Researching Diviner's Sage

As I mentioned before I worked in a rat lab, and over the next few weeks I'd like to write a bit about some of the research I did as a graduate student at UMSL. I spent my time depressing rats and treating some of  them with novel plant-derived compounds (some poor rats just got depressed and given placebo). Before I can tell you more about my project I'd like to share with you some of the work that influenced me.

"If I have seen further it is by standing on the shoulders of Giants ." -- Isaac Newton

One of the first sources of inspiration for me was an article I read in Wired about research done by Catherine Willmore (et al.) back in 2007. She was researching a relative of Sage from the Lamiaccae family, Salvia divinorum, AKA Diviner's Sage, AKA Mexican Mint. The plant produces hallucinatory effects in humans and thus has been used by religious and recreational consumers. But since salvinorin A (the main active extract derived from the plant) is selective to kappa-opioid receptors, and is one of the few non-alkaloidal hallucinogens, it has potential to influence the development of a new class of pharmacological drugs and is thus interesting to study. Also because many states lack laws regarding sale and use of Salvia it has grown in popularity amongst the youth. (Don't do drugs)

The researchers used a drug discrimination paradigm in rats to verify that salvinorin A does in fact target kappa-opioid receptors as a primary mode of action. This was my first exposure to this (apparently well-accepted and robust) paradigm. The researchers began by conditioning rats to press a lever when exposed to an established synthetic kappa-opioid agonist (U-69593 obtained from Sigma-Aldrich right here in St. Louis). To do this, they limited the rats' diet, and then put them into a response box with two levers, on days when they got U-69593 they were rewarded with food after pushing the lever on the right, and on days when they got a saline injection they were rewarded when pushing the left lever. Thus once the rats were sufficiently trained on lever pushing then they were assumed to be able to discriminate between a kappa-opioid agonist and control injections. At that point the trained rats were given salvinorin A instead of U-69593 and they still pushed the correct (right) lever, indicating a similar subjective pharmacological experience between U-69593 and salvinorin A. But it is possible the rats had associated "different from saline" with pushing the right lever. So next the researchers injected the rats with nor-BNI (a kappa-opioid antagonist) which will prevent kappa-opioid agonists from having an effect. After treatment with nor-BNI the rats were given a dose of salvinorin A and placed in the response box.  This time the rats pushed the left lever indicating an effect similar to saline.

So I think this falls under the heading of talking to the animals. Not in the Doctor Doolittle sense, but this paradigm asked rats, "Does this drug (salvinorin A), make you feel the same as this other drug (U-69593)?" and the rats kindly answered, "Yes. Yes it does."

Cool paradigm not withstanding, the results of the experiment largely confirm (in an animal model) information that we already suspected. This is the research that introduced me to Salvia and after some digging I found that there hadn't been a whole lot of science done on this mysterious plant. So that gave me an opportunity to ask some new research questions of my own.

Willmore-Fordham CB, Krall DM, McCurdy CR, & Kinder DH (2007). The hallucinogen derived from Salvia divinorum, salvinorin A, has kappa-opioid agonist discriminative stimulus effects in rats. Neuropharmacology, 53 (4), 481-6 PMID: 17681558