A central sensitization has been advocated to explain
chronic daily headache (CDH) due to sustained peripheral sensitization of allogenic 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.