My brother Michael was a famous researcher, specializing in the transmission of pain from cells that receive the pain signal to the brain. One of his first papers, published in Science, discussed the pain-killing effects of an enkephalin analog, which is a synthetic molecule similar to one of the body’s naturally-occurring pain-killers (Abstract here; the paper is surprisingly readable).

Enkephalins are polypeptides, long chains of amino acids, which operate in the cells that transmit pain. They fold up, like other proteins, into different shapes. The shapes are like a key that fits into a lock on the cell, and stop it from firing. This prevents the transmission of the pain signal. Wikipedia has a good description of the process of pain transmission, which is called nociperception.

I visited Michael in the mid-90s at Brown University, and he took me to see his lab. He pointed to his newest toy, a mass spectrometer, and explained that he could measure a few tens of thousands of molecules of his beloved polypeptides. He had begun working on the pain-killing properties of marijuana, and had at that time identified over 30 cannabinoids, polypeptides found in marijuana. He thought one of them might be the equivalent of a human polypeptide called anandamide, which blocks pain transmission. Wiki tells us that the name is derived from the Sanskrit word, ananda, meaning bliss or delight. Anandamide blocks pain at the level of the peripheral nerves, as well as in the central nervous system.

Opiods, like heroin and morphine, fold up into shapes like enkephalines or endorphins. They suppress pain very well, but they operate primarily in the central nervous system, in the brain. They lead to slow breathing, and possibly death. They also slow down peristalsis, the movement of food through the intestines, so a lot of addicts have really bad constipation, another reason to stay away from heroin, if you needed one.

Cannabinoids fold into shapes like anandamide. They work in the CNS, but they also work very well in the peripheral nervous system. There are a large number of receptors for cannabinoids in the spinal column. My brother explained that if you could get a good idea of the shape of the receptor, or the lock, you could find a key that would fit it and stop pain before it got to the brain. That would be a big deal for all of the people who can’t tolerate opiods.

Michael’s later papers are dense, but here is the abstract of a widely-cited paper from 1999, just because I think it’s fun to read the precise language in the originals:

Synthetic cannabinoids produce behavioral analgesia and suppress pain neurotransmission, raising the possibility that endogenous cannabinoids serve naturally to modulate pain. Here, the development of a sensitive method for measuring cannabinoids by atmospheric pressure-chemical ionization mass spectrometry permitted measurement of the release of the endogenous cannabinoid anandamide in the periaqueductal gray (PAG) [an area in the brain] by in vivo microdialysis in the rat. Electrical stimulation of the dorsal and lateral PAG produced CB1 cannabinoid receptor-mediated analgesia accompanied by a marked increase in the release of anandamide in the PAG, suggesting that endogenous anandamide mediates the behavioral analgesia. Furthermore, pain triggered by subcutaneous injections of the chemical irritant formalin substantially increased the release of anandamide in the PAG. These findings indicate that the endogenous cannabinoid anandamide plays an important role in a cannabinergic pain-suppression system existing within the dorsal and lateral PAG. The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.

This means that the cannabinoids actually stop pain, without interfering with transmission of other information coming in from the nervous system. You don’t lose your sense of balance, you don’t lose your sense of touch or your notion of where your arms and legs are in space.

And, interestingly, the research appears to have been funded by the National Institutes of Health. Of course, this was during the Clinton Administration. Under the next Administration, my brother received grants to do the same work from the National Institute on Drug Abuse.

The next time someone tells you marijuana has no medical uses, please tell them about my brother and his work. I hope it will bring pain relief to millions.

Ed Walker