Spreading depression and central nervous system pharmacology.

Spreading depression is a reversible response of brain tissue to a local insult. It has been postulated to be the physiological substrate for the aura phase of classic migraine. The properties and mechanisms of spreading depression were studied in the parietal neocortex of the alfentanil-anesthesized rat, by using a cup electrode that provided close control of the electrical stimulus while allowing specific ion (K+) and potential recordings to be made directly beneath the cathode, the region of origin of the stimulus-induced spreading depression. Cathodal stimulation caused the extracellular K+ concentration to rise, and spreading depressions were observed when this concentration exceeded 8-12 mM in the upper 100-200 microns of cortex. In some experiments extracellular [K+] continued to increase for 5-10 sec after termination of the stimulus, without detectable after-discharge in the potential record, before subsiding. While spreading depression could easily be induced by pressure on the cortex, local damage incidental to opening the dura rarely induced spreading depression. This suggests that a local (1-mm2) neurovascular injury is not likely to induce spreading depression--at least in normal cortex--and so is probably not the source of the spreading depression postulated to generate the aura of classic migraine. Mechanisms of spreading depression, and drugs that influence spreading depression, are reviewed, and possible uses of spreading depression in the pharmacology of the central nervous system are considered.