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.

Keywords: CGRP; Trigeminal neurons; neuromodulation; neuropeptides; satellite glial cells; signaling.

Figure 1.

Histological characteristics of rat trigeminal ganglion. (a) Horizontal section (haematoxilin-eosin staining) showing aggregations of primary afferent somata in the ophthalmic (V1), maxillary (V2) and mandibular division (V3). In rodents, the ophthalmic and maxillary branches originate close together, while the mandibular branch is clearly separated. (b) Trigeminal ganglion neurons stained by fluorescent tracer DiI applied to the spinosus nerve near the mandibular division of the ganglion. Courtesy of Markus Schueler, Erlangen. (c), (d) Neurons immunostained for CGRP and neuronal NO synthase (nNOS), same section. Some neurons show both markers (arrows). Courtesy of Anne Dieterle, Erlangen. (e)–(g) Neurons immunostained for CGRP and the CGRP receptor component CLR, same section. Most CGRP-immunoreactive neurons are small to medium sized (red in (f)), CLR-immunoreactive neurons are mostly of middle size (green in (e)). Neurons can show both CGRP and CLR immunoreactivity (yellow in (g)) but neurons showing CGRP and all CGRP receptor components are extremely rare. Courtesy of Jochen Lennerz, Boston.

Figure 2.

Representation of receptor expression and signaling processes in and between trigeminal ganglion cells. Coloured arrows denote diffusing or transported signal molecules or receptor proteins, inflected broken arrows through the nucleus indicate gene expression. Small neurons (mostly with unmyelinated fibers, right hand, C) expressing CGRP may signal to satellite glial cells (SGCs) and to middle-sized neurons (typically with myelinated, rarely unmyelinated fibers, left hand, Aδ/C) expressing CGRP receptors (144). CGRP release by Ca²⁺-dependent exocytosis can be induced by activating Ca²⁺-conducting ion channels like TRPA1, for example by nitroxyl (NO⁻) (117). Autocrine activation by CGRP may occur via CGRP-binding amylin receptors (49). CGRP and amylin receptors may activate intracellular cascades involving cAMP response-element binding protein (CREB) or mitogen-activated protein kinase (MAPK) to induce gene expression of purinergic (P2X3) receptor channels in neurons (145) and P2X7 channels (107) as well as purinergic (P2Y) receptors in SGCs (146), enzymes like nitric oxide synthase (NOS) (105), cytokines like interleukin 1β (IL-1β) (106) as well as growth factors like brain-derived neurotrophic factor (BDNF) (109). Nitric oxide (NO), cytokines and BDNF may signal back to neurons facilitating expression of purinergic receptor channels (145), CGRP (147) and CGRP receptor components like RAMP1 (118). In addition, ATP, possibly released from neurons under the influence of CGRP (108), may activate SGCs (148) and macrophage-like cells (MLC), which can signal back to neurons by cytokines like tumor necrosis factor (TNFα). Other neuropeptides like PACAP may also be involved in intercellular signaling (54). Many of the gene products like CGRP, CGRP receptor proteins and BDNF can crucially influence neuronal transduction and synaptic transmission, because they are delivered by axonal transport through the neuronal processes (surrounded by Schwann cells, SC) to the peripheral and/or central terminals of trigeminal afferents.