EMLA.

Voltage-gated Na+ channels are the molecular targets of local anesthetics, class I antiarrhythmic drugs, and some anticonvulsants. These chemically diverse drugs inhibit Na+ channels with complex voltage- and frequency-dependent properties that reflect preferential drug binding to open and inactivated channel states. The site-directed mutations F1764A and Y1771A in transmembrane segment IVS6 of type IIA Na+ channel alpha subunits dramatically reduce the affinity of inactivated channels for the local anesthetic etidocaine. In this study, we show that these mutations also greatly reduce the sensitivity of Na+ channels to state-dependent block by the class Ib antiarrhythmic drug lidocaine and the anticonvulsant phenytoin and, to a lesser extent, reduce the sensitivity to block by the class Ia and Ic antiarrhythmic drugs quinidine and flecainide. For lidocaine and phenytoin, which bind preferentially to inactivated Na+ channels, the mutation F1764A reduced the affinity for binding to the inactivated state 24.5-fold and 8.3-fold, respectively, while Y1771A had smaller effects. For quinidine and flecainide, which bind preferentially to the open Na+ channels, the mutations F1764A and Y1771A reduced the affinity for binding to the open state 2- to 3-fold. Thus, F1764 and Y1771 are common molecular determinants of state-dependent binding of diverse drugs including lidocaine, phenytoin, flecainide, and quinidine, suggesting that these drugs interact with a common receptor site. However, the different magnitude of the effects of these mutations on binding of the individual drugs indicates that they interact in an overlapping, but nonidentical, manner with a common receptor site. These results further define the contributions of F1764 and Y1771 to a complex drug receptor site in the pore of Na+ channels.

Anesthetics, Local↗

PubMed1996

Increased neurite outgrowth of cultured rat dorsal root ganglion cells following transection or inhibition of axonal transport of the sciatic nerve.

Dissociated dorsal root ganglion cells (DRGs), taken from rats 2 weeks after sciatic nerve transection, have an increase in the percentage of cells with neurites compared to DRGs taken from normal animals. This study examines the possible factors that may contribute to the nerve injury-induced increase in neuritogenesis. Topical application of the local anaesthetic, bupivicaine, either to the nerve trunk prior to transection or to the proximal nerve stump for 2 weeks had no effect on the increased neurite outgrowth induced by nerve transection. Neurite outgrowth was also not influenced by administration of either nerve growth factor (NGF) via the femoral artery into normal rats or anti-NGF antiserum to the proximal nerve stump. Inhibition of axonal transport by topical application of vinblastine, however, induced a significant increase in neurite outgrowth compared to untreated controls. In addition, vinblastine-treated animals also develop hyperalgesia to mechanical stimulation and transganglionic labelling of sensory neurons with choleragenoid-horseradish peroxidase shows that the area of termination of myelinated sensory neurons in the spinal cord expands into lamina II. The results suggest that nerve injury-induced increase in neurite outgrowth is not dependent on NGF nor nerve impulses generated at the site of injury and supports the view that the absence of an inhibitory factor(s), that in normal animals may regulate neuronal outgrowth.

Anesthetics, Local↗