Chronic Pain Reorganizes the Brain

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Chronic Pain Reorganizes the Brain

Dr. Marco Martina

Studies of people suffering from chronic pain have shown that depression and specific cognitive declines are associated with the condition. In humans, the prefrontal cortex is known to be important in higher-order cognitive and emotional functions, and a subsection, the medial prefrontal cortex, has been correlated with chronic pain, suggesting a pathological reorganization of this brain region. For the first time, research led by Marco Martina, MD, PhD, assistant professor of physiology at the Feinberg School, shows structural and functional changes in neurons and their dendrites induced by chronic pain in a rodent model.

Dr. Martina and colleagues examined neurons from the contralateral medial prefrontal cortex in a spared-nerve injury (SNI) model of chronic pain in rats. “It’s important to emphasize that the structure and function of the prefrontal cortex in rodents and primates do not exactly overlap,” says Dr. Martina. However, the changes they found in rodents correspond to the human brain region previously shown to be involved in back pain perception by A. Vania Apkarian, PhD, professor of physiology, and colleagues at Northwestern.

One week after surgery, the researchers compared neurons of SNI rats with those from a control group. Patch-clamp recording of electrical potentials and microscopic analysis of the neurons revealed striking differences. “The dendrites—branches that come out of the neuronal body—are longer, more complex, and have more spines on them,” explains Dr. Martina. “Functionally, the glutamatergic currents, particularly the NMDA current, which mediates most of the calcium entrance to the cell, are very strongly potentiated compared to the control animals.” NMDA is a receptor for glutamate, a common neurotransmitter in the brain. NMDA receptors are found on the spines of dendrites, which become more numerous in the chronic pain condition.

“Overall the dendritic and glutamatergic excitation of these neurons increases as a result of chronic pain,” continues Dr. Martina. “We examined these neurons only one week after surgery, yet we saw a very important rearrangement of the connectivity of the cortex. The bigger dendrites sample over larger areas in the brain, have more spines, and induce more currents. As far as we know, there has never been any demonstration of such changes at the single-cell level of the brain associated with chronic pain.”

The paper was published in the February 17 issue of the Proceedings of the National Academy of Sciences and was chosen as a “must read” by the Faculty of 1000, an online service for which more than 4,500 leading researchers and clinicians evaluate and highlight the most important articles in biology and medicine. “We don’t know yet if these rearrangements will lead to the same atrophy and loss of gray matter that were seen in the human studies, but we have experiments planned to find out.”

Another implication of these observations involves the mechanism behind chronic pain. The electrical activation patterns seen in the rodent prefrontal cortex in this research resemble the patterns scientists have observed in the hippocampus that are associated with memory. “It may be that you cannot ‘forget’ your pain,” speculates Dr. Martina. “This paper opens that path of inquiry. Today no scientifically validated treatment for chronic pain exists. Knowing that the glutamatergic system is affected constitutes the rationale for testing drugs that affect that system in the treatment of chronic pain.”

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