Glutamate and Nitric Oxide Pathway in Chronic Daily Headache: Evidence From Cerebrospinal Fluid

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Abstract
A central sensitization has been advocated to explain chronic daily headache (CDH) due to sustained peripheral sensitization of algogenic structures responsible for sustained trigeminovascular system activation. Several mechanisms have been suggested to underlie central sensitization, but have been poorly investigated in CDH. They involve N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide (NO) production and supersensitivity and increased and maintained production of sensory neuropeptides. The present study supports the above pathogenic mechanisms demonstrating a significant increase in glutamate and nitrite levels in the CSF of CDH patients, without a significant difference between patients without and those with analgesic overuse headache (P < 0.0001 and P < 0.002). The increase in CSF nitrites was accompanied by a significant rise in the CSF values of cyclic guanosine monophosphate (cGMP) in patients in comparison with controls (P < 0.0001). A statistically significant correlation emerged between visual analogic scale (VAS) values and glutamate, nitrites and cGMP. Although substance P (SP) and calcitonin gene-related peptide (CGRP), and to a lesser extent neurokinin A, were significantly increased in CSF compared with control subjects, their values did not correlate with glutamate, nitrites and cGMP levels in CSF in the patient group. The present study confirms the involvement of glutamate-NO-cGMP-mediated events underlying chronic head pain that could be the target of a new therapeutic approach which should be investigated.