New target identified for chronic pain therapy

November 17, 1999

Scientists funded by the National Institute of Neurological Disorders and Stroke (NINDS) may soon be able to reduce sensitivity to stimuli that are associated with chronic neuropathic and inflammatory pain by disabling certain nerve cells that send pain signals to the brain.

Research reported in the November 19, 1999, issue of Science show that, in an animal model, combining substance P with the ribosome-inactivating protein saporin (SAP) will inhibit the pain associated with nerve injury when administered before or after the development of neuropathic pain and will significantly reduce sensitivity to stimuli associated with inflammatory pain. Previous data have suggested that in the peripheral nervous system, neuropathic and inflammatory pain arise from different mechanisms and are conveyed to the spinal cord by distinct groups of primary afferent neurons. Study findings suggest that these different types of pain conditions, which can arise via different mechanisms, may be conveyed to the spinal cord by the same substance P receptor-expressing neurons. Further, the study found that, following substance P-SAP treatment, opiates such as morphine remain a viable therapy for breakthrough pain. This discovery could lead to new treatments for chronic pain and the development of more targeted pain-relieving drug therapy.

Researchers at the University of Minnesota injected a combination of substance P (a neurotransmitter known to stimulate pain receptors) and SAP into the dorsal horn of the spinal cord in rats. Receptors for substance P--large molecules found on the surface of spinal cord nerve cells--served as portals for the compound's entry. Within days, the targeted neurons, located in the outer layer of the spinal cord along its entire length, absorbed the compound and were neutralized. Results indicate the substance P-SAP treatment reduced the number of spinal cord neurons that express substance P receptor as well as lessened the pain response to thermal and mechanically-induced pain following nerve injury, inflammation, and the long-term effects of pain produced by capsaicin injection. The results appear to be long-lasting and do not affect other nerve cells.

Scientists already know that spinal cord neurons that express substance P receptors play a role in pain, but its specific role in signaling--relaying or conveying pain signals--is not entirely understood.

Investigators believe that these results suggest that this small group of neurons that express substance P play a critical role in communicating chronic pain information from the spinal cord to the thalamus, the brain's pain center.

The concept of using specific receptors to introduce therapeutic compounds may pave the way for a new pain therapy. Such compounds might be first introduced through a lumbar puncture, a technique commonly used for collecting spinal fluid. The compounds would then serve to relay information through the spinal cord to the thalamus, thus blocking pain signals.

"These findings are extremely important to the study of peripheral and neuropathic pain and our treatment of persons with persistent pain," says Patrick Mantyh, Ph.D., of the University of Minnesota and the Veterans Affairs Medical Center in Minneapolis, who led the study. "We were able to administer a potential treatment and specifically channel it to certain cells, disabling them. We can now focus on the biology of these cells and look at new ways of silencing these cells in other types of persistent pain."

"This discovery is critically important to our understanding of the pain process," says Cheryl Kitt, Ph.D., program director for pain at the NINDS. "Understanding pain pathway changes at the cellular level offers great potential for more effective treatment for pain."

Scientists now need to perform toxicology studies in large animals to demonstrate the safety and efficacy of this treatment in another species. If these studies are successful, approval would be sought to treat terminally ill patients who have severe chronic pain (cancer pain) to determine the extent of the relief of chronic pain in humans.
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The NINDS, part of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency in the Congressionally designated Decade of the Brain. The NINDS celebrates its 50th anniversary in the year 2000.

NIH/National Institute of Neurological Disorders and Stroke

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