Fig. 1

Putative CNS sites responsible for migraine or cluster headache-like pain in MS patients. Different sites could be involved in head pain generation in MS. A Lymphoid follicle-like structures in meninges can promote activation of trigeminal nociceptors (top of figures). This mechanism could be relevant for pain in both relapsing-remitting and progressive form. In the bottom of the figure, the mechanisms involved in trigeminal ending activation are shown. In particular, lymphocytes can produce proinflammatory cytokines, chemokine and other soluble mediators in the proximity of the meningeal and pial vessel wall which can promote sensitization of trigeminal nociceptors. The role played by CGRP released from trigeminal endings on T and B cell function in this context remain to be established. Mast cells can also be recruited and activated at the meningeal site. Mast cells possess multiple receptors for cytokines and chemokines and once activated secrete a large spectrum of preformed (early) and de novo synthesized (later) mediators including multiple cytokines and chemokines. Preformed mediators can mediate local vascular changes (PPE) and can promote further recruitment of other immune cells such as monocyte/macrophages and perhaps lymphocytes. Sensitized trigeminal endings convey nociceptive information from TG to TNC in the pons and from this nucleus to thalamic nuclei projecting to the primary somatosensory cortex, insular cortex, limbic structures and hypothalamus (not shown in the figure). Their activation is responsible for conscious perception of head pain as well as pain-related behaviours and autonomic responses. B Demyelinating lesions strategically located in different CNS sites related to trigeminal processing can be responsible for pain. Strategical sites include (i) the entry root site of trigeminal nerve in the pons, where the presence of a demyelinating lesion could be responsible for cluster headache-like or trigeminal neuralgiform pain; (ii) the spinal trigeminal nucleus where the presence of a demyelinating lesion may induce migraine or tension type-like headache; and (iii) the periaqueductal grey matter where the presence of a demyelinating lesion could cause a de novo migraine-like pain