By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
"Burnt child fire dreadeth."
That homely bit of folk wisdom goes back to the earliest years of the last millennium. One recent redaction puts it: "Once burned, twice shy." Both versions embody a significant biological fact: Pain sensation is not merely a transient, acute ouch; it also can nourish a long-remembered, persistent hurt.
One striking instance of this feeling of pain well after its source has faded is the "phantom pain" that bedevils victims of a lost - but still hurting - limb. This dichotomy of pain and memory reflects the finding that certain specific regions in the forebrain process both pain perception and memory retention.
N-methyl-D-aspartate (NMDA) receptors are expressed at synapses throughout the central nervous system. Among the wide range of brain processes that NMDA mediates are memory formation, neuronal injury in ischemia and central sensitization during persistent pain.
One of NMDA's key receptor subunits is the protein NR2B, which allows nerve cells to communicate sensations of chronic and persistent pain.
In the February issue of Nature Neuroscience, pain researchers at Washington University in St. Louis report on "Genetic enhancement of inflammatory pain by forebrain NR2B overexpression." They found that transgenic mice overproducing NR2B were more aware of minor ouches for longer periods of time, as compared with their normal littermates.
"That sustained response," observed the paper's senior author, neurobiologist Min Zhuo, "appears to mimic what happens in people who experience pain long after its painful stimulus has disappeared. So interfering with NR2B in humans," he pointed out, "might be a strategy for treating chronic pain."
Like TV dish antennas, these receptors perch on a nerve cell's surface, tuned in to messages sent out by neighboring neurons. NMDA receptors function only when the number and intensity of neuronal messages reach a set threshold level. This discrimination accounts for their role in learning, memory, injury and persistent pain.
The researchers compared the strain of transgenic NR2B-overdoing mice with intact, wild-type animals. Both reacted to acute pain stimuli in the same way. But the NR2B rodents displayed stronger or longer behavioral responses to two different chemicals - dilute formaldehyde and Freund's adjuvant - which produced more persistent, inflammatory pain. After a shot of formaldehyde in the hind paw, both transgenic and normal mice licked and bit the injection site. But the NR2B animals kept right on licking long after their wild-type partners had stopped.
And in response to contact with a small heat source that normally provokes no reaction, the NR2B mice injected with Freund's adjuvant would pull back their paw and escape. "Perhaps the animals with excess NR2B can detect pain in case of injury," Zhuo surmised.
"That could help them avoid more serious harm. But if an injury is unavoidable, the enhanced NMDA receptor activity in the forebrain would make them more likely to feel persistent pain."
Zhuo made the point that "deactivating the NR2B protein may help people with chronic pain, particularly those suffering from allodynia." This is a nervous ailment in which the slightest physical contact, such as a gentle touch, triggers a severe painful reaction. "Many current pain-relieving drugs that target NMDA receptor activity," he observed, "work by interfering with all of its subunit receptors. Therefore, they also block acute pain, which can be protective. However, it can also be considered maladaptive, when pain from a previous injury persists, and cannot be avoided.
"You want to be able to feel painful heat on your skin when you're cooking," he explained, "so you can quickly withdraw your hand if you need to. Our study has provided a target for the development of drugs that would be highly selective for persistent pain. That," he concluded, "would enable people to ignore chronic pain while leaving the rest of the pain system intact."
Upsetting Body's Rheostat For Balancing Iron Metabolism Led To Parkinson's Hallmarks In Mice
In human cultural history, the Iron Age succeeded the Bronze Age about 3,000 years ago. But in basic biology, humans, and virtually all other forms of life, are still living on iron. It's an essential nutrient for most cells because iron-containing proteins catalyze many essential reactions of energy metabolism. But not all of us can get enough of the biologically precious metal, which is famously rich in spinach, among many other food sources. (See BioWorld Today, May 22, 2000, p. 1.)
About 30 percent of the world's population is anemic - suffering from iron deficiency. At the opposite end of the spectrum is a common disease, hemochromatosis, meaning iron overload throughout the body. Hence, there's a cellular mechanism that fine-tunes levels of iron metabolism. Dietary iron is absorbed by cells lining the intestines, and trafficked to the rest of the body by a binding protein called transferrin. To maintain appropriate levels of the element, cells produce two types of iron regulatory proteins (IRPs). One of these, IRP2, is more abundant in the brain than elsewhere.
In the February issue of Nature Genetics, cell biologists at the National Institute of Child Health in Bethesda, Md., report: "Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegeneration disease in mice." Deprived of IRP-2, the neurons that accumulate iron degenerated, and the mice developed movement disorders, including the ataxia and tremor that characterize Parkinson's disease.
Endostatin Teamed Up With Integrins Stopped Angiogenesis In Ploy To Starve Solid Tumors
In the continuing widespread efforts to scotch the growth of solid tumors by cutting off their blood supply, a recent entry, in the Proceedings o the National Academy of Sciences (PNAS) dated Jan. 30, 2001, bears the title: "Interaction of endostatin with integrins implicated in angiogenesis."
Endostatin, a potent antagonist of angiogenesis - formation of new capillaries from pre-existing blood vessels - inhibits tumor growth in mice by an unknown mechanism. The PNAS paper implicates integrins as potential targets for endostatin function.
The authors report that endostatin interacts with certain integrins on the surface of human umbilical vein endothelial cells, and acts as an antagonist of these proteins to inhibit endothelial cell functions. n