Tonabersat Inhibits Trigeminal Ganglion Neuronal‐Satellite Glial Cell Signaling

Migraine patients often report sinus pressure or pain and nasal congestion during severe migraine attacks and it has been suggested that sinus pathology can act as a trigger of migraine.1,2 Furthermore, patients suffering from acute allergic rhinitis experience headache and migraine at a much higher frequency than nonallergic subjects.3 While migraine and rhinosinusitis exhibit considerable comorbidity, the underlying cellular mechanisms are not well understood. However, it is well established that activation of trigeminal nerves and the peripheral and central release of neuropeptides are involved in mediating the inflammatory and nociceptive events characteristic of both migraine and rhinosinusitis.4–6 The trigeminal nerve consists of 3 major branches referred to as the ophthalmic (V1), maxillary (V2), and mandibular (V3) branches. Each branch provides somatosensory innervation of distinct regions of the head, face, nasal, and sinus cavities.7 Primary afferent neurons, whose cell bodies reside in the trigeminal ganglion, convey sensory information from peripheral tissues implicated in migraine and rhinosinusitis to the central nervous system (CNS). The pathophysiological events involved in migraine and rhinosinusitis involve both peripheral and central sensitization.4,8–10 Peripheral sensitization, which is the result of increased activity of trigeminal nociceptors, is thought to play a key role in the initiation of migraine and rhinosinusitis, while central sensitization, which involves enhanced excitability of second-order neurons, leads to pain.11 Peripheral sensitization is characterized by increased neuronal excitability and a lowering of the threshold for activation. In this context, activation is defined as causing changes in the cell that allow it to perform functions beyond those present in a basal state.12 It is now thought that glia cells that are closely associated with peripheral and central neurons can directly modulate the functional and excitability state of these neurons.12,13 Furthermore, neuronglia interactions are reported to be involved in all stages of inflammation and pain associated with several CNS diseases.14,15 Within the trigeminal ganglion, the cell bodies of neurons are completely surrounded by specialized glial cells known as satellite glia that together form distinct, functional units.13 Morphological studies have provided evidence that neurons and satellite glial cells extend processes that are thought to facilitate exchange of chemicals between neurons and glia.16,17 In addition, it was recently shown that trigeminal ganglion neurons and satellite glial cells can communicate directly via gap junctions.18 Gap junctions serve as intercellular conduits that allow for direct transfer of small molecular weight molecules, such as ions, that regulate cellular excitability, metabolic precursors, and second messengers.19,20 Gap junctions are found in most neurons and glial cells and function to facilitate neuron-neuron, glia-glia, and neuron-glia communication. Within the CNS, gap junctions are abundant and allow for extensive intercellular coupling between cells that form a communication network.19,21 Each cell contributes a hemichannel composed of 6 transmembrane proteins known as connexins. The connexin family includes more than 20 members.22 However, only 10 connexin proteins are known to be expressed by neuronal or glial cells.21 Connexins are dynamic membrane proteins that exhibit short half-lives.23 Changes in the expression of connexins and hence, communication through gap junctions, are associated with numerous CNS diseases including Alzheimer’s disease, as well as cortical spreading depression.19 Similarly, we have recently provided evidence of enhanced neuron to satellite glia communication occurring through gap junctions within trigeminal ganglion in response to inflammatory stimuli.18 The expression of connexin proteins involved in forming gap junctions between neuronal and satellite glial cells within the trigeminal ganglion under normal and disease states is not known. In addition, we have observed cross activation within the ganglion by which stimulation of neurons in one branch caused a rapid and sustained activation in the other branches, an example of intraganglionic communication.18 Based on our previous findings, we propose that neuronal-satellite glial cell signaling is involved in initiating and maintaining peripheral sensitization within the ganglion and, thus, contributes to the significant comorbidity reported for migraine, acute sinusitis, and allergic rhinitis. In this study, we used an in vivo animal model to test whether treatment of V2 neurons by tumor necrosis factor-alpha (TNF-α), a cytokine whose levels are elevated in nasal secretions during allergic rhinitis, can reduce the amount of stimulus required for cellular changes in neurons located in the V1 region, and thus act as a potential trigger. Increased neuron-satellite glia communication via gap junctions, as well as increased levels of connexin 26 and active p38, was observed in neurons and glia located in both V1 and V2 regions in response to cotreatment with TNF-α and capsaicin. Another significant finding from our study was that pretreatment with the anti-migraine drug tonabersat decreased gap junction communication and the level of connexin 26, and blocked p38 activation in both neurons and satellite glia.