During the last decade, a series of studies in The New England Journal of Medicine chronicled the potential benefits of rescuing patients from stroke, heart attack and other conditions by lowering body temperature to reduce demand for oxygen. Depressed body temperature may also have manifold effects beyond the ones described—anything from prolonging life span to inducing a lower metabolic state suitable for long-distance spaceflight.
A hurdle to lowering body temperature to protect brain cells after stroke is the body's own cold-defense mechanisms. Unless a patient is anesthetized, blood vessels in the skin constrict, shivering begins, brown fat generates heat and a patient experiences the natural urge to seek a warmer environment. All of these "thermo-effector responses" are there to keep things steady at 37 degrees Celsius (98.6 degrees Fahrenheit).
An experimental drug demonstrated by researchers at the Fever Lab in Saint Joseph's Hospital and Medical Center in Phoenix and their collaborators points to a way around the thermo-effector blockade. The agent blocked a receptor on nerve cells in mice and rats called TRPM8 that is normally activated by skin cooling to set in motion the body’s cold-defense armamentarium. The drug, a compound called M8-B, stopped even moderately chilled animals from mounting a cold response, thereby lowering core body temperature. "The body stops defending its temperature," says Andrej Romanovsky, who heads the Fever Lab.
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Particularly in Europe, physicians already do something similar in clinical practice by using an intravenous cooling solution along with moderate skin reheating to prevent shivering. This complex and imprecise procedure—balancing the exact amounts of heat and cold needed is challenging—makes implementation difficult outside the setting of a major hospital. By contrast, a drug like M8-B might be administered at a military field hospital or by emergency medical technicians, along with a set of cold packs, to achieve the same outcome.
Others took notice of the work, reported in the February 8 edition of The Journal of Neuroscience. "The TRP family of thermal receptors are the major sensors for skin temperature," says Daniel Sessler, an anesthesiologist at the Cleveland Clinic and an expert on thermoregulation. "Blocking these receptors should blunt thermoregulatory defenses to induction of therapeutic hypothermia, and this work supports this theory. A drug like M8-B that blocks those receptors may well prove clinically useful."
Romanovsky was able to procure M8-B from Amgen, one of a slew of drug companies that have been interested in these receptors that stud sensory nerve cells, and that exhibit contrasting properties. TRP receptors that trigger the burning sensation of a chili pepper are being considered as a new kind of analgesic. Romanovsky has even speculated with his lab-mates about the use of a temperature-reducing TRP drug during extended spaceflight to diminish an astronaut's nutrient intake. "If you can decrease bodily metabolism by 10 percent, you can extend the length of spaceflight," Romanovsky says. The ability to selectively control the body's cold defenses through tweaking cell receptors may eventually lead to an entirely new class of pharmaceutical—what Romanovsky and colleagues dub "thermopharmacology."
