By David N. Leff

Science Editor

Say you're in a car accident and get a bad cut on one arm - so deep that it slices through nerves. "As scar tissue forms," said neuroscientist J. Michael Walker, "what the nerve tries to do is reconnect up its severed ends. Instead, it may form a neuroma, which is a little ball of pathological neural tissue that sits there, sending pain impulses into your spinal cord, day and night. This pain is unremitting," he added, "and of the most severe type you can imagine. In most cases, opiates - such as morphine - are ineffective in treating a neuroma; so people suffer terribly.

"In animal models," he said, "compounds called cannabinoids were extremely good at alleviating this kind of pain. As they move toward clinical trials, maybe we'll find out whether or not this analgesic effect would carry over to people."

Anandamide, produced by the brain, pharmacologically resembles delta-9-tetrahydrocannabinol, which is the main psychoactive ingredient extracted from the female marijuana plant (Cannabis sativa) - also known as hemp. The word anandamide comes down to us from the ancient Sanskrit, where it meant "internal bliss."

Walker, a professor of psychology and neuroscience at Brown University, is lead author of a research paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Oct. 12, 1999. It bears the title: "Pain modulation by release of the endogenous cannabinoid anandamide." His second co-author, Susan Huang, will present the same data on Tuesday, Oct. 26th, to the 29th annual meeting, in Miami, of the Society for Neuroscience, at a session on "Pain pathways: modulation."

"The goal of this study," Walker told BioWorld Today, "was to determine whether the electrical stimulation of nerve cells in a circuit that inhibits pain causes the release of anandamide, which might work to kill pain. And whether pain itself can turn on the release of this neural modulator, as we know is the case of other messengers, such as the endorphins."

When American and Scottish neuroscientists discovered endorphins/enkephalins nearly a quarter-century ago, these molecules became known as "the brain's own morphine." More recently, anandamide has been described in some circles as "the brain's own pot," inasmuch as cannabinoids, like endorphins, are produced naturally in the human brain. (See BioWorld Today, Dec. 22, 1992, p.1.)

"I think our paper is the first very clear demonstration," Walker observed, "that cannabinoids - in a fashion not dissimilar from the endorphins - are endogenous pain suppressors." He and his co-authors made this demonstration by way of two high-tech in vivo brain experiments in living rats.

Tubular Canal In Brain Mediates Pain Pathways

Their point of departure was a critical brain region called the "periaquaductal gray," PAG for short. Walker explained: "PAG consists of gray matter surrounding the so-called aqueduct, a canal that is part of the ventricular system, which bathes the brain in cerebrospinal fluid. The third ventricle is in the diencephalon, an area around the hypothalamus. PAG feeds into this third ventricle, almost like a tubular canal that runs through the midbrain, and opens up into the fourth ventricle underneath the cerebellum.

"Surrounding this canal is gray matter, which is composed mainly of cell bodies and dendrites. That's where we electrically stimulated the brains of living rats. The role of the PAG in pain modulation," Walker added, "has been known for many years. In 1962, an eminent Chinese neuroscientist named Kang Tsou, a posthumous co-author on this paper, demonstrated for the first time that if he injected morphine into PAG, it caused analgesia."

Walker said that "Everything we did was in vivo, in anesthetized rats, so they didn't suffer too much pain. In the first experiment," he noted, "we lowered a pair of stimulating electrodes into the PAG. Between them we had a probe, at the tip of which was a slice of semipermeable dialysis membrane, so that molecules below a certain size could pass through by diffusion, and get captured in a small vial.

"Then we subjected the contents of the vial to a state-of-the-art instrument that combined liquid chromatography and mass spectrometry (LCMS). We found that when we electrically stimulated, using parameters that cause analgesia in the rats, at the same time we got the release of anandamide.

"The key thing to think about here," Walker pointed out, "is that we were collecting from the extracellular space This is very different than excising a chunk of tissue - because there you're just measuring what's in the cell. The fact that we could pick it up from the extracellular fluid told us that the cell released it. The development of this LCMS method, which is thousands of times more sensitive than any previous method, was required to measure the very low amounts that we got.

"The second experiment," he said, "was to put a probe in the PAG, and then inject formalin, a painfully irritating chemical, into the hindpaw footpads of rats, to see if pain itself would cause the cells to release anandamide. That also happened.

PAG Feels Your Pain

"Because the spinal cord's pain neurons make a massive input into the PAG," Walker pointed out, "when you cause pain, the PAG knows about it through natural physiological pathways." The result of these rat experiments, he said, "is that anandamide seems to fulfill the requirements for a neuromodulator in the PAG, where its function appears to be to suppress pain."

As for practical implications, Walker said, "I guess - at least in animals - that cannabinoids suppress circuits that transmit pain messages to the brain. So there is a rational basis for clinical trials with cannabinoids. And I think that conclusion is supported very strongly by the report last March from the National Academy of Sciences (NAS) Institute of Medicine, which basically came to the same recommendation, based on published data. The NAS was pushing very strongly in its report for clinical trials of cannabinoids as analgesics.

"The main issue being," Walker concluded, "that there's some very heavy political baggage attached to marijuana-related compounds, so no drug company wants to get involved in anything like this."