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.
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