Pharmacologic Regulation of Local Anesthetic Conduction Block by Cyclic AMP

Abstract

The phenomenon of tachyphylaxis (acute tolerance) is generally explained on the basis of the physicochemical properties of local anesthetic agents. The most popular concept suggests that there is a reduction in the amount of free base available for block due to a progressive decrease in local pH. An alternative hypothesis suggests that tachyphylaxis may be due to a true reduction in effect of the local anesthetic at the receptor level. Further progress in understanding the molecular basis of tachyphylaxis requires identification of the events at the membrane level that are responsible for controlling ionic flux. Although it is well-established that local anesthetic agents produce nondepolarizing conduction block by inhibiting sodium ion flux through axonal membrane sodium channels, the specific biochemical events governing the process remain unknown. Previous studies have shown that adenosine 3´, 5´cyclic monophosphoric acid (cyclic AMP) is a key factor in the regulation of narcosis [1]. The lipid soluble, phosphodiesterase-resistant 6-N, 2-0, dibutyryl analog of cyclic AMP (db-cyclic AMP) when administered intracerebroventricularly, dose-dependently shortened narcosis induced by amobarbital [2] and a wide variety of anesthetic, sedative-hypnotic, and tranquilizer agents [3]. It was of interest to determine whether the dibutyryl analog of cyclic AMP and other adenine nucleotides regulate conduction anesthesia as well.