Charlotte Kinloch ID 11037888 CNS Pharmacology 3HCS646: Paper

Review

Review of: Inhibition of nociceptors by TRPV1-mediated entry of impermeant

sodium channel blockers
Binshtok, Bean & Woolf (2007)
This study provides early evidence of a new mechanism of a currently available local
anaesthetic drug which can work to block pain without causing numbness or
paralysis of the injection site.
The research was initiated by the integration of several observations. Firstly,
Nociceptors unlike any other types of neurons express high threshold transducer
channels including in many casesTRPV1. TRPV1 stands for transient receptor
potential cation channel V1 and is a nonselective ligand gated channel which
responds to stimuli such as intense (burning) heat, acidic pH and capsaicin.
Secondly, that TRPV1 is activated and opens in response to the presence of
capsaicin and has a particularly large channel which has been found to allow
molecules as large as 452 Da to pass through.
Thirdly, that the synthetic molecule QX-314, which is a positively charged lidocaine
derivative, has a molecular mass of only 263 Da and, although it has no effect on
sodium channels when applied extracellularly, has been found to block sodium
channels when applied intracellularly. Blocking neuronal sodium channels is of
course the standard modus operandi for any local anaesthetic worth its salt (no pun
intended).
Binshtok et al. reasoned that if capsaicin was injected with the QX-314 the capsaicin
would open the TRPV1 channels which due to their large size QX-314 would be able
to pass through into the cell. Once inside the cell the QX-314 would be able to block
sodium channels and inhibit the neuron from firing. Only Nociceptors would be
targeted as only nociceptors have the TRPV1 channel thus QX-314 would be unable
to enter other types of neuron and outside the cell membrane QX-314 has no effect.
Binshtok et al. first determined that the effect they had envisioned would occur in
vitro using whole-cell voltage-clamp recording. After identifying nociceptors taken
from rat dorsal root ganglion membranes by detecting expression of TRPV1
channels using a short administration of capsaicin, they applied capsaicin along with
QX-314 to the bathing solution and found that sodium current was blocked almost
completely (98%, ±0.4% inhibition) and that this was significantly greater than the
sodium blocking effect of capsaicin alone (31%, ±9% inhibition). The application of

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Charlotte Kinloch ID 11037888 CNS Pharmacology 3HCS646: Paper
Review

QX-314 alone had no effect on sodium channels as was expected. QX-314 requires
the opening of TRPV1 channels by capsaicin in order to pass into the interior of the
neuron.
They then repeated the above using large diameter dorsal root ganglia neurons and
found that neither capsaicin alone nor capsaicin applied with QX-314 had a
significant effect on sodium channel function. Suggesting as expected that without
the presence of TRPV1 in the neuronal cell membrane QX-314 is unable to pass into
the cell where it has its effects.
The finding was that QX-314 applied with Capsaicin has the ability to block sodium
channels in nociceptors but not in other types of neuron meaning that the desired
effects of local analgesia can be obtained without the (sometimes) unwanted effects
of paralysis and numbness. This combination would specifically inhibit the sensation
of high threshold (pain) stimulus whilst still allowing low threshold (non-pain) stimulus
sensation and motor transmission to remain normal.
Binshtok et al. tested this finding in vivo on rat subjects. They looked at initial
flinching upon injection; mechanical stimulus threshold using von Frey filaments; and
latency of removing a paw from a radiant noxious heat stimulus as an indicator of
noxious heat threshold.
They found that injection of QX-314 alone had no effect. Injection of Capsaicin alone
caused initial flinching, decreased mechanical stimulus threshold and noxious heat
threshold after both 15 and 30 minute intervals. Injection of the QX-314/Capsaicin
combination did not significantly reduce the initial flinching caused by capsaicin
alone but removed the effect of the capsaicin on mechanical and noxious heat
thresholds at 15 and 30 minutes, causing them to remain at baseline levels. At 60
minutes the mechanical stimulus threshold began to increase, reaching double the
baseline level at 120 minutes. Sensitivity to noxious heat showed a similar pattern.
The problem with the above use of QX-314/Capsaicin combination is that the initial
injection of the combination causes pain from the capsaicin. A local anaesthetic that
causes initial pain, even if it then inhibits pain is not going to be very popular with
patients.
Binshtok et al. seem to realise this, although they do not explicitly mention it in their
report, as in the second part of the study they counter this initial effect by injecting
the QX-314 into the nerve bundle 10 minutes before injecting the capsaicin. The

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Charlotte Kinloch ID 11037888 CNS Pharmacology 3HCS646: Paper
Review

reasoning being that the QX-314 would already be in place to anesthetise the effects
of the capsaicin as soon as they occur. In this case they found that the initial pain
response did not occur but that the prolonged anaesthetic effect remained.
However it should be noted that in this final experiment they injected the drugs into
the sciatic nerve rather than the paw as in the previous tests. Why they didn’t test the
delayed application of capsaicin on the paw as well is not clear.
Overall this is a well conducted study in the way that the researchers controlled for
the effect of the administration of capsaicin alone and QX-314 alone in displaying the
effect of administering then together. The conclusions drawn relate directly to and
completely explain the findings.
This paper reports an extremely interesting initial investigation of a new method of
anaesthesia using a drug already available. As already stated the mechanism they
have uncovered will allow specific inhibition of pain whilst allowing non pain
sensation and motor function to carry on unaffected. As the authors point out this will
be particularly useful in cases such as childbirth and dental treatment where the
patient needs local pain relief without losing motor function or sensation. Overall this
is a fascinating article.

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