成熟ラット脊髄膠様質におけるTRPA1 チャネルのリドカインによる活性化
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概要
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Transient receptor potential (TRP) channels, nonselective cation channels, are gated by a variety of chemical and physical stimuli. Among them, there are TRPV1 and TRPA1 channels, both of which are thought to be involved in thermosensation and nociception. TRPV1 channels are activated by noxious hot temperature, protons and capsaicin while TRPA1 channels are by noxious cold temperature, mustard oil, cinnamon oil, ginger and garlic. These TRP channels are expressed in dorsal root ganglion (DRG) neurons; their activation in the central terminals of the neurons results in an increase in the spontaneous release of L-glutamate to spinal dorsal horn, particularly substantia gelatinosa (SG; lamina II of Rexed), neurons from nerve terminals. Although local anesthetics (LAs) were recently reported to activate TRP channels which are cloned and expressed in DRG neurons, this has not been thoroughly examined yet in the CNS. We examined the effects of amine-type LAs (lidocaine, ropivacaine, prilocaine and levobupivacaine) and ester-type LAs (procaine, tetracaine and pramoxine) on glutamatergic spontaneous excitatory synaptic transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Bath-applied lidocaine dose-dependently and reversibly increased the frequency but not the amplitude of spontaneous excitatory postsynaptic current (sEPSC) recorded at a holding potential of -70 mV in SG neurons. The effect of lidocaine was unaffected by the voltage-gated Na+-channel blocker, tetrodotoxin (TTX), and the TRPV1 channel antagonist, capsazepine (Capz), but was inhibited by the non-selective TRP channel antagonist, ruthenium red (RR). In the same neuron, the TRPA1 channel agonist, allyl isothiocyanate, and lidocaine both increased sEPSC frequency. Tetracaine also increased sEPSC frequency in SG neurons in a manner insensitive to TTX and Capz while sensitive to RR, an action similar to that of lidocaine, but this action was delayed in onset by about 2.5 min compared to that of lidocaine. Like lidocaine and tetracaine, pramoxine increased sEPSC frequency; prilocaine had a tendency to do so. On the contrary, procaine, ropivacaine and levobupivacaine reduced sEPSC frequency. It is concluded that some of the amine-type and ester-type LAs activate TRPA1 channels in the SG to increase the spontaneous release of L-glutamate from nerve terminals. This action could contribute to an increase in the excitability of SG neurons.
- 日本疼痛学会の論文
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