Wiping Out Pain Through the Pathways of Memory

It is difficult to pinpoint the source of persisting pain once an injury has healed; thus chronic pain patients are often told the pain “is all in your head.”  But new research led by a team of neuroscientists at McGill University could change what it means to have chronic pain — that it in fact lies in neuronal pathways and is far more complicated than simply being “in your head.”

The research paper, which was published in Molecular Pain, pinpoints a new drug with the acronym “ZIP,” which selectively removes certain pain memories while leaving others intact.  Scientists have known for years that there is a connection between chronic pain and neuronal pathways, but this is the first time a drug can actually erase the pathways to remove pain.

“This is the first time that we can foresee medications that will target an established pain memory trace as a way of reducing pain hypersensitivity,” Dr. Terrence Coderre, a McGill professor of anesthesiology and neuroscience who led the research team, said in an interview with Science Daily.  “We believe it’s an avenue that may offer new hope to those suffering from chronic pain.”


What is chronic pain?

In 2010, the National Institute of Health came up with a blueprint to push forward partnerships between pain scientists and non-pain neuroscientists to examine the transition from acute to chronic neuropathic pain.  “Chronic neuropathic pain conditions are difficult to treat and we currently lack an understanding of the mechanisms underlying the transition to a chronic pain state after acute nerve injury,” the report states.

There are 116 million Americans suffering from chronic pain, compared to the 11.9 million Americans with cancer, according to the Institute of Medicine of the National Academies and the American Cancer Society, respectively.  Worldwide, there are about 1.5 billion people suffering from chronic pain.

“Chronic pain is any pain that lasts for more than 3-6 months and beyond that,” said Dr. Terrence Coderre.  “In a number of injuries, the tissue that’s injured may heal, but the pain will remain.”  The McGill team’s report published in Molecular Pain perhaps defines chronic pain in the most succinct way: “Chronic pain occurs when normally protective acute pain becomes pathologically persistent.”

Whether back pain, arthritis, or phantom limb syndrome — chronic pain is a major health problem in the US.  According to the NIH report, chronic pain has an economic burden of $100 billion per year in medical expenses and lost productivity in workers.  A 2006 survey conducted for the American Pain Foundation, meanwhile, discovered that 51% of respondents felt they had no control over their pain; 77% felt depressed, and 86% said their pain caused an inability to sleep well.

In the past, a number of different approaches have been used to treat chronic pain.  Anti-inflammatory drugs are commonly used to treat pain caused by arthritis, but if used over a long period of time, can cause damage to organs.  The use of opiates to treat pain could eventually lead to abuse and dependence.  But ZIP could remove this memory trace once and for all–given there isn’t any “periphery” pain (like inflammation) continuing, which would in turn create new neuronal pathways.

“We were interested in targeting something other than periphery or opiate systems of the brain,” Dr. Coderre said.  “We wanted to target memory traces.”

But the word “memory” is not to be confused with the traditional sense of cognitive memory — the kind that holds your dreams, thoughts, and images of your past.  There is, so to speak, two different types of memory that will be discussed in this article — the first being memory dealing with chronic, or physical, pain; the second being cognitive memory, which is the conscious memory of an event.  The neurons involved are in different places — for cognitive memory, they lie in the hippocampus, while the pain neurons lie in these pain traces.

“In a pain memory trace, the neurons amplify the signals and get accentuated, causing the pain to last longer,” Dr. Coderre said.  “You develop what’s called pain hypersensitivity.”


ZIP and PKMzeta

If chronic pain has been so difficult to treat, then how exactly does ZIP work?  Dr. Todd Sacktor, Professor of Neurology at SUNY and co-author of the McGill study, has been interested in memory research for nearly 30 years.  He was particularly interested in how long-term memories were stored, and discovered a particular enzyme called PKMzeta 20 years ago.

“Memories are thought to be a strengthening of connections between neurons,” Dr. Sacktor said.  “No one knew what was causing this strengthening in a persistent fashion… In 2006, it became clear that PKMzeta is the main storage mechanism for long-term memory.”

As an enzyme, PKMzeta catalyzes chemical reactions.  What ZIP does is prevent the chemical reaction from occurring, and thus the neuron connections are not strengthened.

“ZIP is a little peptide that fits into the PKMzeta molecule like a key fitting into a lock, but it’s a broken key,” Dr. Sacktor said.  “The way it usually works is that ‘keys’ get locked in PKMzeta, and then the altered key gets spat out and is functionally different, and acts to strengthen the synapse.  But ZIP is a broken key that doesn’t get out, and so the memory collapses.”


Cognitive Memory and “Eternal Sunshine”

When many first hear about a drug erasing memories, they immediately recall the science fiction movie “Eternal Sunshine of the Spotless Mind,” in which the main character undergoes memory removal to forget the painful breakup of a relationship.  This may be possible in the future, if ZIP is targeted at cognitive memory.

“The important thing to note about… ZIP is that it could potentially work in all neurons, including the area of the brain that’s responsible for your cognitive memories,” said Dr. Coderre.  “Therefore, you could potentially affect all your memories.”

It goes back to the little enzyme: all memories — whether you think about them or not — are being maintained by PKMzeta.

Although the McGill team including Drs. Coderre and Sacktor did not concentrate on ZIP’s effect on cognitive memory, there is another branch of research called “reconsolidation blockade” that is investigating this front.  Reconsolidation occurs every time a long-term memory is brought out of storage and “remembered,” changing slightly each time the brain recalls it (in other words, memories aren’t accurate documentations of the past like we may have thought).  The memories are then re-stored in the brain as the slightly altered version.  The goal is to develop an extremely specific version of ZIP, which only becomes active when a certain memory is recalled.

“This might allow a specific, recalled long-term memory to be erased, rather than all long-term memories,” Dr. Sacktor said in a 2009 New York Times interview.  “How this reconsolidation work fits in with PKMzeta is actively being explored.”


Ethical Implications, Future Steps

There is already an ethical debate — a theoretical one — in which people are arguing over the implications of ZIP.  If a highly advanced version of this drug got into the hands of the wrong people (political dictators, for example) could it be used as a form of torture or brainwash (literally)?  Or are these merely the dismissible arguments of conspiracy theorists and science fiction fanatics?  Dr. Sacktor believes that even though it may take 10 years or more before ZIP can be used clinically, human manipulation of memory is eventually bound to happen.

“When it actually happens, people who are scared of it are going to be even more scared of it,” he said.  “People who want it, are going to really want it — it’ll be the same as in vitro fertilization and abortion.  Religion will say it’s the end of the world.”

But perhaps what is most fascinating about this research is that it opens doors into the arena of other memory disorders such as Alzheimer’s.  PKMzeta was discovered to be involved in the web-like clusters found in the brains of Alzheimer’s patients, although research is still in the beginning stages on this front.

“Elucidating the molecular mechanism of long-term memory may one day be key, I hope, to developing treatments of memory disorders,” Dr. Sacktor said in The New York Times interview.  “But don’t forget how long this development from basic science discovery to clinical usefulness takes— decades for even the most important findings, such as germ theory and the structure of DNA.”

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