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NIH Record

Glimpses Into the Future of Pain Relief

(Continuation of story from last issue)

By Stephanie E. Clipper

Scientific advances reflect a new understanding of pain as something no longer felt or experienced, but rather something that can be visualized as well through the structures, chemistry and microanatomy of the nervous system. Research advances are helping us understand pain better and select potential targets for new therapeutic agents. Speakers at the recent "New Directions in Pain Research" symposium outlined a number of possible sites for advances in drug development.

  • Systems and Imaging: The idea of localizing cognitive functions in the brain dates back to phrenology, the now archaic practice of studying bumps on the head. Positron emission tomography, functional magnetic resonance imaging, and other imaging technologies offer a brilliant picture of what is happening in the brain's structures as it processes pain. Using imaging, investigators can now see that pain activates three or four key areas of the brain's cortex. Similarly, poststroke patients suffering from central pain syndrome show activation of the thalamus deep within the brain.

  • Channels and Transducers: Ion channels continue to represent the frontier in the search for new drug targets. Dorsal root ganglion cells, found within the spinal cord, show a clear, visible response after injury. For example, after injury to nerves, sodium channels accumulate in neurons, increasing the extent of injury. The possibility now exists of developing new classes of drugs that would act at the site of ion channel activity.

  • Trophic Factors: A class of "rescuer" or "restorer" drugs may emerge from our knowledge of trophic factors, natural chemical substances found in the human body. These compounds affect the survival and function of cells. Trophic factors can also promote cell death, but little is known about how something beneficial can become harmful. For example, experimental treatment with trophic compounds can reverse changes in neurons following injury. Conversely, investigators have observed that over-accumulations of certain trophic factors in the nerve cells of animals result in heightened pain sensitivity. Certain receptors found on cells respond to trophic factors and interact with each other; these may provide other targets for new pain therapies.

  • Molecular Genetics: Certain genetic mutations can change pain sensitivity and behavioral responses to pain. People born genetically insensate to pain -- that is, individuals who cannot feel pain -- have a mutation in part of a gene that plays a role in cell survival. Using "knockout" animal models -- animals genetically engineered to lack a certain gene -- scientists are able to visualize how mutations in certain genes cause animals to become anxious, to make noise, rear, freeze, and become hyper-vigilant. These genetic mutations cause a disruption -- or alteration -- in the processing of pain information as it leaves the spinal cord and travels to the brain. Knockout animals offer a tool that can be used to complement efforts aimed at developing new drugs.

  • Plasticity: Following injury, the nervous system undergoes a tremendous reorganization. This phenomenon is known as plasticity. For example, the spinal cord is "rewired" as axons make new contacts -- called sprouting -- which disrupts the cells' supply of trophic factors. Scientists can now identify and study the changes that occur during the processing of pain. For example, using a technique called polymerase chain reaction, scientists can see the distribution of proteins in cells and along the axons and dendrites of the dorsal horn in the spinal cord following injury. Scientists believe these proteins, which may be "switched on" following injury, may play a role in cell survival and in the prevention of apoptosis or programmed cell death. Pain, in fact, may be stored in the brain as a molecular event, indicating the involvement of a number of mechanisms and regions of the brain used in learning and memory.

  • Transmitters: As mutations in genes may affect behavior, they may also affect a number of neurotransmitters involved with control of pain. Investigators can now visualize what is happening in the spinal cord. From this, new therapies may emerge that can help maintain pain sensibility or obliterate severe or chronic pain. For example, investigators have isolated a tiny population of neurons, located in the spinal cord, that together form a major portion of the pathway responsible for carrying persistent pain signals to the brain. When given injections of a lethal chemical cocktail, the cells, whose sole function is communication of this type of pain, are killed off, directly affecting the transmission of pain from the spinal cord to the brain.

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