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.
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
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