Abstract
The pivotal role of nerve growth factor in inducing hyperalgesia and central sensitization has been emphasized in experimental pain models. Higher nerve growth factor levels have recently been found in the cerebrospinal fluid of patients with chronic daily headache. These levels were significantly correlated with the cerebrospinal fluid levels of substance P and calcitonin gene-related peptide, supporting the involvement of this neurotrophin in enhancing the production of the two sensory neuropeptides of the trigemino-vascular system in chronic daily headache. This may, in part, account for the long-lasting sensitization and activation of this system, which could contribute to headache chronicity. More recent research has shown a significant correlation between the higher cerebrospinal fluid levels of nerve growth factor and those of another neurotrophin, the brain-derived neurotrophic factor, as well as glutamate in chronic daily headache patients. These findings suggest the potential involvement of nerve growth factor-mediated upregulation of brain-derived neurotrophic factor in persistent head pain. Therefore, nerve growth factor appears to indirectly exert its effect through enhancing glutamatergic transmission involved in the processing of head pain via brain-derived neurotrophic factor. Based on these data, a potential application can be hypothesized for novel strategies targeting neurotrophins (nerve growth factor and brain-derived neurotrophic factor) and their receptors to chronic daily headache. To date, the majority of the molecules discovered in this regard have been scarcely or never proved in animal pain models and are far from clinical use in chronic pain, including chronic daily headache. If this approach is to be developed in the near future, research should be focused on identifying strategies with few central side effects and specific selective action on central sites involved in chronic head pain and more generally in chronic pain conditions. This will represent a very difficult challenge, taking into account the pleiotropic effect of nerve growth factor and the wide range of intracellular signalling pathways activated by this neurotrophin which are not limited to the nociceptive system.