Activation of AMPA receptors in the cerebral cortex may be protective against migraine headache [abstract]

ABSTRACT

The pathogenesis of migraine involves a spreading depression of neurons in the cerebral cortex resulting from over-excitation by released neurotransmitters or electrolytes. Glutamic acid is the most common excitatory neurotransmitter in the brain and spinal cord of mammals. Analogues of glutamic acid including AMPA (DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-asparatic acid) act on different receptors to depolarize the neurons of the cerebral cortex. Previous work has shown that evoked electrical potentials recover from the effects of NMDA on this neuronal network, suggesting a form of neuronal desensitization or network adaption. We have extended these observations by examining the effects of AMPA in the cerebral cortex, the interactions between AMPA and NMDA and the interactions between AMPA and spreading depression. Male Sprague-Dawley rats were anaesthetized with urethane and potentials evoked at the cortical surface by electrical stimulation of the contralateral forepaw. The compounds were applied topically to the cortex by a cortical cup. NMDA at 0.05-0.25mM caused a concentration-dependent decrease in the amplitude of the potentials, with the highest concentration always abolishing them. AMPA at 0.05mM did not affect the evoked potentials when applied alone, but when 0.25mM NMDA was preceeded by an application of AMPA, the latter prevented the NMDA effects in a concentration-dependent manner. Such AMPA-NMDA interactions were inhibited by CNQX (6-cyano-7-nmitroquinoxalinne-2, 3-dione, an antagonist of AMPA) and ehanced by cyclothiadize (which prevents AMPA desensitization). Topical application of AMPA, (0.5mM) prevented the electrophysiological manifestation of spreading depression in the cerebral cortex. Chlormethiazole, a GABA-mimetic drug that is known to prevent epileptic seizures, at 0.2-2mM, was not effective in preventing the spreading depression. These results suggest that, in the rate cerebral cortex, activation of the AMPA receptor (a glutamic acid receptor subtype) can induce a loss of neuronal response to activation of another glumatic acid receptor subtype, the NMDA receptor. Also, activation of the AMPA receptor in the cerebral cortex seems to have a neuroprotective role against the spreading depression that has been implicated in migraine. (AU)