By David N. Leff

One of the most painful diseases known is shingles, i.e., herpes zoster. It wraps its agony around half the body's trunk — right side or left side — from backbone to abdominal midline.

One recommended anti-shingles painkiller consists of applying cloths soaked in Tabasco sauce.

This seemingly surreal home remedy actually has a basis in fact. The fact is that the active pungent ingredient of Tex-Mex-style hot sauces and salsas is a fiery plant protein called capsaicin (cap-SAY-uh-sin). The plant in question is Capsicum frutescens, a burning bush that presumably secretes the painfully hot capsaicin to fend off predators intent on eating its fruit.

Capsaicin is also the active component of a high-potency prescription skin cream, Zostrix by name, described as "clinically effective in controlling pain from . . . shingles (herpes zoster)." And at least one over-the-counter soothing skin ointment purports "to relieve minor arthritis, backache, simple sprains and strains."

How can a burn-inflicting chemical assuage pain?

The Zostrix label admits that, "although the precise mechanism of action is not fully understood, current scientific evidence suggests that capsaicin renders skin and joints insensitive to pain by depleting . . . substance P in peripheral sensory neurons. Substance P is thought to be the principal chemomediator of pain impulses from the periphery to the central nervous system."

As for capsaicin, molecular biologist and biochemist David Julius pointed out that "it is long known to be a pain-producing compound, and as such a sort of touchstone in the pain field."

For lack of a biochemical mechanism to measure the hot pepper's degree of heat, experts have recourse to subjective taste testing. On a scale of one to 1 million, the spice industry ranks the peppery plants from less than one for bell peppers to 1,000 for jalapeños to 100,000 for habaneros to 1 million for pure capsaicin.

Now Julius, a professor of cellular and molecular pharmacology at the University of California, San Francisco, has discovered a molecule that bids to replace guesswork with finite neurophysiology in gauging the pain of peppers and of thermal heat.

His paper in the current issue of Nature, dated Oct. 23, 1997, bears the title: "The capsaicin receptor: a heat-activated ion channel in the pain pathway."

That capsaicin receptor, Julius told BioWorld Today, "is to pain research what the T cell is to immunology. It's one of the first molecules to really be implicated in the direct process of transduction of painful stimuli. "The receptor," he pointed out, "is activated by two ligands — capsaicin and elevated temperature — that is, heat in the noxious or nociceptive range.

"Remarkably," he said, "we found that the same receptor that binds capsaicin on the surface of pain-sensing neurons also detects burning heat. We believe that hot peppers feel hot because capsaicin and heat stimulate the same protein sensor in the neurons."

Ouch Factor In Heat, Thermal And Chemical

Julius explained current thinking as to how the sensation of noxious pain, either from the Tabasco sauce or thermal heat itself, gets from the injured tissue to neuron to brain:

"Say, the Tabasco sauce's capsaicin finds sensory nerve endings by being in your mouth or in your eye. It crosses the epithelial membrane and gets to the sensory nerve endings. And once it activates the receptor, the receptor depolarizes the neuron by allowing calcium and sodium ions to flow in and fire an electrochemical action potential. That," Julius went on, "sends a signal into the projection from the sensory neuron to the spinal cord. This presumably activates some cells that connect with a number of synapses to the brain."

As for how the brain translates those electrical signals into psychologically perceived pain, Julius allowed: "I have no idea. I think the answer is up for grabs."

In their laboratory of neurotransmitter action in receptor structure, Julius and his co-authors expression-cloned the molecule, after screening DNA sequences identified by the ion influx activity. The cDNA thus derived contains an open reading frame of 2,514 nucleotides, which encode the 838-amino-acid receptor protein.

"Cloning the gene for the capsaicin receptor," Julius pointed out, "will enable us to produce large quantities of the protein in cells grown in petri dishes, making it easier to test the effectiveness of potential treatments."

Search For Gene Under Way

Finding just where in the human genome the full-length gene resides, he said, is work now in progress. He also plans on using transgenic mouse experiments to elucidate the neuronal pathways of thermal pain perception.

"We'd like to know at a biochemical level how this thing works. How it senses heat. How it senses vanilloid (capsaicin and capsaicin-like) compounds. Where the sites are for those kinds of things," he observed. "We have a lot of structure-function work ahead of us."

Julius perceives two potential applications for his discovery:

"One would be, with this molecular probe in hand, one can begin to see what changes might occur to the expression of this receptor, or its function in various pathological states, like chronic inflammatory pain or injury or local pain.

"The other," he continued, "would be to probe the function of this molecule in normal nociceptive acute or chronic pain models, by making new drugs that block or activate the receptors very selectively."

The university has filed to patent his capsaicin receptor, Julius noted. The Society of Neuroscience, of which he is a member, points out that "Ninety-seven million Americans suffer chronic debilitating headaches, back pain or arthritic pain each year," representing a prospective market for such analgesics.

David Clapham, of Harvard Medical School, Boston, wrote a commentary to Julius' Nature paper, titled: "Some like it hot: spicing up ion channels."

It concluded: "Certainly, clinical management of chronic pain . . . could use some new therapeutic strategies. At the very least, Mexican restaurants might be able to provide antidotes for their jalapeño-challenged clientele." *

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