Modeling relief on the action of marijuana.

Scientists have long known that tetrahydracannabinol (THC), the active ingredient in marijuana, is an effective painkiller. But THC's kaleidoscopic effects, including sedation, giddiness, and paranoia, limit its use in medicine. Now, researchers have fabricated a drug that alleviates pain through a mechanism similar to that of THC, but without the side effects.

The drug, dubbed AM1241, binds to one of the two types of cannabinoid receptors in the body. These protein-based switches, which sit on a cell's exterior, respond primarily to THC.

In tests with rats, the researchers targeted an ailment known as neuropathic pain. Often severe and disabling, this pain differs from the central nervous system's alarm-raising response to injury or inflammation. Animals feel neuropathic pain when the central nervous system itself goes awry. As a result, it can radiate pain signals without any stimulus or cause hypersensitivity to stimuli that would not otherwise be painful--even something as benign as the light touch of a breeze.

While neuropathic pain doesn't respond to conventional anti-inflammatory drugs such as ibuprofen, it can sometimes be alleviated with narcotics. But there's a problem. "Virtually all the treatments we have for neuropathic pain work not only on the parts of the nervous system causing the pain, but on other parts of it as well," explains T. Philip Malan Jr. of the University of Arizona in Tucson. That leads to side effects similar to those caused by THC.

The new drug circumvents this problem by acting only on cannabinoid receptors located on cells outside the central nervous system. These so-called CB2 receptors appear primarily on immune cells.

To test the drug, Malan and his colleagues used rats that had a form of neuropathic pain. The scientists had surgically altered nerves exiting the animals' spinal cords so the rats were especially sensitive to stimuli.

The researchers tested the rats' tolerance to heat or to prodding of their paws. "All they have to do to stop the pain is lift their paw," Malan says. "We're not subjecting them to prolonged pain or restraining them."

Rats given AM1241 were less sensitive to the stimuli than nondrugged rats were. In fact, after receiving the drug, the surgically treated rats were even less sensitive than rats that hadn't had the surgery. The results will appear in an upcoming Proceedings of the National Academy of Sciences.

"This study provides robust evidence that the CB2 receptor is cardinal for moderating neuropathic pain," comments George Fink of the pharmaceutical company Pharmos based in Iselin, N.J. Previous research had shown that activating both types of cannabinoid receptors dulls several types of pain. The new study is the first demonstration that binding a chemical to only CB2 receptors has an analgesic effect, Fink says.

The researchers aren't sure how receptors on immune cells have a role in pain relief. Malan says that immune cells regulate pain sensitivity by releasing substances that make the nerves outside the central nervous system more or less sensitive to pain.

"AM1241 could cause the immune cells to release opioids and other substances which inhibit pain," Malan suggests.

The drug will have to undergo extensive toxicological testing before it can be tried in people. Malan cautions that one of the things that preliminary testing needs to address is whether the drug undermines the immune system.