N-Methyl-d-aspartate receptor open-channel blockers memantine and magnesium modulate nociceptive trigeminovascular neurotransmission in rats

Experimental and clinical studies suggest that the low-affinity N-methyl-d-aspartate (NMDA) receptor open-channel blockers Mg²⁺ and memantine are effective in reducing trigeminal nociceptive activation. The aim of this study was to investigate the apparent effectiveness of these channel blockers using a model of trigeminal activation in vivo. Rats were anaesthetized before electrically stimulating the dura mater adjacent the middle meningeal artery. Neurons responding to stimulation were recorded extracellularly using electrophysiological methods. l-Glutamate or NMDA, and Mg²⁺, memantine, or sodium controls were applied locally using microiontophoresis. Microiontophoretic application of Mg²⁺ or memantine into the trigeminocervical complex inhibited mechanically and electrically stimulated craniovascular afferents, and l-glutamate or NMDA-evoked neuronal activity at the second-order trigeminal synapse of craniovascular afferents. By contrast, intravenous administration of MgSO₄ (100 mg/kg) or memantine (10 mg/kg) did not significantly affect electrically stimulated afferent-evoked activity within the trigeminocervical complex. The Mg²⁺ and memantine concentrations achieved after systemic administration may not effectively inhibit activation of the trigeminocervical complex, perhaps providing an explanation for the relatively poor efficacy of these NMDA receptor open-channel blockers for headache treatment in clinical studies. Nevertheless, the present results suggest blocking of NMDA-receptor open channels inhibits nociceptive activation of the trigeminocervical complex. Further exploration of such channel blockers as a therapeutic strategy for primary head pain is warranted.