Doubling up on discoveries

Sufferers of arthritis and other inflammatory diseases may soon find respite from the excruciating pain caused by their afflictions.

Researchers at the University of Calgary Faculty of Medicine recently identified a new pain receptor active in inflammatory conditions and mapped its activation and transmission pathways. Fortuitously, the team also identified a substance that interferes with the receptor’s normal operation.

"This was an extremely serendipitous finding," declared Dr. John Wallace, a U of C professor of pharmacology and therapeutics. "It is very fortunate that we were studying both PAR-2 and the tree sap simultaneously."

The inflammatory response characteristic of arthritis and Crohn’s disease causes tissue degeneration by triggering the release of protein-devouring enzymes called proteases. The enzymes begin a nervous transmission at a Protease Activated Receptor (PAR) whose end result is interpreted as pain.

Wallace’s lab discovered a new pain receptor dubbed PAR-2, located in the skin, joints and digestive system. PAR-2 is a key element in the discomfort associated with diseases such as arthritis, pancreatitis and Crohn’s. In concert with this discovery, Wallace’s team–by chance–discovered a naturopathic medicine that seems to block the activation of PAR-2. The product is filtered sap from the Sangre de Grado (Dragon’s Blood) tree, harvested in the rainforests of Peru and marketed in North America as a dietary supplement.

"Traditional painkillers like aspirin act somewhere between the initial transmission of the pain message and the receipt and interpretation in the brain," explained Wallace. "The development of the new drug is based on the fact that if we can block the initiation of the signal, we can diminish the pain perceived."

The team is making rapid progress in laboratory studies. Genetically altered mice in which the PAR-2 gene was removed seem to behave normally. They exhibited no visible differences from non-altered mice.

As for clinical tests, professor Christopher Powell of the U of C Clinical Neuroscience Department is beginning trials using the tree sap as a painkiller. Patients suffering from neuropathy, a disease that damages peripheral nerves in the body, will be treated for pain with the sap.

"In the most general case, the time period between the discovery of a receptor and the development of a drug is around 10 years," said Wallace. "We have been given a head start with the natural product. Although it’s very difficult to estimate such time frames, I’d say that if we isolate the active molecules in the sap within the next few months, we could be looking at a feasible treatment in six to seven years time."

The discovery came as a surprise to many in the pharmaceutical community because of the unconventional approach involving naturopathic medicine. Typically, researchers isolate the molecule that activates a particular site and synthesize structurally similar chemical "impostors." The manufactured molecules are similar enough to occupy the activation site, but lack certain characteristics resulting in decreased effectiveness.

"Dr. Morley Hollenberg, a member of our research team and one of the authors of the paper, attempted this method," said Wallace. "Strangely enough, the chemical impostors seemed to mimic the protease too well."

A principle benefit of treating inflammatory diseases with a PAR-based painkiller is that key pain receptors are situated in the body’s periphery. In contrast, drugs like morphine must cross the blood-brain barrier, a characteristic suspected to cause addiction.

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