Nerve Receptor Found To Be Key To Intestinal Inflammation

The results of their studies, which were carried out in rats, could point toward a potential therapy aimed at blocking the receptor, known as vanilloid receptor type 1 (VR-1). Interestingly, they said, VR-1 is the receptor on sensory neurons that receives and transmits the "heat" and "pain" impulses felt when eating raw chili peppers.

The results of the Duke study were reported today (May 1, 2003) in the May issue of the journal Gut.

IBD is a general term given to a constellation of chronic disorders in which the intestine becomes inflamed, typically resulting in recurring abdominal cramps, pain and diarrhea, in some cases bloody. The cause of IBD is unknown, and it is believed that up to 2 million Americans suffer from this disorder, the researchers said.

"We know that immune modulators known as cytokines are responsible for the inflammation that is the hallmark of the disease, so research has focused on discovering a viral or bacterial trigger," said Christopher Mantyh, M.D., colorectal surgeon and senior member of the Duke team.

"However, our studies have shown that by blocking the VR-1 receptor, we can halt the development of IBD in an animal model," he continued. "So it would appear that the activation of the VR-1 receptor is the signal, or trigger, that 'revs up' the release of cytokines."

It has long been appreciated that sensory neurons within the intestinal system can play a role in the development of inflammation. Key to this process is Substance P, a neurotransmitter found in minute quantities in the human nervous system and intestines. It is primarily involved in the transmission of pain impulses and is also a potent pro-inflammatory mediator in the intestines.

"Studies have shown that using Substance P antagonists as well as denervation -- either surgical or chemically -- can block some forms of intestinal inflammation," Mantyh said. "However, what is missing is that trigger. What was not known was how the nerve cells in the intestine were stimulated to begin the inflammatory process."

In their experiments, the Duke team focused on the newly cloned VR-1 receptor, which can be activated by heat, acid and capsaicin, the ingredient that gives chili peppers their "heat."

Capsaicin stimulates the pain and heat response by binding, like a lock-and-key, to the VR-1 receptors on neurons. Just as long-time chili eaters find that prolonged consumption renders them immune to the peppers' effects, over-stimulation of VR-1 receptors can cause them to become desensitized.

The researchers used three groups of rats. The first group was administered capsaicin at birth, which chemically denervated them by "overstimulating' the VR-1 receptors to the point of inactivating them permanently. They were allowed to reach adulthood. The second group, which were adults, were given the agent capsazepine (CPZ), a VR-1 antagonists which blocks the receptor. The third group, the control, received no additional treatments.

The team then induced colitis, or intestinal inflammation, in all three groups of rats by giving them dextran sulphate sodium (DSS) in their water for a week. The animals' reactions to the treatment were carefully monitored and after one week, detailed studies were made of their intestinal tracts.

"In the control rats, DSS caused active colitis with its trademark ulceration of the intestinal lining," Mantyh said. "However, the two other groups showed significantly lower levels of disease. The treated rats were protected from the damaging effects of DSS administration. This data provides strong evidence that an animal model of colitis requires neurons containing VR-1.

"Inhibition of the VR-1 receptor in humans -- either by small doses of CPZ or other antagonists -- may represent a novel therapeutic pathway to prevent IBD," Mantyh continued.

The research was supported by grants from the National Institutes of Health, the American Surgical Association and the Department of Veterans Affairs.

Other members of the Duke team were Naoki Kihara, M.D., Sebastion de la Fiente, M.D., Kazunori Fujino, M.D., Toku Takahashi, D.M.D., and Theodore Pappas, M.D.