Researchers block body's response to cold, open doors to new drug treatments

As much as human beings have evolved throughout history, at least one thing hasn’t changed much – the way our bodies react to the cold. But researchers at St. Joseph’s believe they have finally discovered a way to block the body’s response to cold using an individual drug, a finding that could have significant implications in treating conditions like stroke and cardiac arrest.

The groundbreaking research, led by Andrej Romanovsky, MD, PhD, director of the Systemic Inflammation Laboratory, or FeverLab, part of St. Joseph’s Trauma Program, was published in the Feb. 8 issue of the Journal of Neuroscience and was also highlighted in Scientific American earlier this year. The research took place at St. Joseph’s, in collaboration with Amgen Inc. and several academic institutions.

Lowering the body’s temperature is an effective way to treat certain conditions because of the body’s decreased need for energy and oxygen at low temperatures. However, natural defense mechanisms to maintain a steady temperature – such as shivering, narrowing of blood vessels in the skin and generating heat in the so-called brown fat tissue – can make it difficult to lower body temperature in unanesthetized patients.

Dr. Romanovsky, research team members Camila Almeida, PhD, and Andras Garami, MD, PhD, and collaborator Narender Gavva, PhD, believe they have discovered a pharmacological method to inhibit these natural defense mechanisms.

“Humans have used external heating and insulation as the only approaches to defend themselves against cold since the days of the caveman. We have proposed something new,” says Dr. Romanovsky. “Our study is significant because it is the first time we have been able to inactivate the body’s natural defense mechanisms by using a drug that selectively blocks the sensation of cooling in the skin.”

The research focuses on the TRPM8 (transient receptor potential melastatin-8) receptor, a protein responsible for relaying the sensation of skin cooling, and on the drug M8-B, a TRPM8 antagonist. In other words, the M8-B drug blocks the TRPM8 protein from relaying cold signals from the skin to the brain.

Researchers discovered that M8-B inhibited multiple cold-defense mechanisms in mice and rat models, effectively lowering their body temperature. This TRPM8-antagonist-induced hypothermia is the first example of a change in the deep body temperature of an animal as the result of using a drug to block tem- perature signals at the thermoreceptor level.

Lowering body temperature to treat a medical condition is not a new concept. For example, Barrow neurosurgeons pioneered the cardiac standstill, a technique in which surgeons cool the body and drain its blood in order to operate on cerebral aneurysms. However, until now, inducing hypothermia has required the use of general anesthesia, which, in essence, temporar- ily shuts down many functions of the brain.

Using drugs that target cold signals from the skin specifically may allow doctors to induce hypothermia in unanesthetized patients, paving the way for new treatment options.

“We believe that this approach will be used in the future to induce mild therapeutic hypothermia in unanesthetized patients, as well as to maintain deep body temperature, and perhaps the activity of some thermoeffectors, at desired levels,” says Dr. Romanovsky. “It’s a whole new direction.” Conditions that could benefit from therapeutic hypothermia include cardiac arrest and stroke.

Dr. Romanovsky adds that the pharmacological control of thermoregulation might also be used in instances in which we need to conserve the body’s energy, such as in space travel. If we can block the body’s response to cold, we can save the energy that might otherwise be used trying to keep it warm.

These applications represent just the beginning of the emerging field of thermopharmacology – or, put more simply, using drugs to regulate body temperature.

For now, says Dr. Romanovsky, these applications are still speculative and his research team continues to look at other receptors, in addition to TRPM8, that may be involved in thermoregulation.

“There are many cold and heat defenses, and they are very diversified, but if we can identify the specific drugs that block specific responses, then we can develop new treatments,” he says.