Probing the molecular pathways of pain, scientists have shown that a protein lodged on the surface of many sensory nerves triggers the nerves to fire pain signals when it is exposed to Death Valley-like heat or the fiery properties of peppery food. The research is the first to demonstrate that the protein, known as the capsaicin receptor, performs this function in living animals, and it boosts confidence that blocking the receptor would ease some kinds of pain.
The research, led by molecular biologists and neuroscientists at UC San Francisco, also showed that the receptor contributes to the pain experienced when tissue is injured or inflamed.
The findings are reported in the April 14 issue of the journal Science, and are highlighted on the issue's cover.
"We have demonstrated how a single molecule affects the behavior of the whole animal," said David Julius, PhD, professor of cellular and molecular pharmacology at UCSF and senior author of the Science paper. "It looks like the capsaicin receptor could be a target for drugs to reduce the sensitivity to some kinds of pain caused by tissue injury."
(In 1997, Julius and Michael Caterina, MD, PhD, then a post-doctoral researcher in Julius' lab, attracted attention by cloning the gene for the capsaicin receptor. A number of pharmaceutical companies have since begun screening drugs to inactivate the receptor.)
The new study shows that activation of the capsaicin receptor contributes to pain in normal, healthy mice, and demonstrates that the receptor is activated by heat and noxious chemicals, as well as protons, normally released from injured tissue.
The research confirms that the receptor is essential for sensing temperatures between about 110 and 120 degrees Fahrenheit -- temperatures most animals must avoid quickly to survive -- and for sensing the heat caused by ingredients in particularly hot foods.
The capsaicin receptor, better known as the vanilloid receptor, or VR1, acts as a channel on the nerve surface. When certain compounds bind to it, the receptor channel opens, allowing a stream of charged sodium and calcium molecules to rush into the nerve cell. This generates an electrical signal that travels to the brain to produce pain.
In the experiments reported in Science, researchers found that not only does the chili pepper's active ingredient, capsaicin, bind to the receptor, but so do protons.
"The interaction of the VR1 receptor with protons lowers the temperature threshold at which heat causes pain," said neuroscientist Allan Basbaum, PhD, whose UCSF lab collaborated in the mouse studies. "Patients can usually avoid temperatures that would produce pain from injury, but sensory nerves in the body's internal organs express VRI as well, and if these organs become inflamed from infection, the nerves that innervate them could become active at the body' s normal temperature and cause persistent pain." Basbaum is professor and chair of anatomy at UCSF.
The activity of VR1 may contribute to the excruciating pain of gallstones, kidney stones or pancreatic cancer, Basbaum suggests, while drugs that target the capsaicin receptor may ease visceral pain conditions.
In the UCSF-based research, the team used "knockout mice" lacking the gene for VR1 and compared them with normal mice in their responses to a range of moderately unpleasant heat and mechanical stimuli to the paw. Normal mice withdraw from these stimuli. In contrast, mice lacking theVR1 gene responded more slowly to the heat stimulus. Thus VR1 is critical for heat, but not mechanical pain sensitivity. Also, the mice didn't hesitate to drink water spiked with capsaicin, suggesting that the spicy nature of hot cuisine is sensed via the capsaicin receptor.
Most importantly, the increased sensation to heat pain normally associated with inflammation was lost in the knockout mice. This probably reflects the inability of protons to interact with the capsaicin receptor, the researchers conclude, and suggests that blocking the receptor with a drug could control some kinds of pain.
The research provides one of the first molecular pieces in the puzzle of pain sensation, Julius says. While much progress has been made in understanding the senses of taste and smell and sight at the molecular level, the molecules that underlie the perception of pain are just now being studied.
"This is just a beginning," says Julius, "but it identifies one of the basic factors involved in the signaling of pain in a normal animal." "Each receptor molecule is a potential target for drugs to reduce pain," adds Basbaum. "Negative side effects are currently the major limit to pain therapy, but if these molecules are uniquely expressed by 'pain' neurons, the likelihood of side effects is dramatically reduced."
First author on the Science paper is Michael Caterina, MD,PhD, now an assistant professor of biology at Johns Hopkins University or School of Medicine.
Co-authors with Caterina, Julius and Basbaum are A.B. Malmberg, PhD, W.J. Martin, PhD, former postdoctoral researchers in Basbaum's lab, and UCSF graduate students J. Trafton, and K.R. Petersen-Zeitz, as well as M. Koltzenburg, MD, professor of Neurology at the University of Wurzburg, Germany, and A. Leffler, a graduate student in his lab.
The research was funded by the National Institutes of Health and the Deutsche Forschungsgemeinschaft, by the Sandler Family Supporting Foundation and by fellowships from the American Cancer Society and the National Alliance for Research on Schizophrenia and Depression.
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Science