Now, scientists from the University at Buffalo may have found an answer.
In study results presented today (Nov. 10, 2003) at the annual meeting of the Society for Neuroscience in New Orleans, the researchers present the first evidence that the effectiveness of antidepressant drugs such as amitryptyline in treating pain stems from their ability to inhibit the production of the inflammatory protein tumor necrosis factor (TNF) in the brain.
This study, conducted in rats as an animal model, builds on their earlier published research showing a direct link between an increase in pain and an increase in TNF production in the brain. The new results also shed light on how these same antidepressant drugs work to treat depression.
"We've discovered that a primary action of antidepressant drug treatment for depressive behavior and chronic pain symptoms is to decrease levels of TNF in the brain," said Robert N. Spengler, Ph.D., UB associate professor of pathology and anatomical sciences and senior researcher on the project.
Tracey A. Ignatowski, Ph.D., UB assistant research professor of pathology and anatomical sciences, is a co-author on the study. Jessica L. Reynolds, a doctoral student in Spengler's lab, is first author.
The findings showed that the time required for the drug to increase neurotransmitter release in the brain, as well as to eliminate pain, was the same in rats as in humans, suggesting the results may apply directly to humans.
"Our findings should contribute significantly to the development of new strategies to treat chronic pain, which affects more than six million people in the U.S. alone," Spengler said.
The work is based on the knowledge that impulses arising from specific regions of the brain and spinal cord may influence the way pain is perceived. "Normally, stimulation of a certain group of neurons in the brain and spinal cord that release the neurotransmitter norepinephrine from nerve terminals along their axons inhibits the conscious perception of pain," said Spengler.
Norepinephrine acts similarly to adrenaline, which is released from the adrenal gland in response to arousal and stress, such as might occur during combat, for example. Increases in adrenaline enable persons to perform necessary functions in spite of increased fear or stress. "Our laboratory has evidence that constant painful stimulation, such as occurs from back injury, may make neurons that normally inhibit pain when exposed to norepinephrine actually enhance pain in the presence of norepinephrine," said Spengler.
In this study, the researchers found that this change from pain inhibitor to pain facilitator is caused by increased production of TNF in the brain during chronic pain, and that this increase in TNF, in turn, caused neurons to decrease their release of norepinephrine. An imbalance of this neurotransmitter also is linked directly to symptoms of depression.
By manipulating the amount of TNF in this animal model of chronic pain and monitoring release of norepinephrine, as well as behavioral responses to pain, the researchers were able to mimic these cellular changes in the rat brain and produce the same changes that take place when naturally occurring chronic pain develops.
By administering the antidepressant drug, they showed that the drug causes a decrease in TNF and an increase in norepinephrine release, resulting in a decrease in pain and its symptoms.
"These findings provide novel information concerning this proinflammatory protein," said Spengler. "Not only have we shown that neurons make TNF, we've shown that norepinephrine regulates TNF, and vice versa, suggesting a physiologic role for TNF. These results will provide insight into diseases, including chronic pain, caused by alterations in the levels of TNF or by changes in the regulation of neurotransmitter release from neurons," Spengler said.
"Knowledge obtained from these experiments will provide a better understanding of how neurons produce and regulate the production of specific proteins that ultimately control neurotransmission. While these studies establish a role for TNF in the treatment of depression, as well as for chronic pain, our next investigations, already on-going, will identify the precise mechanism of action for the analgesic effect and for the delayed clinical effect of antidepressant drugs," he said.
The research was funded by the Charles A. Dana Foundation and the National Institutes of Health.