If the pain won't go away
It was considered one of the tenets of physiology that the immune system works independently of the central nervous system. New research into neuropathic pain - the kind of searing, stabbing pain that standard painkillers fail to relieve - is now providing evidence that the immune system is heavily involved in triggering and maintaining this pain through the production of certain proteins called cytokines. Scientists led by neuropharmacologist Joyce DeLeo, assistant professor of anesthesiology and pharmacology at Dartmouth Medical School, have discovered that at least three of these proteins - interleukin-1, interleukin-6 and tumor necrosis factor alpha - are made by cells in the spinal cord as a result of nerve injury. One of these products, interleukin-6, produces pain-associated behaviors, even in the absence of injury. In addition, researchers have found that blocking certain cytokines inhibits pain behavior.
The work, presented at the annual meeting of the American Association for the Advancement of Science in Philadelphia in February 1998, proposes new methods for the treatment of neuropathic pain based on drugs that inhibit the production of cytokines inhibit. "While it is somewhat surprising to discover such a biological overlap between the immune system and the central nervous system, it also seems reasonable that there is some redundancy in these systems," says De Leo.
Although pain plays a role in healing in that it forces us to take a break, thereby reducing the likelihood of further injury, some forms of chronic pain persist and become even more severe after healing appears to be complete is. Researchers discovered that a constant barrage of nerve signals from a site of tissue or nerve damage could sensitize the nervous system in ways that lead to an increased perception of pain.
This mechanism appears to be involved in neuropathic pain, an excruciating and untreatable form of chronic pain that can be caused by surgery or injury, and is often found in people with cancer, diabetes, AIDS, or shingles (a complication of the chickenpox virus in adults).
To study this process and look for possible treatments, Dartmouth University scientists developed rat models of neuropathy that faithfully mimic human responses. By injuring a single nerve, the researchers were able to reproduce the hypersensitivity to temperature and touch in rats that occurs after similar injuries in humans."This is comparable to the extreme pain of having a warm shower on sunburned skin," says DeLeo.
Scientists discovered that hypersensitivity to temperature or touch is greatest when the number of certain immune cells within the damaged nerves are highest - suggesting that the products of these cells, small peptides called cytokines, are involved in the production of pain involved. Studies of the spinal cord showed that a parallel process takes place there, involving the same products of the immune cells - even when the site of injury is far from the brain and spinal cord. "The central nervous system and the immune system are the two systems that the body uses to 'sense' and respond to the environment," says DeLeo. "So it's certainly reasonable that the two 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, influenced by the presence of hormones, inflammation and other cytokines. Recent research has demonstrated a critical role for cytokines in the development and maintenance of the nervous system.
Current research is now focused on identifying the cells that produce cytokines in the central nervous system. These include microglia, the macrophages of the nervous system, and astrocytes, star-shaped cells long thought to function primarily as structural supports for nerve cells and neurons. Astrocytes appear to play a key role in the generation and maintenance of pain.
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