Turning Off Pain's Pathways

By Jason Socrates Bardi

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

Every analgesic from opiates to hypnotism to electroshocks to balms have 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 and decreases sensitivity to pain.

Unfortunately, the receptors that THC bind to are also widely expressed in other parts of the brain, such as 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, according to the National Institute of Drug Abuse, distorted perception, difficulty in problem-solving, loss of coordination, and increased heart rate and blood pressure, anxiety, and panic attacks.

The challenge of THC and other cannabinoids is to use them to produce effective, long-lasting relief from pain without the deleterious side effects. Now Ben Cravatt, an investigator in The Scripps Research Institute's (TSRI) Department of Cell Biology and The Skaggs Institute for Chemical Biology, thinks he knows just how to do that.

Regulating the Pathway of Internal Bliss

"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 which is 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 other molecules metabolize the anandamide. The compound has a half-life of only a few minutes in vivo.

In some ways, THC is superior to anadamide as a pain reliever because it is not as readily metabolized. But THC goes on to generally 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.

Even an analogous compound—another CB-1 receptor agonist like THC—would not be ideal because the cannabinoid receptors are so broadly expressed. "You couldn't possibly control what would happen as the receptor was activated all over the body," says Cravatt.

The solution, as Cravatt sees it, is to increase the efficacy of the natural anadamide the body produces to modulate pain sensations. When anandamide is expressed, it is expressed in a cascade that results from a particular sensation, like pain, and this cascade is tightly controlled and localized.

This localization is crucial, because the pathways that mediate pain do not affect cognition. "How do you selectively inhibit those pathways?" asks Cravatt.

One candidate he has come across in the course of his investigations is fatty acid amide hydrolase (FAAH), a 587-amino acid membrane-bound enzyme that metabolizes endocannabinoids, including anandamide and other small molecules.

FAAH is a target for pain therapy not only because it breaks down the molecules that provide the pain relief but also because it turns out that FAAH seems to be the only enzyme responsible for doing so.

"It is stunning how singular the enzyme is in terms of what it is doing," says Cravatt. "If you could manipulate this enzyme, then you have a good shot at manipulating the endogenous system and get the outcome of a selective effect [of decreased sensitivity to pain]."

Cravatt's hope is that controlling the action of FAAH while the body is sensing pain and releasing anandamide would increase the longevity of anandamide throughout in those pathways that are being stimulated.

"I envision that if someone could make a specific inhibitor to FAAH," he says, "in principal, you could get pain relief without any of the side effects."

To Regulate the Regulators

The work on FAAH came out of Cravatt's graduate research, in which he was identifying another neurologically active fatty acid amide called oleamide. Oleamide appears in the cerebrospinal fluid of tired animals, and the last part of Cravatt's thesis characterizes how it works.

"I was working on identifying proteins associated with the fatty acid amide oleamide," says Cravatt, "I wanted to find enzymes associated with oleamide and get their associated genes and manipulate the system that way. That's how we got FAAH."

"FAAH is a member of a large family of enzymes," says Matthew Patricelli, a former student of Cravatt's who did much of the research on the enzyme while completing his thesis. "But FAAH has a new type of mechanism."

FAAH belongs to a large group of serine hydrolases, a class of enzymes containing active site serine residues that catalyze the hydrolysis of specific substrate molecules. These enzymes arose very early in evolution and are ubiquitous in nature—found even in the earliest single-celled organisms. Almost all mammalian trypsin serine hydrolases cleave their substrates through a reaction involving a Ser– His–Asp active site catalytic triad, but FAAH uses a Lys–Ser catalytic dyad. There is no histidine in the active site.

The fact that this mechanism is unique is a boon to possible therapies because the active site of FAAH is also unlike other serine hydrolases. One could block FAAH without worrying about repercussions to other enzymes.


Next Page | The Proteomics in Three dimensions

1 | 2 |



Benjamin Cravatt is assistant professor of cell biology and is a member of The Skaggs Institute for Chemical Biology.