title: Paradoxical effect of QX-314 on persistent inward currents and bistable behavior in spinal motoneurons in vivo.
abstract: Spinal motoneurons can exhibit bistable behavior, which consists of stable self-sustained firing that is initiated by a brief excitatory input and terminated by brief inhibitory input. This bistable behavior is generated by a persistent inward current (I(PIC)). In cat motoneurons with low input conductances and slow axonal conduction velocities, I(PIC) exhibits little decay with time and thus self-sustained firing is long-lasting. In contrast, in cells that have high input conductances and fast conduction velocities, I(PIC) decays with time, and these cells cannot maintain long duration self-sustained firing. An alternative way to measure bistable behavior is to assess plateau potentials after the action potential has been blocked by intracellular injection of QX-314 to block sodium (Na(+)) currents. However, QX-314 also blocks calcium (Ca(2+)) currents and, because I(PIC) may be generated by a mixture of Ca(2+) and Na(+) currents, a reduction in amplitude of I(PIC) was expected. We therefore systematically compared the properties of I(PIC) in a sample of cells recorded with QX-314 to a control sample of cells without QX-314, which was obtained in a previous study. Single-electrode voltage-clamp techniques were applied in spinal motoneurons in the decerebrate cat preparation following administration of a standardized dose of the noradrenergic alpha1 agonist methoxamine. In the sample with QX-314, the average value of I(PIC) was only about half that in the control sample. However, the reduction of I(PIC) was much greater in cells with slow as compared with fast conduction velocities. Because a substantial portion of I(PIC) originates in dendritic regions and because conduction velocity covaries with the extent of the dendritic tree, this result suggests that QX-314 may fail to diffuse very far into the dendrites of the largest motoneurons. The analysis of the decay of I(PIC) and plateau potentials in cells with QX-314 also produced an unexpected result: QX-314 virtually eliminated time-dependent decay in both I(PIC) and plateau potentials. Consequently, I(PIC) became equally persistent in high and low input conductance cells. Therefore the decay in I(PIC) in high input conductance cells in the absence of QX-314 is not due to an intrinsic tendency of the underlying inward current to decay. Instead it is possible that the decay may result from activation of a slow outward current. Overall, these results show that QX-314 has a profound effect on I(PIC) and thus plateau potentials obtained using QX-314 do not accurately reflect the properties of I(PIC) in normal cells without QX-314.
authors.affiliation: Departments of Physiology and Physical Medicine and Rehabilitation, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Lee
authors.forename: C J
authors.initials: CJ
authors.lastname: Heckman
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002415:Cats; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000294:innervation; D009431:Neural Conduction / Q000187:drug effects; D012044:Regression Analysis; D013116:Spinal Cord / Q000502:physiology*
chemical_list: D000779:Anesthetics, Local; C012647:QX-314; D008012:Lidocaine