Chili Peppers Continue to Help Unravel Mechanism of Pain Sensation

BUFFALO, N.Y. -- Capsaicin, the active ingredient in chili peppers, generally is viewed as an irritant that produces a burning sensation when applied to a sensitive area of the body, such as the cornea.

Paradoxically, the same compound also may reduce pain. Capsaicin creams are natural pain-relieving folk medicines, commonly found over the counter, and are effective for a variety of pain syndromes, from minor muscle or joint aches to those that are very difficult to treat, such as arthritis and neuropathic pain.

Scientists at University at Buffalo now link the analgesic effects of capsaicin to a lipid called PIP2 in the cell membranes.

Results of the research, headed by Feng Qin, Ph.D., associate professor in the Department of Physiology and Biophysics in the University at Buffalo's School of Medicine and Biomedical Sciences, appear Feb. 24 in the journal PLoS Biology.

Capsaicin works by stimulating a receptor on nerve endings in the skin, which sends a message to the brain and generates the sensation of pain. The receptor also senses heat, making chili peppers taste hot.

"The receptor acts like a gate to the neurons," said Qin. "When stimulated it opens, letting outside calcium enter the cells until the receptor shuts down, a process called desensitization. The analgesic action of capsaicin is believed to involve this desensitization process. However, how the entry of calcium leads to the loss of sensitivity of the neurons was not clear."

Previous research from the UB group and others implicated the significance of the PIP2 lipid. Calcium influx induces strong depletion of the lipid in the plasma membrane. By combining electrical and optical measurements, the authors now have been able to directly link the depletion of PIP2 to the desensitization of the receptor.

The authors also found that the receptor is still fully functional after desensitization. "What changed was the responsiveness threshold," said Qin. "In other words, the receptor had not desensitized per se, but its responsiveness range was shifted. This property, called adaptation, would allow the receptor to continuously respond to varying stimuli over a large capsaicin concentration range."

"Adaptation" is a property that is found in other sensory receptors, such as those in hearing and vision, and is identified in pain receptors as well.

The findings have implications for pain-sensation mechanisms as well as clinical applications, the authors note. With an adaptive response, the receptors are essentially autoregulated without a fixed threshold. The intensity that causes pain is dependent on the history of activity.

Plasticity of pain is known at the central level. The study now shows that it may also be present at the peripheral site, although the sensation of pain is complex and involves many types of receptors and messengers. The lipid dependence of the receptor also will provide novel strategies for development of safe analgesics like capsaicin, a natural pain reliever, but with less irritation.

Jing Yao, Ph.D., a post-doctoral research student in the UB Department of Physiology and Biophysics, is second author on the paper.

The study was supported by a grant from the National Institutes of Health.

The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.