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Review of: Binshtok, Bean & Woolf (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers

Review of: Binshtok, Bean & Woolf (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers



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Published by Charlotte Kinloch
Review of Article by Binshtok, Bean and Woolfe 2007
Review of Article by Binshtok, Bean and Woolfe 2007

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Published by: Charlotte Kinloch on Mar 25, 2009
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Charlotte Kinloch ID 11037888CNS Pharmacology 3HCS646: PaperReview
Review of: Inhibition of nociceptors by TRPV1-mediated entry of impermeantsodium channel blockersBinshtok, Bean & Woolf (2007)
This study provides early evidence of a new mechanism of a currently available localanaesthetic 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
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 whichresponds 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 allowmolecules as large as 452 Da to pass through.Thirdly, that the synthetic molecule QX-314, which is a positively charged lidocainederivative, has a molecular mass of only 263 Da and, although it has no effect onsodium channels when applied extracellularly, has been found to block sodiumchannels when applied intracellularly. Blocking neuronal sodium channels is of course the standard modus operandi for any local anaesthetic worth its salt (no punintended).Binshtok et al. reasoned that if capsaicin was injected with the QX-314 the capsaicinwould open the TRPV1 channels which due to their large size QX-314 would be ableto pass through into the cell. Once inside the cell the QX-314 would be able to blocksodium channels and inhibit the neuron from firing. Only Nociceptors would betargeted as only nociceptors have the TRPV1 channel thus QX-314 would be unableto 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 invitro using whole-cell voltage-clamp recording. After identifying nociceptors takenfrom rat dorsal root ganglion membranes by detecting expression of TRPV1channels using a short administration of capsaicin, they applied capsaicin along withQX-314 to the bathing solution and found that sodium current was blocked almostcompletely (98%, ±0.4% inhibition) and that this was significantly greater than thesodium blocking effect of capsaicin alone (31%, ±9% inhibition). The application of 
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Charlotte Kinloch ID 11037888CNS Pharmacology 3HCS646: PaperReview
QX-314 alone had no effect on sodium channels as was expected. QX-314 requiresthe opening of TRPV1 channels by capsaicin in order to pass into the interior of theneuron.They then repeated the above using large diameter dorsal root ganglia neurons andfound that neither capsaicin alone nor capsaicin applied with QX-314 had asignificant effect on sodium channel function. Suggesting as expected that withoutthe presence of TRPV1 in the neuronal cell membrane QX-314 is unable to pass intothe cell where it has its effects.The finding was that QX-314 applied with Capsaicin has the ability to block sodiumchannels in nociceptors but not in other types of neuron meaning that the desiredeffects of local analgesia can be obtained without the (sometimes) unwanted effectsof paralysis and numbness. This combination would specifically inhibit the sensationof high threshold (pain) stimulus whilst still allowing low threshold (non-pain) stimulussensation and motor transmission to remain normal.Binshtok et al. tested this finding in vivo on rat subjects. They looked at initialflinching upon injection; mechanical stimulus threshold using von Frey filaments; andlatency 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 alonecaused initial flinching, decreased mechanical stimulus threshold and noxious heatthreshold after both 15 and 30 minute intervals. Injection of the QX-314/Capsaicincombination did not significantly reduce the initial flinching caused by capsaicinalone but removed the effect of the capsaicin on mechanical and noxious heatthresholds at 15 and 30 minutes, causing them to remain at baseline levels. At 60minutes the mechanical stimulus threshold began to increase, reaching double thebaseline 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 initialinjection of the combination causes pain from the capsaicin. A local anaesthetic thatcauses initial pain, even if it then inhibits pain is not going to be very popular withpatients.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 injectingthe QX-314 into the nerve bundle 10 minutes before injecting the capsaicin. The
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