Marijuana contains a complex mix of chemicals, some with medicinal effects, others with an effect that, well, have led it to be classified as a controlled substance. The cannabinoid THC, the primary active ingredient, seems to do both. It's responsible for many of the psychoactive qualities of marijuana, but is also a potent analgesic, blocking a variety of pain. A study that was released over the weekend, however, indicates that some of its painkilling effects are mediated via a receptor that wasn't previously known to interact with the cannabinoids. In the process of characterizing this new receptor, the authors find a chemical that blocks pain, but has no apparent psychoactive effects.

The study was prompted by a rather odd finding. THC, as a prototypical cannabinoid, binds the (wait for it...) cannabinoid receptor in order to trigger most of its effects. But it's possible to breed mice that lack genes for one of the cannabinoid receptors, and these mice still respond to THC doses with a reduction in pain, at least based on one assay. (The "tail flick response" test, in which the tails of the mice are hit with some focused heat, and the time it takes them to respond by moving their tails.)

A few reports had suggested that the receptors for glycine, a small amino acid that also acts as a neurotransmitter, might be involved in the response to cannabinoids. The authors provide some pretty definitive looking evidence that this is the case. Neurons that express the glycine receptor were give small bursts of glycine to trigger activity. As more THC was added to the cells, the response to the glycine increased in magnitude.

Using structural information, the researchers identified a critical spot on the surface of the glycine receptor that interacted with THC, and showed that the interaction was mediated by a hydrogen bond between the receptor and THC. That led them to create a set of modified THCs that lacked potential hydrogen-bonding sites. One of these (5-desoxy-THC) could still bind the glycine receptor, but had reduced affinity for its other targets, the cannabinoid receptors.

This difference in affinity let the authors test the role of the two different types of receptors. The 5-desoxy-THC continued to have an analgesic effect—meaning it blocked the pain response that triggers tail flicks—but it didn't trigger the locomotion issues commonly associated with THC's psychoactive effects. So, it appears that the authors have created a chemical that provides the painkilling of THC without some of the other effects of that chemical.

It turned out to be a bit more complicated than that, though. Other aspects of pain apparently do require the cannabinoid receptors, since the 5-desoxy-THC had no effect on how long mice would remain on top of a metal plate as it heated up. The hot plate response to pain appears to involve processing in the brain, while the tail flick is a reflex that's handled entirely by the spinal cord, so the authors ascribe the difference in response to that.

It appears that 5-desoxy-THC is a very specific painkiller. It blocks reflex responses to pain, but doesn't inhibit higher-level processing of painful sensations; on the plus side, it doesn't have the psychoactive side effects of the THC from which it was derived. Some may consider that a disappointment, but the possibility of creating cannabinoid variants that confer pot's benefits without its controversy could help a lot of people.

Nature Chemical Biology, 2011. DOI: 10.1038/nCHeMBIO.552 (About DOIs).