Neurotrophic factors and tension-type headache: another brick in the wall?

Abstract

T ension-type headache (TTH) is the most prevalent primary headache and the second most prevalent disorder in the world 1 . However, despite the great progress made in understanding the putative physiological and biological abnormalities of migraines in recent decades 2 , the same cannot be said for their counterpart, TTH, which has been relegated to the background by most investigators 3 and, now neglected 4 , can be considered the "ugly duckling" of headache disorders classified by the International Headache Society (IHS). In what is perhaps a vicious circle, few initiatives have been taken by independent academic or industry-financed researchers to change this situation.The physiological basis of TTH was explored in the 1990s 5, and the findings allowed hypotheses for putative biochemical mechanisms associated with this type of headache to be drawn up 6 . Nevertheless, these hypothetical mechanisms have yet to be confirmed and, with few exceptions, the studies that have been carried out did not use animal models or test these mechanisms to the same level of detail as in migraine studies 2 . It is against this background that the paper in this edition by Domingues et al., who studied the role of neurotrophic factors in TTH down to the molecular level, acquires particular importance 7 . In a well-designed and carefully conducted cross-sectional study, Domingues et al. determined serum levels of brain-derived neurotrophic factor (BDNF), nerve-growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) in forty-eight TTH patients and forty-eight age and gender-matched controls. The authors searched for a correlation between these neurotrophic factors and TTH (both episodic and chronic) as well as other measurable psychosocial variables 7 . Early studies of the pathophysiology of TTH supported the muscle-contraction theory, although TTH can occur with or without pericranial tenderness. The widespread acceptance this theory gained can be observed in a review by Maekawa et al. 8 , who discussed the factors supporting and refuting the putative role of adrenergic receptors and muscle hypoperfusion in myofascial pain.Following a different line of investigation, and probably considering the similarities between migraine and TTH, such as their sharing of common triggers 3,9 , Ashina et al. searched unsuccessfully for changes in neuropeptides such as substance P, neuropeptide Y and vasoactive intestinal polypeptide (VIP) in peripheral blood of patients with chronic tension-type headache (CTTH) 10,11 . Their findings may have in fact been anticipated by Bach et al., who found normal levels of calcitonin gene-related peptide (CGRP) in the cerebrospinal fluid of patients with TTH 12,13 . To date, the most consistent finding in the pathophysiology of CTTH has been the evidence that glyceryl-nitrate (GNT) infusion can induce late-onset tension-type-like headache in CTTH sufferers 14,15 . These findings prompted a cross-over trial, which showed that NG-monomethyl-L-arginine hydrochloride (L-NMMA), an NOS inhib...