By David N. Leff

When you take a bottle of Tex-Mex Hot Sauce out of the refrigerator, why don't you call it Tex-Mex Cold Sauce? The answer is simply semantic: It depends on what you mean by "hot."

Heat perceived by the brain derives from two main sources: thermal (hot stove) and chemical (hot sauce).

"Your body has a lot of mechanisms for sensing temperature changes," explained neuroscientist Michael Caterina, at the Johns Hopkins Medical Institution. "Mechanisms for sensing minor changes, for instance - mild warmth or coolness, body heat, those sorts of things - are referred to as innocuous thermal sensations. And your body also has the capacity to send the brain's pain perception neurons potentially dangerous thermal stimuli, such as extreme heat and extreme cold.

"At the same time," he continued, "there is this peculiar phenomenon where drugs such as capsaicin [the peppery chemical payload of hot sauce] produce in us a sensation that is very reminiscent of what we feel when exposed to extreme heat."

As for why the fridge doesn't turn hot sauce into cold sauce, Caterina observed, "The English language has evolved such that one word describes both of those sensations - the one perceived when encountering a potentially dangerous thermal stimulus, and the sensation perceived when consuming hot peppers, or other exposure to capsaicin."

Caterina is lead author of a paper in the April 14, 2000, issue of Science, titled: "Impaired nociception [pain perception] and pain sensation in mice lacking the capsaicin receptor." (Appropriately, that issue's cover features a mouse perched atop a red-hot chili pepper, which rests on a mild, yellow, garden-variety Bell pepper.)

The Science paper's senior author is molecular biologist and biochemist David Julius, at the University of California-San Francisco. Two and one-half years ago, he and Caterina reported cloning a cDNA sequence that encodes a receptor for capsaicin. (See BioWorld Today, Oct. 29, 1997, p. 1.)

Dual Heat Response: Thermal, Chemical

"At the time," Caterina told BioWorld Today, "we defined this receptor as a protein that appeared to be expressed in the neurons that respond to painful stimuli - such as capsaicin. And when we put this protein into a non-neuronal, kidney-derived epithelial cell, we could get it to respond in an appropriate way to capsaicin and to thermal heat."

The co-authors named their novel protein "vanilloid receptor 1 (VR 1)" - vanilloid denoting the chemical family of compounds to which capsaicin belongs. Then they did more detailed studies to track VR 1 to its sensory neuron location, and also determined that protons - the acidic form of the hydrogen atom - are additional activators of VR 1. All of their earlier findings were from in vitro cell cultures.

"But just because a protein can respond to certain activators when you put it into a foreign cell," Caterina observed, "that doesn't mean that's what it's actually doing in vivo. So we asked, 'What is it specifically that VR 1 is doing in the context of the living animal?' Using standard gene knockout methods, we generated mice that lacked this VR 1 protein. We were able then to test the responses to painful stimuli both of the neurons derived from these animals, when we looked at them in vitro, and of the animals themselves."

To assess pain-related behavior, the team injected capsaicin into the hind paw pads of their KO mice and wild-type controls. The latter vigorously licked and shook their swollen paws, but their VR 1-minus buddies hardly responded at all. When the co-authors spiked the animals' sugar water with the hot-sauce ingredient, the controls took one sip of the capsaicin-laced drink, rubbed their snouts hard and long, and eschewed all further consumption. The VR 1-null mice showed no aversion, and continued to tipple at the previous day's rate.

Capsaicin causes a drop in core body temperature. When challenged with a single peripheral injection of the hot sauce ingredient, wild-type control animals experienced a drop of 6 degrees Celsius within 30 minutes, and recovered two hours later. VR 1-minus mice didn't even raise a sweat.

Caterina said, "What our group aims to do next will involve several different directions. One part of it will be trying to understand which types of pain are dependant upon activation of VR 1, and which ones aren't. Another part will try to understand what is responsible for the residual acid in heat-evoked responses that we see in these KO animals. That tells us there are other mechanisms in these animals for sensing extreme heat. So understanding what those are will be a major focus of my laboratory."

"We have demonstrated," Julius commented, "how a single molecule affects the behavior of the whole animal. It looks as if the capsaicin receptor could be a target for drugs to reduce the sensitivity to some kinds of pain caused by tissue injury."

Various pharmaceutical and biotech companies are reportedly seeking pain-killing drugs based on antagonists to the capsaicin receptor. But Caterina observed, "I don't know of any substantiated reports of antagonists that have been discovered using these receptors. There are some antagonists, identified a long time ago, that haven't shown very much promise as clinical drugs."

Drug Targets: Antagonists Vs. Agonists

He pointed out, "Really, the pharmaceutical industry has taken two approaches to developing drugs based upon these molecules. One is to try to develop antagonists. The other effort tries to develop agonists that can desensitize capsaicin-sensitive neurons. That derives from the age-old observation that capsaicin when applied to these neurons initially excites them and creates a sensation of burning pain, but over time it desensitizes the neurons, and can actually lead to their regression - to the dying off of their nerve terminals.

"So some drug companies," Caterina observed, "have focused on trying to develop drugs that are better at desensitizing or killing the nerve terminals than at creating a sensation of burning pain. There are promising candidates there," he concluded, "and some of them are in clinical trials."

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