Chemistry Reference
In-Depth Information
to have massaged chili pods onto their inflamed gums to ease dental pain.
8,9
The analgesic effects of capsaicin was found to act through the ion channel
known as the vanilloid receptor 1 (VR1 or TRPV1). TRPV1 (transient receptor
potential vanilloid 1) is a polymodal nociceptor, which belongs to the transient
receptor potential (TRP) ion channels family and was first cloned and char-
acterized by Caterina and Julius at the University of California, San Fran-
cisco.
10
Subsequently, an explosion of research from pharmaceutical and
biotech companies ensued that positioned TRPV1 as a key target for devel-
oping novel pain therapeutics.
11-14
As a result of these efforts, TRPV1 as a
potential therapeutic target,
15-17
as well as the progress made towards identi-
fying selective antagonists of TRPV1, has been extensively reviewed.
18-22
This
highly Ca
21
permeable receptor is predominantly expressed in sensory neu-
rons
23-25
and is involved in the detection of painful stimuli. The endogenous
activators of TRPV1 are generated as a result of tissue injury and inflammatory
conditions in research animals
26-28
and in humans,
29,30
and include heat
(442 1C), protons (pH 5),
31
and ligands such as the endocannabinoid anan-
damide
32
and lipoxygenase metabolites.
33
When delivered topically, the exogenous ligand capsaicin selectively activates
TRPV1 in a certain population of unmyelinated primary sensory neurons.
Although painful initially, TRPV1 hyperactivation has an analgesic effect since
it leads to long-term desensitization of the sensory neurons to additional
agonist challenges. Capsaicin is still in wide use today and is the active pharm-
acological ingredient of several topical analgesic creams used to relieve minor
aches and pains of muscles and joints associated with arthritis.
34
The clinical
uses of TRPV1 agonists such as capsaicin, however, are limited due to side
effects of burning sensation and irritation, and neurotoxicity
3
resulting from
the continuous influx of Ca
21
ions into the cells. On the other hand, blockade
of the pain-signaling pathway with a TRPV1 antagonist represented a pro-
mising new strategy for the development of novel analgesics
35
with potentially
fewer side effects. The concept is that TRPV1 antagonists would be able to
produce analgesia without the associated nerve damage seen with capsaicin.
Early support of this approach came from the study of capsaicin derivatives,
for example capsazepine (2), the first reported competitive antagonist of
TRPV1 (Figure 13.1). It was demonstrated that capsazepine blocks the cap-
saicin-induced uptake of Ca
21
in neonatal rat dorsal root ganglia, and shows
species-dependent ecacies
in various
in vivo models of
inflammatory
HO
HO
N
N
N
HO
MeO
S
O
Cl
2
1
Figure 13.1
The TRPV1 agonist capsaicin (1) and the TRPV1 antagonist capsazepine
(2).
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