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Sticky Business
Much of the cannabinoid system is still a mystery to researchers
in the field, largely because the cannabinoid system is a
difficult one to study.
Part of the problem is that cannabinoids are lipid molecules—one
of a plethora of long-chain fatty acid molecules that are
major constitutive components of the brain. Rather than looking
for a needle in a haystack, looking for the cannabinoids in
the brain is like liking for a particular type of hay in a
haystack. Further complicating matters is that cannabinoids
have degradation systems that remain uncertain, although TSRI
Associate Professor Benjamin Cravatt has made great strides
in recent years on elucidating the details of the degradation
mechanism modulated by the enzyme fatty acid amide hydrolase
(FAAH)—including solving the structure of FAAH last year.
Even if scientists can separate the cannabinoid lipids from
the other long-chain fatty acids, the molecules are still
hard to work with because of the nature of these substances.
"They stick to your tubing, your experimental apparatus,"
says Schweitzer. "To sort out and work with these molecules
is difficult."
For this reason, the field is still relatively new, even
though it has grown rapidly in the last few years. It was
only a decade ago, says Schweitzer, that the first cannabinoid
receptor was discovered. And it was only in the mid-1990s
that chemicals that could block these receptors were developed.
Schweitzer himself started in the field by looking at the
specific question of how THC works in the brain, but has since
expanded his horizons to encompass a few larger questions.
One of these is what purpose the endogenous cannabinoid system
serves in the brain—especially given the vast number
of CB1 receptors there and their concentration in vital parts
of the brain, like the hippocampus.
"How do cannabinoids work and what are they there for?"
asks Schweitzer. "We still don't know why they are there."
There is no shortage of opinions in the scientific community
on this, says Schweitzer. And the implications of this field
for politics and drug enforcement makes some of the debates
as sticky as the lipidic molecules themselves. But scientists
like Schweitzer are slowly gathering the tools and making
the analyses needed to begin to unravel the complexities of
the endogenous cannabinoid system and the effect that THC
has on it.
Hunger and Pain?
One of Schweitzer's main goals is the potential applications
that would follow if this endogenous cannabinoid system could
be manipulated to achieve a desired effect. "This is of primary
importance—the objective of pharmacological research,"
he says.
When you feel pain, you release natural endocannabinoids,
which provide some natural pain relief. For example, the body
releases an endogenous cannabinoid called anandamide, a name
derived from the Sanskrit word meaning "internal bliss." Recently,
Schweitzer, in collaboration with Daniele Piomelli, who is
now at the University of California, Irvine, characterized
another endogenous cannabinoid found in the brain. This new
cannabinoid, called 2-arachidonylglycerol, turned out to be
present in much larger amounts than anandamide in the brain.
When the body senses pain, these substances bind to CB1
and nullify pain by blocking the signaling. However, this
effect is weak and short-lived as other molecules metabolize
the endogenous cannabinoids. These compounds have a half-life
of only a few minutes in vivo.
The possible applications for designer chemicals that could
inhibit the degradation of endogenous cannabinoids, inhibit
their transport, or enhance their formation are tantalizing.
If the right chemicals could be made, they might be developed
into drugs for a number of clinical conditions—from appetite
modulation to safer and more effective painkillers. The market
for such compounds would be huge.
The challenge for scientists is to use the cannabinoid system
to produce effective, long-lasting relief from pain or viable
appetite modulation without the deleterious side effects of
marijuana use.
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