Researchers Identify New Mechanism Underlying Pain

February 13, 1998

PHILADELPHIA, PA. -- It's been a tenet of basic physiology that the immune system operates independently of the central nervous system. New research on neuropathic pain -- the kind of burning, shooting pain for which standard analgesics provide little relief -- is producing evidence that the immune system is intimately involved in the initiation and maintenance of pain, through production of proteins called cytokines.

Investigators led by Dartmouth Medical School neuropharmacologist Joyce DeLeo, assistant professor of anesthesiology and of pharmacology, have discovered that at least three of these small proteins -- Interleukin-1, Interleukin-6 and Tumor Necrosis Factor-alpha -- are expressed by cells in the spinal cord as a result of nerve injury. One of these products -- Interleukin-6 -- has been shown by DeLeo to generate pain-associated behaviors in the absence of injury. In addition, researchers have found that blocking the action of certain cytokines inhibits pain behavior.

The work, which will be presented this week at the annual meeting of the American Association for the Advancement of Science in Philadelphia, suggests new approaches to treating neuropathic pain, based on agents that block production of these potent substances.

"Though it's something of a surprise to discover such biological overlap between the immune system and the central nervous system, it also seems rational that there would be redundancy in these systems," says De Leo.

Though pain plays an adaptive role in healing, forcing us to rest and reducing the likelihood of further injury, some forms of chronic pain persist and become even more intense after healing apparently is complete. Researchers are finding that a persistent barrage of nerve signals from a site of tissue or nerve damage may sensitize the nervous system to a heightened perception of pain and may even alter the way the nervous system functions.

This mechanism appears to be involved in neuropathic pain, an agonizing and untreatable form of chronic pain that can result from surgery or injury, and is often seen in people with cancer, diabetes, AIDS and shingles -- an adult complication of the chicken pox virus.

To study the process and to search for possible treatments, the Dartmouth group has developed rat models of neuropathy that reliably mimic human responses. By injuring a single nerve, researchers were able to reproduce in rats the subsequent hypersensitivity to temperature and touch that occurs after similar human injuries. "This is comparable to the way a warm shower can be extremely painful on sunburned skin," says DeLeo.

Investigators discovered that hypersensitivity to temperature or touch peaks when the numbers of certain immune cells within the damaged nerve are highest -- suggesting that the products of these cells, small peptides called cytokines, are involved in producing pain. Studies of the spinal cord showed that a parallel process, involving the same products of immune cells, takes place there -- even when the injury site is far from the brain and spinal cord. "The central nervous system and the immune system are the two systems the body uses to 'sense' and respond to the environment," says DeLeo, "so it's certainly reasonable that they should communicate with each other."

Scientists first described cytokines in terms of their activities in the immune system. Their actions and interactions are known to be complex and interdependent, affected by the presence of hormones, inflammation and other cytokines. New research is demonstrating an essential role for cytokines in the development and survival of the nervous system.

Current research is focusing on identifying the cells that produce various cytokines in the central nervous system such as microglia, the macrophages of the nervous system; astrocytes, the star-shaped cells long thought to function chiefly as structural support for nerve cells; and neurons. Astrocytes, which produce proteins that change the function of cells, appear to play a key role in the production and maintenance of pain.

"We may be on the verge of a new pharmacopoeia for preventing and treating pain," says DeLeo,"but cytokines are a double-edged sword, with both beneficial and destructive actions. To tailor effective treatments, we will need to learn more about the timing and balance of these powerful immune proteins."

The Geisel School of Medicine at Dartmouth

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