Current understanding of trigeminal ganglion structure and function in headache

Abstract

Introduction The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its cellular components. Being mainly responsible for the sensory innervation of the anterior regions of the head, it is a major target for headache research. One intriguing question is if the trigeminal ganglion is merely a transition site for sensory information from the periphery to the central nervous system, or if intracellular modulatory mechanisms and intercellular signaling are capable of controlling sensory information relevant for the pathophysiology of headaches. Methods An online search based on PubMed was made using the keyword "trigeminal ganglion" in combination with "anatomy", "headache", "migraine", "neuropeptides", "receptors" and "signaling". From the relevant literature, further references were selected in view of their relevance for headache mechanisms. The essential information was organized based on location and cell types of the trigeminal ganglion, neuropeptides, receptors for signaling molecules, signaling mechanisms, and their possible relevance for headache generation. Results The trigeminal ganglion consists of clusters of sensory neurons and their peripheral and central axon processes, which are arranged according to the three trigeminal partitions V1-V3. The neurons are surrounded by satellite glial cells, the axons by Schwann cells. In addition, macrophage-like cells can be found in the trigeminal ganglion. Neurons express various neuropeptides, among which calcitonin gene-related peptide is the most prominent in terms of its prevalence and its role in primary headaches. The classical calcitonin gene-related peptide receptors are expressed in non-calcitonin gene-related peptide neurons and satellite glial cells, although the possibility of a second calcitonin gene-related peptide receptor in calcitonin gene-related peptide neurons remains to be investigated. A variety of other signal molecules like adenosine triphosphate, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion cells and may act at receptors on adjacent neurons or satellite glial cells. Conclusions The trigeminal ganglion may act as an integrative organ. The morphological and functional arrangement of trigeminal ganglion cells suggests that intercellular and possibly also autocrine signaling mechanisms interact with intracellular mechanisms, including gene expression, to modulate sensory information. Receptors and neurotrophic factors delivered to the periphery or the trigeminal brainstem can contribute to peripheral and central sensitization, as in the case of primary headaches. The trigeminal ganglion as a target of drug action outside the blood-brain barrier should therefore be taken into account.

Current understanding of cortical structure and function in migraine

“…Although the role of the cortex in initiation of headache is not completely understood, it is clear that the cortex contributes to modulation and representation of head pain as well as amplification of sensory inputs (11). Additional network circuits implicated in migraine pathophysiology include thalamo-cortical, hypothalamic, as well as those involving brainstem and trigeminal ganglia, based on evidence for altered cellular biochemical or bioelectrical properties, microstructures, and functional connectivities (11–18).

Figure 1.Schematic representation of the cortex in relation to the trigeminovascular pain pathway.

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The fifth cranial nerve in headaches

“…monoclonal antibodies, gepants, triptans) elicit their effects [16]. Because of this evidence it is likely that CN V is an integral part in understanding headache pathophysiology [17].…”

Neurotransmitter and tryptophan metabolite concentration changes in the complete Freund’s adjuvant model of orofacial pain

“…KYNA as an endogenous NMDA receptor antagonist, is a molecule of interest for CNS drug development in case of several neurological conditions [74], but due to its poor ability to cross the blood-brain barrier (BBB) and its rapid clearance from the body [75], its application for most CNS-related alterations is limited, and therefore several KYNA analogs were synthetized [76][77][78][79]. However, the first order neuron of pain processing is located outside the BBB [80], so KYNA itself may have therapeutic potential as well. Accordingly, the antinociceptive properties of KYNA were proved in animal models of pain [29,81].…”