So, I want to talk to you about sex differences in pain and I’ll start off by pointing out that one of the fun things about doing sex differences research, is that unlike most scientific questions, the public think they know the answer. You go out on the street and ask people which sex is more sensitive to pain, men or women? Everyone will guess, they’ll all guess wrong, or most of them will guess wrong, because what we know about this, in fact from just voluminous data at this point now, first of all is that women endorse having the symptoms of chronic pain at higher rates, you can see in every single large epidemiological study done but one, there was an excess prevalence in females. That could be because they’re more sensitive to pain, it could also be because- well I learned ten minutes ago that men do go to the doctor, but they certainly don’t go to the doctor at the same frequency that women do. So, it could be simply that women end up being chronic pain patients because they become patients. It could also simply be that they’re more susceptible to disorders that happen to be painful. Really, the only way to answer the question is to take them into the laboratory and this has been done hundreds and hundreds of times and the result is this: it’s in my mind one of the most robustly answered questions I’ve ever seen in science, women are in fact more sensitive to pain than men.
Now you can argue by how much, and whether that matters very much, it is clearly true. It is also in the grand scheme of things, not particularly important. What is a much bigger issue is the mismatch between the clinical problem and how we study it pre-clinically, and how we study it is with male rats and mice. This is overwhelmingly true, it’s been true for a long time, I looked at papers published in the journal, Pain, over a 10 period and found that 79% of the studies used male rats or male mice only. I did this again for a piece in Nature in 2015, and I found that it hadn’t budged.
That’s the bad news, I want to give you a little piece of good news, which is in fact it’s getting better! SABB policies actually work, and as Cara pointed out, in 2011, Canada got its act together, and in 2016, the US got its act together, and things are shifting! So, you can see that by 2019, the percentage of papers published in the journal, Pain, using only male rats or only male mice has significantly decreased, and the number using both males and females, and with discussion of whether there was or wasn’t a sex difference, is also apparently on the rise. So that’s great!
But we are left with a deeply biased literature that I’m going to try to describe over the next few minutes. It matters because we’ve shown, and others are now showing in the pain space, that there is biology that is entirely sex specific. So, a few years ago, we showed that one of the biggest advances in pain research over the last 20 years, the idea that it wasn‘t only the neurons in the spinal cord that were involved in pain processing, but the glial cells as well, especially the microglia. This turns out to be only true in males and no one had any idea about that, because all of our experiments were done in males, but in fact if you block microglia there, there, there, if you knock them all out in the toxin, these have effects in male rats and mice, as advertised in the literature, do absolutely nothing whatsoever to female mice and rats, female mice and rats are not using microglia, they’re using something else to produce exactly the same ends, to the exactly the same degree.
So, this is an old story, I want to tell you about a new story and I’m going to do it very very quickly. First because you don’t care, and second because this is a lightning talk, and third because I’m trying to prove a larger point, but I want to walk you through very quickly some work we’ve been doing recently, looking at the relationship between pain and death. John Liebeskind, my former advisor, pointed out a long time ago that pain can kill you, it just doesn’t do it directly, and now the epidemiology is actually caught up. So, it turns out that people with chronic pain pooled across a bunch of studies have a 1.57 increase mortality risk compared to those who aren’t living with chronic widespread pain, I have no idea what that means, so I asked Gary Macfarlane to turn that into a more understandable concept. And it looks like I’ve gotten rid of it for purposes of time.
Basically, having chronic widespread pain, makes you six years older than your chronological age, and that much closer to death. It’s actually a pretty big deal, deserves an explanation. When you think death, you think of telomeres, or at least I do, there are exactly three papers in the literature showing an effect of pain on telomere length, the interaction between pain and telomere length. We decided to try to study this pre-clinically. So, we used a nerve injury model that produces very long lasting, note that those are changes over months, not days but months, so very long lasting allodynia in mice, that is accompanied starting at 4 months but not before and continuing to 13 months with telomere reduction and there’s a nice correlation between the behavioral changes in the telomere length reduction. We have reason to believe that the relationship is bi-directional, so not only does pain cause telomere reduction, but telomere length reduction can cause pain. The best evidence for that is through these mutant mice that lack one of the genes that produces telomere rays and these mutants show increased sensitivity to pain, including mechanical allodynia over very long periods of time. We didn’t expect to see this but the effect was hugely robust, and so not only did these mutant mice have a pain phenotype, but pain phenotype actually effected mortality in a telomere dependant matter, such that the mutant mice that already die younger because of the mutation, if they are put in chronic pain, die even younger than that, and that is a very big effect in a critter that only lives for 2.5 years.
We think the telomeres are effecting pain through the phenomenon of cellular senescence, I wont bore you with the details, but we have data that in fact there is cellular synesis in the spinal cord produced by chronic pain, it correlates with the behavior, and if you reduce the synesis, the p53 inhibition, you can normalize the response in animals, but only if they’re old or at least if it’s a long time after the injury, not if they’re young and its only two weeks past injury.
So that’s the story we have and now you’re saying to yourself “well why is he talking about this in a talk on sex differences”. Well I’m sorry why hasn’t anybody seen this before! Cellular senescence is a very well-studied phenomenon, but no one’s ever reported in the literature and the simple answer is, is that no one has looked long enough. So, I can only find a dozen papers in the literature where anyone has ever looked at chronic pain past 3 months, and usually people are looking at 2 weeks after the injury. Remember you don’t start seeing these effects until 4 months later, this means that the entire chronic pain literature, isn’t really studying chronic pain at all.
Why this is in a sex difference talk, is because everything I’ve just told you is entirely male specific. The behavioral effect is male specific, the telomere reduction is male specific, the phenotype of the mutant type is male specific, the mortality effect is male specific, the p53-dependence is male specific, and we think the reason this is all male-specific is because the telomere reduction is happening in microglia, and microglia apparently are only involved in chronic pain in males and not females.
Why did I tell you this story? Because I’m starting to wonder why every time I do a study, not looking for sex differences, we find sex differences. And so, I decided to go into the literature and see if it’s only me or this is happening to other people. We did a search- I did a search, of the entire pre-clinical pain literature, and there were a number of papers that came up, some of the differences were quantitative differences; males were higher than females on some measure, or lower than females on some measure, and that’s the way it played out. But a lot of the findings were qualitative differences. The authors did something, and that manipulation worked in one sex and didn’t work in the other sex. Normally you would imagine this would happen equally, but it wasn’t even close. When manipulations work in one sex and not in the other, it was always in the male.
What that means is the entire literature is biased towards coming up with hypotheses that turn out to be male-specific. Why is that? It’s because we’ve only been using males. And so, the situation, even though we’re fixing it, has got us into a really big problem that’s going to take a long time to get out of it. And with that, I winna thank the folks who did the work. Thank you for your attention.