The effects of the antiarrhythmic drug propafenone at c-type kv1.4 channels in Xenopus laevis oocytes were studied with the two-electrode voltage-clamp techinique. Defolliculated oocytes (stage V-VI) were injected with transcribed cRNAs of ferret Kv1.4 delta N channels. During recording, oocytes were continuously perfused with control solution or propafenone. Propafenone decreased the currents during voltage steps. The block was voltage-, use-, and concentration- dependent manners. The block was increased with positive going potentials. The voltage dependence of block could be fitted with the sum of monoexponential and a linear function. Propafenone accelerated the inactivate of current during the voltage step. The concentration of half-maximal block (IC(50)) was 121 micrometer/L. With high, normal, and low extracellular potassium concentrations, the changes of IC(50) value had no significant statistical differences. The block of propafenone was PH- dependent in high-, normal- and low- extracellular potassium concentrations. Acidification of the extracellular solution to PH 6.0 increased the IC50 values to 463 micrometer/L, alkalization to PH 8.0 reduced it to 58 micrometer/L. The results suggest that propafenone blocks the kv1.4 delta N channel in the open state and give some hints for an intracellular site of action.
Animals ; Anti-Arrhythmia Agents/*pharmacology ; Hydrogen-Ion Concentration ; Inhibitory Concentration 50 ; Kv1.4 Potassium Channel/*antagonists & inhibitors/metabolism ; Oocytes/drug effects/metabolism ; Patch-Clamp Techniques ; Potassium/*metabolism ; Potassium Channel Blockers/*pharmacology ; Propafenone/*pharmacology ; Xenopus laevis

Trigeminal neuralgia is a paroxysmal disorder with severely disabling facial pain and thus continues to be a real therapeutic challenge. At present there are few effective drugs for treatment of this pain. The present study was aimed to explore the involvement of BK(Ca) channels and Kv channels in the mechanical allodynia in a rat model of trigeminal neuropathic pain. Here the effectiveness of drug target injection at the trigeminal ganglion through the infraorbital foramen was first evaluated by immunofluorescence and animal behavior test. Trigeminal neuropathic pain model was established by chronic constriction injury of the infraorbital nerve (ION-CCI) in rats. BK(Ca) channel agonist and Kv channel antagonist were administered into the trigeminal ganglion in ION-CCI rats and sham rats by the above target injection method, and the facial mechanical pain threshold was measured. The results showed that the drug could accurately reach the trigeminal ganglion by target injection which was more effective than that by the normal injection around infraorbital foramen. Rats suffered significant mechanical allodynia in the whisker pad of the operated side from 6 d to 42 d after ION-CCI. BK(Ca) channel agonist NS1619 significantly and dose-dependently attenuated the facial mechanical allodynia and increased the facial mechanical pain threshold in ION-CCI rats 15 d after operation. Kv antagonist 4-AP was able to reduce the threshold in ION-CCI rats when facial mechanical threshold was partly recovered and relatively stable on the 35th day after operation. These results suggest that BK(Ca) channel agonist NS1619 and Kv channel antagonist 4-AP can significantly affect the rats' facial mechanical pain threshold after ION-CCI. Activation of BK(Ca) channels may be related to the depression of the primary afferent neurons in trigeminal neuropathic pain pathways. Activation of Kv channels may exert a tonic inhibition on the trigeminal neuropathic pain.
4-Aminopyridine ; administration & dosage ; Animals ; Benzimidazoles ; administration & dosage ; Constriction ; Facial Pain ; physiopathology ; Injections, Intralesional ; Kv1.4 Potassium Channel ; antagonists & inhibitors ; Large-Conductance Calcium-Activated Potassium Channels ; agonists ; Male ; Orbit ; innervation ; Pain Threshold ; physiology ; Rats ; Rats, Sprague-Dawley ; Trigeminal Ganglion ; drug effects ; Trigeminal Neuralgia ; drug therapy ; physiopathology