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VIP's importance to temperature regulation may be pre-empted by substance P

October 25, 2006

Researchers zero in on how the body regulates its response to heat stress

An elusive neurotransmitter pathway in the skin may have been isolated by University of Oregon researchers, a discovery that, if confirmed, would be a leap forward in understanding how temperature regulation occurs. In other words, they may have found a major player in the machinery that allows people to release body heat and stay cool.

Experiments involving 11 young men and women looked closely at the relationship of the peptide substance P and its related neurokinin-receptor 1 (NK-1), both independently and in conjunction with nitric oxide activity in the skin. Both substance P and nitric oxide are widely distributed in the body and have been associated with many regulatory roles.

Reporting in a paper appearing online ahead of regular publication by the Journal of Physiology, two UO researchers concluded that when NK-1 receptor activity was diminished, so went the dilation of blood flow necessary for bringing warm blood from the body's core to the skin where the heat is lost by sweating.

For some 70 years, researchers have known that the rise in skin blood flow and sweating are linked. They've theorized but failed to definitively prove that the neurotransmitter vasoactive intestinal polypeptide (VIP) - when released with the sweat-causing compound acetylcholine from specialized nerves in the skin during exercise or exposure to hot temperatures - is what mediates the increased blood flow to the skin.

"A lot of people have thought that VIP is the main neurotransmitter, and on many fronts it has been the most likely candidate," said Christopher T. Minson, professor of human physiology at the University of Oregon. "What we've found is that the NK-1 receptor pathway is a major player in this response, and this finding could represent a paradigm shift. Our data implicate the NK-1 receptor pathway, and the primary neurotransmitter for this receptor in humans is substance P, suggesting that this is the putative vasodilator located in specialized skin nerves. However, more work is necessary to clearly define its role in heat stress and other physiological responses."

In the study, the participants were lying down and wearing water-perfused suits. Each person received various injections into the skin of one arm designed to desensitize the NK-1 receptor and block nitric oxide. This step was then followed by circulating heated water through the suit to raise core body temperatures to about 100 degrees Fahrenheit. The investigators then measured the changes in skin blood flow at the infusion sites.

Minson, co-director of the UO Exercise and Environmental Physiology Laboratories, and his doctoral student Brett J. Wong then analyzed the data. They found that desensitization of the NK-1 receptor pathway before body heating significantly reduced the rise in skin blood flow during subsequent heating. They also concluded that NK-1 receptor desensitization combined with the nitric-oxide inhibition caused additional reductions of blood flow. "This is an important distinction as it suggests more than one pathway is involved in the process," Minson said.

In summary, Minson and Wong concluded that "NK-1 receptors contribute to active vasodilation [the rise in skin blood flow] and that a combined NK-1 receptor desensitization and nitric oxide inhibition further diminishes active vasodilation."

However, Minson cautioned: "It's very likely that there is more than one neurotransmitter involved because of the redundancy of the system. We still don't know the specifics of how the rise in blood flow is tied to sweating."

The research, conducted primarily by Wong, was a direct follow-up to a study that appeared in the November 2004 issue of the Journal of Physiology. In that paper, Wong, Minson and additional colleagues reported that the histamine 1 receptor, which is involved in seasonal allergies, has a role in skin blood flow changes during heat stress.

Minson's research primarily focuses on the basic physiological mechanisms of skin blood flow, but he also collaborates with scientists elsewhere who are looking at clinical conditions in which the ability to regulate body temperature is diminished, such as in diabetes, heart failure, multiple sclerosis, Raynaud's phenomenon, cystic fibrosis and even in healthy aging.

"We really need to understand the basic mechanism of skin blood flow responses," Minson said. "There is a wide range of implications for this very basic science. When we find things, these other groups can immediately apply it in their patient populations."

University of Oregon