By David N. Leff

"Gentlemen," declared surgeon John Collins Warren to his assembled colleagues at Massachusetts General Hospital, "this is no humbug."

Warren had just excised a submaxillary tumor from a young man who had been put to sleep with ether, rather than tied down into immobility. The date was October 16, 1846. When Warren's patient came to, he said he had felt nothing.

That event marked the dawn of modern anesthesia.

While ether was indeed no humbug, it seemed an abomination to more than one of New England's clergymen, who warned their flocks that God did not intend people to avoid pain by man-made methods.

Today, U.S. laws ban marijuana and its derivatives in the relief of chronic or long-term pain. Anecdotally — and illicitly — they have therapeutic effects in glaucoma, multiple sclerosis, wasting diseases such as cancer and AIDS, traumas, and other perpetrators of pain. Only eight patients in the U.S. are legally allowed to use medicinal marijuana.

Morphine is the approved analgesic of last resort in controlling severe pain. In fact, the degree of anguish a patient feels can be calibrated by how much escalating morphine dosage he or she demands. But, aside from the fear of addiction (perhaps academic in terminal cancer), morphine has more immediate adverse side effects, such as unremitting nausea and life-threatening hampered breathing.

Marijuana use increases appetite, and affects motor coordination and cognitive behavior.

Despite much basic research, observed neuroscientist and pain specialist Ian Meng, at the University of California, in San Francisco, "Studies of humans have produced inconsistent and controversial results." Meng is first author of a paper in today's Nature, dated Sept. 24, 1998, titled: "An analgesia circuit activated by cannabinoids."

"Of course, the cannabinoids and marijuana are really a relevant issue to society these days," Meng told BioWorld Today. "There was a big question in my mind as to whether it really is an analgesic." Meng is a postdoctoral fellow in the laboratory of neurologist Howard Fields, the paper's first author. Their preclinical research project is funded by the National Institutes of Health.

A bundle of neurons in the brain stem, above the base of the skull, is the group's point of departure in mapping how pain is processed through the body and into the brain. The brain stem connects the spinal cord with the brain proper.

The particular neurons involved in modulating pain carry the name tag, rostral ventromedial medulla (RVM). "The pain signal," Meng explained, "usually goes from the site of injury to the spinal cord, then up to the brain, where you have things taking place such as pain sensation.

Arbitrator Between Hurting And Sensing

"The RVM," he continued, "sends signals back down to the spinal cord, and inhibits pain transmission at that level. For example, when somebody gets severely injured in a war, he often does not feel hurt, because pain-modulating centers in the brain prevent information regarding pain from reaching parts of the brain that are important in the conscious perception of pain. And that's what the RVM is all about."

To trace this neuronal pain traffic, and how it gets sidetracked by marijuana, Meng recruited the favorite animal model of neuroscientists — rats. These rodents carry a built-in "painometer" in their tails. When a researcher places a rat's caudal appendage on a hot plate of measured temperature, the time it takes the animal to flick its tail out of heat's way measures the intensity of its pain perception, and the efficacy of analgesic drugs.

In their first set of experiments, the co-authors injected one group of rats with a synthetic marijuana-like drug, and measured their pain-perceiving tail-flick latency. Another cohort had their RVM activity turned off by a chemical injected into the brain stem neurons.

Results showed that animals that received the pseudo-marijuana drug fix kept their tails on the heat source much longer than those without RVM pain-modulating activity.

Besides its euphoric high, pot has another effect, as traffic cops know well: loss of motor coordination. "Most animal studies," Meng pointed out, "use bodily movement, such as the tail flick, as a sign of pain. This makes results ambiguous when we test a potential analgesic that also produces motor deficits. It could be that the animal isn't moving its tail away from the heat simply because it can't, not necessarily because it isn't feeling any pain. What we were able to do was dissociate the two effects."

He explained: "By shutting down the RVM, we could prevent the analgesia of our cannabinoid drug, but without affecting the motor impairment. So the fact that the animal wasn't flicking its tail away was not due to the motor deficit."

But what if inactivating the RVM simply reversed the motor deficits produced by the marijuana-mimicking drug?

"We tested this hypothesis," Meng recounted, "by placing a rat on a cylindrical rotating treadmill about two inches in diameter, and clocking the time it took the animal to fall off. After a dose of the drug, it simply tumbled off, a sign of motor coordination impairment."

Following up on these and similar experiments, Meng is now "looking more specifically in the RVM to find out, in much more detail at the cellular level, what the actual actions are of the cannabinoids on neurons in the RVM."

At this one-neuron-at-a-time level, he lowers a small wire electrode into an anesthetized rat's brain, and measures RVM activity before and after intravenous injection of the synthetic marijuana-like drug. "Although the animal is not conscious," he said, "certain pain behaviors, such as moving the tail away from the heat source, can still be elicited."

Summing up his lab's work so far, Meng said cannabinoids "may be useful in improving the treatment of pain." *