Vanilloid (Capsaicin) Receptors and Mechanisms - Pharmacological ...

202 SZALLASI AND BLUMBERG
cally distinct currents seem to represent VR1 isoforms
and/or related receptor subtypes and thus imply heterogeneity
of VRs.
VR1 homologs, however, may not necessarily mediate
heat-, acid-, and/or vanilloid-sensitivity. The recognition
domains for these types of activation are not well understood,
and they may not be at all conserved. If there is an
extended VR gene family, it may be associated with a
very diverse biology. The presence of VRs in several of
brain nuclei as well as in nonneuronal tissues lends
support to this prediction.
Inflammatory mediators (like bradykinin and prostanoids)
have been shown to activate VRs in sensory neurons
in an indirect fashion. The intracellular mediator(s)
of this actions is(are) unknown. The competitive VR
antagonist capsazepine prevents the activation of VRs
by inflammatory mediators, which implies the involvement
of an endogenous vanilloid. Moreover, capsazepine
is also effective in animal models of chronic pain and
inflammation. Thus, VRs appear to have a complex regulation,
in which exogenous vanilloid drugs, endogenous
VR activators, low pH, and heat may facilitate each
other’s effects.
Another breakthrough discovery in the field was the
demonstration that compounds structurally unrelated
to typical vanilloids, namely sesquiterpene unsaturated
dialdehydes and other bioactive terpenoids, as well as
triprenyl phenols, may activate sensory neurons via
stimulation of VRs. These novel vanilloids represent
new chemical leads for drug development. Also, their
very existence implies that the term VRs is somewhat of
a misnomer. The identification of endogenous “vanilloids”
will give these receptors a rational name.
Acknowledgments. We thank Drs. Francisco Cruz,
Robert Elde, David Julius, Michaela Kress, Grant D.
Nicol, and Sidney A. Simon for the illustrations they
contributed.
Appendix. Mr. and Mrs. Miklós Jancsó (1949) Desensitization
of sensory nerve endings (in Hungarian),
Kísérletes Orvostudomány (Experimental Medicine)
2(Suppl):15.
There are compounds that can selectively desensitize
sensory nerve endings to noxious chemical stimuli without
causing local anesthesia. In the state of desensitization,
reflex responses (e.g., corneal reflex) mediated by
sensory nerves may be evoked by physical stimuli. However,
the same sensory nerves are unresponsive to noxious
chemical stimuli.
Capsaicin is the paradigm of such desensitizing
agents. Capsaicin effects last for days and protect
against various chemicals. Repeated instillation of capsaicin
into the eye of rats or guinea pigs results in
gradually increasing desensitization which finally becomes
complete. Following capsaicin treatment, eyes do
not respond to other pungent or tear-inducing agents,
either: the sensitivity of eyes to such agents may dimin-
ish by a thousand-fold. Repeated capsaicin treatments
lead to desensitization of skin and airways as well.
Nicotine is nonpungent in the guinea pig eye pretreated
with nicotine, lobeline, coniine, or sparteine.
This desensitization by nicotine is, however, short in
duration (20 min to 2 h) and specific to the stimulus: it
does not protect against capsaicin. Our experiments
show that the nicotine family of toxins act on sensory
nerves and parasympathetic neurons in a similar fashion.
The fact that atropine desensitizes to nicotine highlights
the importance of the piperine structure.
Note Added in Proof. Most recently, the cloning of two
vanilloid receptor homologs has been reported. One homolog
was cloned from rat brain and termed VRL1 for
vanilloid receptor-like protein 1 (Caterina et al., 1999).
This terminology is, however, confusing as VRL1 does
not respond to vanilloids. The other homolog is present
in rat kidney where it is believed to sense stretch (Suzuki
et al., 1999). This receptor is called stretch-inhibitable
nonselective cation channel, or, briefly, SIC. SIC is
not sensitive to vanilloids either.
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