By David N. Leff

Science Editor

Everyone knows the body's immune system is a killer of pathogens. Would you believe that it also acts as a pain killer?

Besides deploying antibodies, T lymphocytes, macro-phages and their ilk to detect, capture and terminate intruding viruses, bacteria and fungi — not to mention allergenic pollens and peanuts — it now appears that the immune defenses also dispatch soothing beta-endorphins to the scene of a painful inflammatory injury.

Endorphins are the brain-produced peptides that morphine mimics and other opiates with its analgesic properties. Finding that helper T cells and other immunocytes also release beta-endorphins on missions of pain-moderating mercy is the recent discovery of research anesthesiologist Christoph Stein and his colleagues at the Free University of Berlin, in Germany, and Johns Hopkins University, in Baltimore.

Stein's latest report on this novel role for the immune system appears in the just-published December issue of Nature Medicine, under the title "Pain control in inflammation governed by selectins."

A companion commentary asks bluntly: "Can inflammation relieve pain?" Its author is pharmacologist Frank Porreca, at the University of Arizona Health Sciences Center, in Tucson.

"I think Stein's news," Porreca told BioWorld Today, "is that there's an endogenous control mechanism in the body that promotes the accumulation of specific types of immune cells at the injury site. That is, those types of cells that contain opiate peptides, such as beta-endorphin. We've long appreciated that there are mechanisms for transmission of the nociceptive [pain-perceiving] information from the peripheral site of an injury to the central nervous system, where the pain can be appreciated. But it's really quite recently that we've started to understand that there are also mechanisms that can turn off the injury process. This looks like a new one that's not yet been appreciated.

"And of course," Porreca observed, "the speculation might be that this could be exploited to produce pretty novel types of analgesic agents. Inflammation is a component of most types of pain. Selectins are adhesion molecules that promote the localization of the immunocytes at the injured area."

Those immune cells, said research scientist Qin Zhang, a co-author of Stein's paper, "are mainly helper T cells, as well as leukocytes and macrophages. Only the immune system and the nervous system are known to secrete endorphin." Zhang recently moved to Guilford Pharmaceutical Inc., of Baltimore. That company's co-founder is neuroscientist Solomon Snyder, of Johns Hopkins University, also in Baltimore. He first described endorphins — "the brain's own morphine" — more than two decades ago.

Rats Prove Immune Cells Deliver Pain Abatement

Selectin glycoproteins are known to help those white blood cells of the immune system roll along the endothelial lining of blood vessels, en route to their target site of injury, and there off-load their cargo of endorphin. By hijacking the trailblazing selectins with an inhibiting chemical called fucoidin, the co-authors were able to decrease the pain-lulling effect in rats that were hurting with induced hind-paw inflammation. Their opposite paw served as a control.

To provoke this painful, feverish, swollen pedal condition, the team injected the rats' paw pads with Freund's complete adjuvant — an angry emulsion of bacterial antigens. Six hours later, they were able to detect an increased number of endorphin-containing cells infiltrating the inflamed tissue.

A separate tribulation the paw-throbbing rodents sustained was the one-minute cold-water swimming test, in a pool just above freezing — one to two degrees Celsius. "This stressful experience," Zhang recounted, "can stimulate opioid peptide release from immune cells, and then have this kind of analgesic effect." Fucoidin, the selectin blocker, substantially decreased that pain-lessening effect. It also lowered the endorphin content, but this did not then raise the pain level back up. This indicates the opiate's purpose is not to completely suppress pain of injury. "Thus," the paper observed, "pain is preserved as a warning signal to prevent further tissue damage."

It continued: "This represents a new concept of endogenous control that involves pathways governing the migration of immune cells traditionally used by the immune system for mounting a host response to pathogens."

Nor did it escape the co-authors' notice that their findings "provide a foundation for the development of a new generation of analgesics." They went on to observe that such drugs "should lack the unwanted side effects typically associated with opioids," such as addiction.

New Analgesics Possible, But Hurdles Remain

While welcoming Stein's latest finding, Porreca pointed out various hurdles that will have to be overcome before new pain-decreasing drugs based on endorphin's activity in peripheral injuries can be developed:

"The drugs would have to promote the accumulation of the appropriate immune cells to the site of the injury," he told BioWorld Today. "So, the first thing that would have to be identified is the mechanism by which that could occur. The next hurdle is how to make that happen, and that's completely unknown — to my knowledge at least. Then, once the cells actually get to the site of injury, they have to be induced to release the endogenous opioid. That's what Stein has shown — that, if he produces the release of the opioids from the immune cell by activating the stress response, one then can produce the analgesia.

"The hurdle in the biotech world," Porreca pointed out, "would be not only to promote the invasion of the injured area by appropriate immune cells, but then to produce the release of the endogenous opioids. And that may require a couple of different molecules, first to produce the cell accumulation, and second to stimulate the release of the endorphin. Which is not an impossible step to overcome, but it is an additional step." *