Teaching old pains new tricks: Links with learning and memory provide clues why pain persists
Some people just learn about pain all too well. That’s the growing notion among neuroscientists and anesthesiologists, who are finding evidence that chronic, persistent pain, including the phantom pain experienced by many amputees and people with spinal cord injuries, is learned, much like our own memories.
Such pain is very real and oftentimes severe. Approximately 60 percent of patients with spinal cord injuries suffer phantom pain – though they have no sensation or ability to move their arms or legs, they still feel pain from those limbs. Within weeks or months of the initial injury, more patients than not report tingling, pins-and-needles pain, and burning and stabbing pain that may never go away. The same can be true with other profound injuries, such as bullet or stab wounds, or from conditions like cancer, diabetes or arthritis.
"There’s good pain and there’s bad pain," says anesthesiologist Jay Yang, M.D., Ph.D., of the University of Rochester Medical Center. "Good pain, though we don’t usually think of it as ‘good,’ is the usual kind we all experience. We cut ourselves and it hurts, or we touch a hot burner and we pull away because we feel pain. That helps us survive and protects us. Bad pain is pathological pain that persists long after your wound has healed. It serves no purpose."
Physicians like Yang are looking at the physical similarities between the way a memory is formed, and the way that pain becomes persistent and chronic. In recent years scientists have recognized that the brain and the rest of the nervous system is much more flexible and adaptable than was once thought; they describe the ways our nerves adapt as "neuronal plasticity" or "synaptic plasticity." For instance, the neurons that store the memory of a loved one’s facial features are actually wired together more closely and completely than other neurons, and the ability of those cells to pass signals to each other is enhanced, like two close friends who can communicate reams of data with a simple knowing nod. The enhanced signaling and connection is part of an ongoing, lifelong process that forms the physical basis for memory and learning.
Yang and other neuroscientists are coming to the conclusion that the same sort of process may underlie persistent and chronic neuropathic pain, which results from damage to nerves. Usually, such pain is based on an initial event, like an amputation, that immediately caused a tremendous discharge of electrical and chemical energy along the nerves of the nervous system. Subsequently, nerves in the spinal cord continue to register pain signals, even though there is no physical cause to the pain, and indeed, in the case of phantom pain, there may not even be a limb to initiate or transmit pain signals.
"We believe that the pain no longer originates with the tissue that was originally damaged, but that it actually begins in the central nervous system, in the spinal cord and the brain," says Yang, a professor in the Departments of Anesthesiology and Pharmacology and Physiology. "The experience changes the nervous system, just like learning. It’s like a memory of pain that recurs again and again in the nervous system."
Yang says that because of past experience, the nervous system has been primed to transmit pain signals more efficiently: Small pain signals may be amplified, resulting in a sensation of pain way out of proportion to the amount of hurt one would normally experience. And more nerve cells become involved in the process.
Such pain often leaves physicians stymied. Opiates such as morphine are the first choice, but oftentimes they don’t work well until side effects like constipation, confusion and sleepiness become burdensome. Sometimes medications normally used to treat depression and seizures help ease the pain somewhat.
Yang and his collaborators, John Kulli and Raymond Zollo of the University of Rochester, are exploring a totally new way to control neuropathic pain: gene therapy. Yang and Christopher Wu, a former Rochester faculty member now at Johns Hopkins University, have published a review of the status of gene therapy as a possible future treatment for chronic pain in the June and July issues of the journal Anesthesiology.
The body presents many attractive targets for gene therapy for pain, since dozens of proteins are involved in the body’s creation and transmission of pain signals. Yang is focusing on a compound known as protein kinase C (PKC). Other scientists have created mice that lack the protein completely; those mice feel normal pain but seem immune to neuropathic or pathological pain. But scientists are a long ways from testing in people a way to knock out the protein completely, and there is no drug available that selectively targets PKC.
So Yang is experimenting with a type of gene therapy that "knocks down" or lessens the amount of one form of PKC. He is using tiny molecules known as oligonucleotides that bind up the messenger RNA that directs the manufacture of PKC, tying up the messenger in a sort of molecular straightjacket and preventing it from making the protein. Yang tested more than 20 sites on the gene before zeroing in on two that allowed him to reduce in rats the amount of PKC to one-fifth its usual level. He found that the rats with the lower level of PKC were much less sensitive to pain.
Yang is not the only one finding links between memory and pain. Earlier this year, scientists at Washington University in St. Louis reported that a protein that allows nerve cells to communicate may enhance perceptions of chronic pain. The team showed that mice with more NMDA receptors have enhanced memory and learning skills – they’re smarter – but they’re also more sensitive to pain. "This type of work reinforces the idea that the basic process that leads to memory formation may be the same as the process that causes chronic pain," Yang says.
Such basic research about pain ultimately benefits patients, Yang says. For instance, many doctors now do pre-emptive analgesia, giving pain medication to patients before surgery. Patients are deeply asleep when surgery is performed, and so they feel nothing even when they have received no pain medication before an operation. But surgery is still traumatic, and recent research suggests that minimizing the effects of would-be pain on the nervous system could help patients later, Yang says. Now, thanks to basic research, many anesthesiologists give pain medication before surgery.
"With the surgeon’s knife, you may introduce a huge pain response, which may result in a change in the spinal cord that will result in heightened post-operative pain," Yang says. Now many anesthesiologists recommend pain treatment before surgery, and initial clinical trials suggest that it’s effective and reduces pain when patients wake up after surgery, Yang says.
Yang’s research is funded by the National Institutes of Health, the New York State Department of Health, and the Department of Defense. He spends more than half his time doing research, even though the demand for anesthesiologists is so great that it’s difficult to take time away from the operating room to do basic research that may or may not pay off.
"I spend a little less time with patients now, but if by doing such research, we can ultimately control pain more effectively in hundreds or thousands of patients, my gosh, that’s wonderful," he says.