How Do You Solve Relief—Structure of Pain-Modulating Enzyme Described by TSRI Scientists

A group of researchers from The Scripps Research Institute (TSRI) has solved the structure of an enzyme that modulates central nervous system (CNS) functions such as pain perception, cognition, feeding, sleep, and locomotor activity.

The enzyme, described in the November 29th issue of the journal Science, is called fatty acid amide hydrolase (FAAH), and it breaks down certain fatty signaling molecules that reside in the lipid membranes of CNS cells. The TSRI group reports that FAAH modulates the action of these fatty signaling molecules through an unusual mechanism of action whereby it scoops them out of the cell membranes and chews them up.

"I envision that if someone could make a specific inhibitor to FAAH, you could, in principal, get pain relief without any of the side effects," says Associate Professor Benjamin Cravatt, one of the paper's lead authors and an investigator in TSRI's Department of Cell Biology, Department of Chemistry, and The Skaggs Institute for Chemical Biology.

"As soon as we had the view of the active site, we knew FAAH could be used to make lead clinical candidates," adds Raymond Stevens, who is a professor in the Department of Molecular Biology and Department of Chemistry at TSRI and the other lead author on the paper. "The deep pocket with well-defined cavities provides the guidance to take the currently available tight binding inhibitors and improve on their specificity and pharmakokinetic properties."

Pain Management and FAAH

Easing pain is practically synonymous with practicing medicine, and since before the days of Hippocrates, doctors have sought the best ways of doing this, looking for compounds that not only ease pain, but do so as fast, effectively, and lastingly as possible—without unwanted side effects.

Every analgesic, from opiates to hypnotism to electroshocks to balms, has side effects, and therein lies the rub, whether relieving the pain or the side effects is more pressing.

One compound that has been hotly debated in the last 10 years is delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana. The reason THC works is that it mimics the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to "CB-1" receptors on cells on the rostral ventromedial medulla, a pain-modulating center of the brain, decreasing sensitivity to pain.

Unfortunately, the receptors that THC bind to are also widely expressed in other parts of the brain, such as in the memory and information-processing centers of the hippocampus. Binding to nerve cells of the hippocampus and other cells elsewhere in the body, THC creates a range of side effects as it activates CB-1 mediated signaling—including distorted perception, difficulty in problem-solving, loss of coordination, increased heart rate and blood pressure, anxiety, and panic attacks.

The challenge posed by THC and other cannabinoids is to find a way to use them to produce effective, long-lasting relief from pain without the deleterious side effects. Now Cravatt and Stevens think they know just how to do that.

The solution, as they see it, is to increase the efficacy of the natural, endogenous cannabinoids ("endocannabinoids") the body produces to modulate pain sensations.

"When you feel pain, you release endocannabinoids [which provide some natural pain relief]," says Cravatt. "Then the amplitude and duration of their activity are regulated by how fast they are broken down."

In particular, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." When the body senses pain, anandamide binds to CB-1 and nullifies pain by blocking the signaling. However, this effect is weak and short-lived as FAAH quickly metabolizes the anandamide—the compound has a half-life of only a few minutes in vivo.

In some ways, THC is superior to anandamide as a pain reliever because it is not as readily metabolized by FAAH. But THC goes on to suppress cannabinoid receptor activity all over the body. This, coupled with the fact that it is a controlled substance, makes THC an unattractive target for developing therapeutics.

FAAH is much more attractive target for pain therapy because inhibiting FAAH would increase the longevity of anandamide molecules—preventing their breakdown and allowing them to continue providing some natural pain relief.

The structure that Cravatt, Stevens, and their TSRI colleagues solved should form a template for designing specific inhibitors that control the action of FAAH when the body is sensing pain and releasing anandamide.

The research article, "Structural Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling" is authored by Michael H. Bracey, Michael A. Hanson, Kim R. Masuda, Raymond C. Stevens, and Benjamin F. Cravatt, and appeared in the November 29, 2002 issue of the journal Science.

The research was funded by the National Institute on Drug Abuse, the Searle Scholars Program, The Skaggs Institute for Chemical Biology, a National Research Service Award, and a Jabinson graduate fellowship.

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This ribbon diagram shows the enzyme fatty acid amide hydrolase (FAAH), whose structure was recently solved by TSRI scientists. FAAH is an attractive target for developing drugs to provide pain relief.