For release: Thursday, June 26, 2008
Two chemicals associated with neurodegeneration and inflammation play important and distinct roles in development of neuropathic pain, a new study shows. The findings may lead to new treatments that can stop neuropathic pain from developing and alleviate it after it begins.
"Most treatments for neuropathic pain just block neurotransmission," says Ru-Rong Ji, Ph.D., of Brigham and Women's Hospital and Harvard Medical School in Boston, who led the new study. Such treatments are only effective temporarily. Dr. Ji's work aims to find improved treatments that will prevent or halt the chain of events leading to neuropathic pain. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the journal Nature Medicine.
Neuropathic pain can result from diabetes, multiple sclerosis, spinal cord injury, shingles, and many other disorders. It causes sensations ranging from burning and shooting pain to itching and uncomfortable numbness. It is often difficult to treat effectively and causes suffering and disability in millions of Americans.
Dr. Ji and his colleagues decided to study how enzymes called matrix metalloproteinases (MMPs) affect the development of neuropathic pain. Previous research has shown that MMPs play important roles in the inflammation and tissue remodeling associated with some neurodegenerative diseases. Studies have shown that neuropathic pain is associated with inflammation, and the investigators suspected that MMPs might be the link between them.
The researchers studied two MMPs, called MMP-2 and MMP-9, in rats and mice with a spinal nerve injury that is known to cause neuropathic pain. They found that production of MMP-9 increased rapidly, peaked within one day after the injury, and began to decrease after three days. MMP-2 did not increase until seven days after injury, but it remained at a high level for several weeks.
By selectively blocking MMP-9 and MMP-2, the investigators showed that neuropathic pain responses depended on MMP-9 for the first several days after injury. MMP-2 then prompted changes that helped to maintain the pain. Mice without the gene that produces MMP-9 had much less pain than normal mice soon after injury, but they developed neuropathic pain symptoms 10 days later. This delayed pain effect was probably due to MMP-2.
Injecting either MMP around the spinal cords of normal mice caused neuropathic pain symptoms, even though the mice had not been injured. However, two proteins called tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) powerfully blocked the activity of the MMPs and stopped the pain.
The two enzymes had very different modes of action. MMP-9 increased primarily in sensory neurons and its rise appeared to trigger the activation of immune cells called microglia in the spinal cord. MMP-2, on the other hand, increased in support cells called astrocytes. Despite these differences, both MMPs triggered activation of a signaling protein called interleukin 1 beta (IL-1 beta). Blocking IL-1 beta stopped neuropathic pain triggered by either of the MMPs.
The study is the first to show that neuropathic pain has different phases and that the phases are controlled by different MMPs. It also shows that TIMP1 and TIMP2 can stop this type of pain. The findings suggest that MMP-9 inhibitors may be useful in treating pain caused by recent nerve damage from surgery, chemotherapy, or trauma. MMP-2 inhibitors, on the other hand, might be useful for treating established neuropathic pain from diabetic neuropathy or other problems.
Several MMP-inhibiting drugs are in clinical trials for cancer and other diseases, Dr. Ji says. Some widely used drugs, such as the antibiotics tetracycline and minocycline, also act as MMP inhibitors. The new study suggests that these drugs might be useful for preventing or treating neuropathic pain. However, currently available MMP inhibitors act on many MMPs instead of just MMP-9 and MMP-2 and may have unwanted effects.
"Matrix metalloproteinases are a very large family of enzymes, and it's hard to target just one of them without affecting the others," says Dr. Ji. The enzymes have many important functions in the body, so long-term use of general MMP inhibitors could cause unfortunate side effects, he adds. Other types of drugs, such as peptide inhibitors or monoclonal antibodies, might allow researchers to block a single MMP and reduce the potential side effects of treatment.
The researchers are now studying the effects of MMPs in animal models for spinal cord injury and inflammatory pain (such as arthritis). They are also trying to identify more of the proteins such as IL-1 beta that are affected by MMP-9 and MMP-2. Finding drugs that inhibit those proteins might allow researchers to stop permanently stop neuropathic pain without significant side effects and revolutionize treatment of this disorder.
The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services. The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Natalie Frazin
Kawasaki Y, Xu Z-Z, Wang X, Park JY, Zhuang Z-Y, Tan P-H, Gao Y-J, Roy K, Corfas G, Lo EH, Ji R-R. "Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain." Nature Medicine, March 2008, Vol. 14, No. 3, pp. 331-336.
Last Modified June 26, 2008