Neuron–Glia Signaling in Trigeminal Ganglion: Implications for Migraine Pathology

Migraine is a chronic, painful, neurovascular disorder that affects an estimated 12% of the population.1 Sensitization and activation of trigeminal ganglion nerves are thought to play a central role in the underlying pathology of migraine and other orofacial diseases.2,3 The trigeminal nerve consists of 3 main branches, the ophthalmic (V1), maxillary (V2), and mandibular (V3), each providing somatosensory innervation of distinct regions of the head, face, and orofacial cavity. Adult trigeminal neurons exhibit a pseudounipolar morphology characterized by a single axon that divides into a peripheral and a central branch.4 Activation of peripheral trigeminovascular afferents of V1 in the meninges releases calcitonin gene-related peptide (CGRP), which mediates neurogenic vasodilation, while central efferent release of CGRP contributes to pain, central sensitization, and allodynia associated with migraine.5,6 Hyperalgesia and allodynia associated with migraine pathology likely involve both peripheral and central sensitization.7-9 Peripheral sensitization, which is the result of increased activity of trigeminal nociceptors, is thought to initiate a migraine attack, while central sensitization, which involves enhanced excitability of second-order neurons, leads to pain.10 While the importance of central sensitization in migraine has become clearer, the role of peripheral sensitization in the trigeminal ganglion is not well understood. Peripheral sensitization is characterized by increased neuronal excitability and a lowering of the threshold for activation. Glia cells, which were thought to serve only a supportive role, are now known to directly modulate neuronal function and activity.11,12 Interestingly, neuron–glia interactions have been shown to be involved in all stages of inflammation and pain associated with several CNS diseases.13,14 Trigeminal ganglia comprise neuronal cells and 2 types of glial cells, satellite cells and Schwann cells, which associate with nerve fibers and produce myelin.15 The cell bodies of the primary afferent neurons that convey sensory information from the periphery to the central nervous system (CNS) are completely surrounded by several satellite glial cells that form distinct, functional units. Morphological studies have shown that flattening processes from glial cells lie in close proximity to the plasma membrane of neuronal cells. It is now accepted that glial cells, which outnumber the neuronal cells 10 to 1 in trigeminal ganglia, directly influence neuronal activity by controlling the microenvironment in the ganglion.12,16 While communication between cells can occur via gap junctions or release of diffusible chemical messengers, the mechanisms by which neuronal–glial cells communicate in trigeminal ganglion under basal or inflammatory conditions is not known. In this study we used an in vivo model of trigeminal nerve activation and glia-enriched primary cultures to investigate neuronal–glial cell signaling within the trigeminal ganglion. Data from our dye-coupling experiments demonstrated enhanced neuron to glia communication occurring through gap junctions within trigeminal ganglion in response to inflammatory stimuli. To our knowledge, this is the first report of this type of signaling within the trigeminal ganglion. In addition, stimulation of trigeminal nerves located in the V3 region of the ganglion caused a rapid increase in expression of the inflammatory proteins S100B and p38 mitogen-activated protein (MAP) kinase in both neurons and glial cells. Somewhat surprisingly, increased expression was also observed in neuronal cell bodies and glial cells located within the V2 and V1 regions. Thus, activation of one branch within the ganglion caused a rapid and sustained activation in the other branches, an example of intraganglion communication. Furthermore, we showed that CGRP, which can be released from neuronal cell bodies, can stimulate glial cells to release inflammatory cytokines. Based on our results, we propose that neuronal–glial cell signaling is likely to play a key role in peripheral sensitization within the ganglion in migraine, rhinitis, and temporomandibular joint (TMJ) disorders that involve trigeminal nerve activation. Furthermore, our data may help explain commonly reported symptoms of comorbid conditions associated with migraine, which may have important implications for further understanding migraine pathology and therapy.