You slam your hand in a door, and the experience becomes etched into your brain. You carry a memory of the swinging panel, the sound as it crushes your flesh and the shooting pain as your skin gives way. Your body remembers it too. For days afterwards, the neurons in your spine carry pain signals more easily form your hand to your brain. As a result, your hand feels more sensitive, and even the lightest touch will trigger an unpleasant reaction. It’s as if your spine carries a memory for pain.
This is more than a metaphor. Two groups of scientists have found that one special molecule underlies both processes. It helps to store memories in our brains, and it sensitises neurons in our spines after a painful experience. It’s a protein called PKMzeta. It’s the engine of memory.
When we learn new things, PKMzeta shows up at the gaps between neurons (synapses) and strengthens the connections between them. These bolstered synapses are the physical embodiment of our memories, and they are fragile things. It turns out that we need to continually recreate PKMzeta at synapses to keep our memories alive. If the protein disappears, so do our memories. Unlike the text of a book or the bytes of a hard disk, the information stored in our brain is constantly on the verge of being erased.
This has to be one of the most surprising discoveries of modern brain science, and it’s the handiwork of Todd Sacktor. In 2006, his team managed to erase memories in the brains of rats with a chemical called ZIP, which neutralises PKMzeta. Even very strong memories, which has been around for months, vanished irreversibly. This year, Sacktor did the opposite – he boosted old, faded memories in rats by giving them extra PKMzeta.
Now, Marina Asiedu and Dipti Tillu from the University of Arizona College of Medicine have shown that PKMzeta does more than stabilise memories in the brain. It’s also behind the lingering pain we feel after an injury.
Asiedu and Tillu knew that after a painful experience, neurons that carry pain signals develop stronger connections, especially those in a part of the spine called the dorsal horn. This is the same thing that happens in the brain when we learn something new, and the duo reasoned that PKMzeta might be involved in both processes.
To test their idea, Asiedu and Tillu injected mice in the foot with a chemical called IL-6 that triggered a mild swelling and made the limb more sensitive for up to three days. It mimicked the feeling that you get after you catch your hand in a door, without actually injuring the animals. Even after the swelling goes away, the paw remains sensitive – the ‘primed’ mice will react to a second chemical called PGE2 that wouldn’t normally bother them.
None of this happened if Asiedu and Tillu used ZIP (the anti-PKMzeta chemical). If they injected the mice with ZIP and IL-6 at the same time, their feet never became more sensitive. Without PKMzeta, they couldn’t develop a memory for the pain. Even if ZIP followed IL-6 by three days, it erased the sensitivity in the rodents’ paws – the treated mice didn’t react to a shot of PGE2. And when Asiedu and Tillu loaded the mice with a protein that mimics PKMzeta, their sensitive streaks returned.
These fresh results tally with those from another study by Korean scientists Xiang-Yao Li, Hyoung-Gon Ko and Tao Chen, which was published last year. They found that PKMzeta is also involved in a different type of chronic pain, caused by more severe damage to nerves around the body. Following this sort of damage, the PKMzeta memory engine starts chugging away in a part of the brain called the anterior cingulate cortex (ACC), leading to consistent and long-lasting pain. An injection of ZIP erased this pain, at least for a few hours.
The two studies have important differences that will need to be unpicked. Why, for example, did Asiedu and Tillu’s manage to erase the “pain memories” in the long-term, while the Korean team only did so for a few hours? Why was the hotspot of PKMzeta activity located in the spine in one study but the brain in another?
The answers to these questions could tell us a lot about the differences between different types of pain. But on the whole, the experiments build a compelling picture of PKMzeta accumulating in neurons after an injury, and priming them for persistent pain.
If the same thing happens in humans, then it might be possible to treat long-lasting pain with drugs that target PKMzeta. This is no trivial matter. A Europe-wide survey found that around one in five adults had suffered pain for more than 6 months. Around half of these people felt their pain constantly, and half had suffered for 2 to 15 years. They continue to suffer because we still know very little about the molecules responsible for this most primal of feelings. With PKMzeta, we’re one step closer to some answers.
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Footnote: This study has a special significance for me, because it was partially inspired by this blog.
A couple of years ago, I wrote a feature for the Times about memories, and I interviewed Sacktor for the piece. As per usual, only a few select quotes made it into the article. But, as I often do, I posted the full transcript of the interview on this blog. In one of his replies, Sacktor suggested that PKMzeta might be involved in pain memory. He said, “There’s also a condition called central neuropathic pain syndrome, where people catch their finger in the car door and even after the injury heals, a memory for the pain is set up in the central nervous system. ZIP could erase that too.”
Theodore Price, the lead scientist behind Asiedu and Tillu’s piece (who blogs as Juniorprof), read the interview and was intrigued. He said to me, “His comment in your interview influenced me greatly and led to some of the experimental design we used in this paper. It was a total eureka moment for me.”
Sacktor is also pleased, especially since PKMzeta, seems to have roles in pain, addiction, post-traumatic stress and more. During his teenage years, Sacktor would argue with his father – a biochemist – about the best way to tackle diseases. His dad would argue that you need to understand the underlying biology first. Sacktor preferred tackling the disease directly. “I realized long ago my Dad was right,” he says. “The possibility that my father was more right and I was more wrong than I could have known, brings me more happiness than I could have imagined.”
Things have, in a way, come full circle – science inspires blog post, which inspires more science, which inspires a new blog post. It’s worth noting that the key quote from Sacktor never made it into the Times piece. Without that transcript, this new paper wouldn’t exist.
And that, I think, is a pretty cool way of celebrating the fact that this is my 1000th post on Not Exactly Rocket Science…
Reference: Asiedu, Tillu, Melemedjian, Shy, Sanoja, Bodell, Ghosh, Porreca & Price. 2011. Spinal Protein Kinase M zeta Underlies the Maintenance Mechanism of Persistent Nociceptive Sensitization. J Neurosci http://dx.doi.org/10.1523/JNEUROSCI.6286-10.2011
More on PKMzeta
May 11th, 2011 at 12:10 pm
Congratulations!
And a great way to mark the milestone.
May 11th, 2011 at 12:16 pm
Congrats, Ed!
Are there proteins other than PKMzeta that ZIP is thought to interact with?
If I were injected with PKMzeta, would I remember more but also be in constant pain?
Fascinating stuff!
May 11th, 2011 at 12:27 pm
Congratulations – for the excellent post and for reaching such a significant milestone. Looking forward to the next 1000!
May 11th, 2011 at 1:06 pm
congrats again Ed,
Love this graphic here, as someone who has stapled themselves in the fingernail a couple of times I can say that my pain memory of the event was quite active even years later…
May 11th, 2011 at 1:28 pm
I wonder how this finding might apply to social pain. There’s a growing body of evidence (fMRI, etc.) that the “pain” of social exclusion and rejection is processed similarly to physical pain, with similar brain regions involved. Also, a related body of research shows that some individuals are particularly sensitive to social pain – normal subjects subjected to ostracism under laboratory conditions return to a normal state within 45 minutes, but socially anxious people are not able to do so – and are also hypersensitive to cues of social rejection.
See, e.g., the work of Kipling Williams and Naomi Eisenberg.
May 11th, 2011 at 3:15 pm
Congrats on hitting 1000 Ed, and what an honor that you marked it by writing about my lab’s work!!
Thanks again for your interview of Todd Sacktor all that time ago too.
Sister Y, its highly unlikely that what you are referring to would be encoded in the spinal cord; however, the ACC may play a major role in such a process… in that case the work from Min Zhuo’s lab is likely highly relevant. Work on PKMzeta in the amygdala may also give some insight into “pain” of social rejection.
May 11th, 2011 at 3:18 pm
and for the record, the eureka moment came when I read the words “after the injury heals”. That told me we were looking at the problem in the wrong way and switched my thinking to the models we used in the paper.
May 11th, 2011 at 4:59 pm
Happy 1000th birthday to NERS! Hearty congrats!
May 11th, 2011 at 8:05 pm
Very interesting post – I work in auditory science and there is a lot of similarity between chronic tinnitus and chronic pain. It would be interesting to see if there are any links with memory for pain.
May 11th, 2011 at 8:54 pm
thanks
May 12th, 2011 at 9:36 am
Great article and great way to celebrate the success of this blog huh? I think that its something that you could never had expected when you started posting here.
I currently found this blog some days agora but im already visiting here everyday.
Just one thing that I keep wondered when I was reading the text. The PKMzeta could also make someones memory stronger? Instead of focusing only in the pain side, this is something that could be HUGE in many aspects, lets say, never more forgeting your childhood memories, the things you have to work on, etc;
May 12th, 2011 at 9:40 am
Thansks Brindes. Check the interview with Sacktor in the links at the bottom, though. There are plenty of other potential applications for PKMzeta but Sacktor talks about ways in which having a better memory could be both a blessing and a curse.
May 12th, 2011 at 9:41 am
Oh and many thanks to Juniorprof for letting me know about his cool study and (I love this) answering commenter questions.
May 12th, 2011 at 1:09 pm
Benvenuto Cellini relates that his father once discovered a salamander resting on a log in the fireplace, impervious to the flames around him. He brought the young lad to view this remarkable event, and then boxed his ears to make sure that he would remember it! It would seem that the relationship between pain and memory has been attested for a long time – at least since the early 16th century. It’s good to have a scientific explanation – now if we could just explain that salalmander…
May 13th, 2011 at 10:55 am
This is pretty cool! You mentioned chronic pain conditions, I wonder if fibromyalgia could have some connection to this?
May 13th, 2011 at 7:30 pm
Very interesting. Hoping this leads to some relief in the future for my chronic MS pain and I wouldn’t mind having some of my unpleasant life memories erased as well
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Stay inspired!
May 15th, 2011 at 8:30 pm
What news for us unfortunates suffering from chronic pain? When can my doctors at Kaiser get ahold of some ZIP, and inject it via trigger point style injections, or perhaps guided flouroscopy, into my SI joint? 6 years of constant pain, suicidal ideation, busted body, ruined relationships, and more, all ZIPed up? Even for a few hours…
Feel free to write me at Darin.Padula@gmail.com or call 808-227-3174 if you need a research trial guinea pig… please.
May 16th, 2011 at 9:05 am
Congrats on the blog milestone, and on having a significant impact on these studies.