, which fires off action potentials which go up to consciousness and say, ouch. Your description of inflammatory pain was pretty good as well. There are a whole slew of different chemicals that are released by inflammation that generate inflammatory pain, and mostly they're not acting on the same ion channels as I spoke a moment ago. The work in my own lab has shown that a different ion channel called HCN2 generates an inward current that causes firing of action potentials, which say pain, pain, pain. Now the view about 20 years or so ago was that, in chronic pain, something different happens because what often happens is that the inflammatory phase subsides and it looks as though it's healed, yet the patient is still in pain. So the rationale was that there had been plastic changes in the spinal cord so that the pain, in a sense, had moved inwards and become a pain memory in the spinal cord. I'm not saying that point of view is wrong, but there's increasing evidence nowadays that pain nerve fibers continue to fire even in chronic pain states. So something is causing them to continue to fire even though apparently the site of the injury has healed up.

Chris - I guess the question then is we all experience pain every day, whether it's tripping over a stone or standing on something or touching the hot cooker, but we don't all develop chronic pain off the back of it. So why is it that some people do get into these pain states and quite commonly in the population, but it's not as common as our everyday experience of acute pain and thank goodness it's not.

Peter - Well, there's typically a pathology of some sort that's driving it. Another example would be rheumatoid arthritis. Patients that suffer from these types of arthritis suffer continuous pain in their joints. So I think there's pretty obvious pathology which is damaged to the joints. Work in my own group has shown that once again, it's these HCN2 ion channels which are driving the pain.

Chris - Is sort of a summary then of that something, we don't know exactly what, but something triggers that particular channel or pore in these pain nerve cells to either become more active or you get more of them. And so the nerve cell becomes more active than it should be. It should have a sort of baseline level of activity and the presence and activity of that poor means it's more active than it ought to be.

Peter - Yes, exactly. Although the baseline activity should be zero because, as I'm sitting here, I feel no pain whatsoever. So, presumably none of my ion channels are active and there are no action potentials, nerve signals that are going up to my consciousness.

Chris - Are those ion channels just sitting there doing nothing normally then and something's turning them on or has something changed in the nerve cell that it now produces those ion channels, those pores and puts them in the nerve ready to make these abhorrent signals?

Peter - As far as we know, it's the first of the two. The ion channels are there all the time. They're silent, they're there to detect pain. Normally you don't have pain, but if pain occurs, they produce the inward current and produce the activity in the pain sensitive nerves.

Chris - So what's turning them on then?

Peter - Well, what's turning them on? Inflammatory mediators. There's one that's very well known to pharmacologists called prostaglandin E2, A chemical that drugs like aspirin and ibuprofen act to reduce the other class of analgesics. The opiates act more centrally on the transmission of the pain signal at the first synapse in the spinal cord. And they're wonderful, wonderful painkillers, but they come with a side-effect burden, which, I'm sure everybody's aware of. Addiction, death as a result from overdose.

Chris - But if one talks to patients themselves, they'll say that 'nothing touches this doc. I take all these pills and I've still got the pain'. Now, is that just because they've taken so many tablets that their pain has outstripped the ability of the tablets to control it? Or is the mechanism different that we are now short of shutting the pain stable door after the pain horse has bolted?

Peter - Well, the work from my lab really shows that it's this HCN2 ion channel, which is critical in triggering long-term pain. And the channel can be driven by inflammatory mediators or possibly changes in the internal ambience of the nerve fibre, which switches on these channels as well. But it seems that these channels are extremely important in generating chronic pain. And one of the things that my lab's been trying to do is to develop blockers for this HCN2 ion channel, which in animals at least, these blockers deliver wonderful analgesia. So we're hoping to develop blockers which could go into use as more effective painkillers with fewer side effects. That's the hope, at least.