Review Cephalalgia 2019, Vol. 39(13) 1661–1674 ! International Headache Society 2018 Current understanding of Article reuse guidelines: sagepub.com/journals-permissions trigeminal ganglion structure DOI: 10.1177/0333102418786261 and function in headache journals.sagepub.com/home/cep Karl Messlinger1 and Andrew F Russo2,3 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 intra- cellular 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 Trigeminal neurons, satellite glial cells, neuropeptides, signaling, neuromodulation, CGRP Date received: 20 April 2018; revised: 24 May 2018; accepted: 9 June 2018 1Institute of Physiology and Pathophysiology, Friedrich-Alexander- Introduction University Erlangen-Nu¨rnberg, Erlangen, Germany 2Department of Molecular Physiology and Biophysics, University of Iowa, The paired trigeminal ganglion (TG), also called the Iowa City, IA, USA semilunar or Gasserian ganglion, is unique among pri- 3Iowa VA Health Care System, Iowa City, IA, USA mary afferent ganglia both in structural and functional Corresponding author: aspects. It is located inside the head and gives rise to Karl Messlinger, University of Erlangen-Nuernberg, Universitaetsstr. 17, three main peripheral nerves providing nearly all intra- Erlangen, D-91054 Germany. and extracranial structures with nerve fibers of various Email: [email protected] 1662 Cephalalgia 39(13) somatosensory functions. Some of these structures, like experiments (7) and electrophysiological recording stu- the cornea and the cranial dura, are mainly or exclu- dies in the cat (8) and the monkey (9), but there is not sively innervated by thin A-delta and C-fiber afferents much information about the topographical distribution with putative nociceptive functions (1,2,3). The of neurons innervating intracranial structures. The so-called trigeminovascular system of the meninges, problem is that the innervation territories of cutaneous denoting the afferent fibers closely associated with afferents only roughly map the territories of meningeal intracranial blood vessels, is regarded as the structural afferents in humans. Furthermore, the areas of head- substrate of headache generation. Notwithstanding, ache sensations are in no way helpful in this problem; this system keeps amazing secrets; for example, the early intraoperative experiments have shown that head- fact that stimulation of the densely innervated pial ache can be referred to areas that may be far from the blood vessels does not cause any sensation (4). meningeal sites of stimulation (10). Thus, it is not known which neurons are involved in headache gener- Location, anatomical structure and ation and it is completely unknown if these neurons are compartments of the trigeminal in any morphological or functional aspect different to ganglion the neurons innervating facial skin and other cranial organs. The TG is located in the Meckel’s cave, a cavern in the petrosal part of the temporal bone on the floor of the Morphological characteristics of cell middle crania fossa, formed by a pocket of dura mater. types in the trigeminal ganglion From the rostro-lateral border of the TG, three large nerves arise, the ophthalmic (V1), the maxillary (V2), The TG consists mainly of primary afferent neurons and the mandibular (V3) nerve (Figure 1(a)). In rodents, of the pseudo-unipolar type and glial cells. In human at their origin V2 and V3 form one thick bundle that trigeminal ganglia, 20,000–35,000 neurons and about divides more rostrally. On the caudal border, the trigem- 100 times more non-neuronal cells have been counted inal ganglion passes into the trigeminal root or so-called (11). The neurons can unequivocally be identified by trigeminal nerve, which contains the central processes of their nearly round and centrally located nucleus, in trigeminal fibers that enter the brainstem at the pontine which nucleoli and chromatin particles may be visible level. In addition, a thin bundle of trigeminal motor (12). In the rat, the diameters of neurons range from fibers passing through the ganglion accompanies the tri- about 10 to 55 mm, with more than 90% being small geminal nerve (root) medially and the mandibular nerve to medium-sized neurons measuring 15–35 mmin rostrally from the ganglion (5). After retrograde tracing diameter (13,14). The size of the somata is loosely of the rat spinosus nerve, an afferent nerve in the dura correlated with the diameters of the nerve fibers. mater arising from the mandibular area, nerve fibers lit In some sections, one or even both processes of a up in the ganglion, which obviously had no contact to neuron can be visualized but it is not entirely clear any cell body. These fibers are presumably propriocep- if both have the same origin, according to the classical tive afferents of head muscles that pass the ganglion on pseudo-unipolar type, which is certainly the case in their way to the mesencephalic nucleus in the brainstem, dorsal root ganglion neurons (15), or if they arise where their somata are located (6). independently from the cell body close to one The mass of nerve fibers is thus occupying a major another (Figure 1(b)). This question is of considerable volume within the ganglion. The fascicles of nerve fibers functional importance because, in the latter case, at separate aggregations of neurons that belong to the least parts of the cell body membrane are necessarily three partitions, V1–V3, which can be fairly distin- depolarized when action potentials travel through the guished according to their location within the ganglion. neuronal processes. In horizontal sections through the rodent TG, the oph- The TG cell bodies are surrounded by a more or less thalmic division is located rostro-medially, the maxil- tight single layer of satellite glial cells. In the embryonic lary division rostro-laterally, and the mandibular trigeminal ganglion, each neuroblast is already accom- division forms a protrusion at the caudal lateral panied by 2–4 glial cells (16). The distal and central border (Figure 1(a)). The ganglion and the three per- afferent processes are wrapped by Schwann cells. ipheral nerves are ensheathed by a tough layer of col- The Schwann cells can be either non-myelinating or lagenous tissue, a duplication of the dura mater, while can form a myelin sheath, as in the case of Ab and Ad the trigeminal root is only equipped with some sparse fibers. In addition to glia, the TG contains fibroblasts connective tissue, which may render it vulnerable to forming collagen fibers, small blood vessels (mainly mechanical impact. capillaries), and several types of immune cells, such as The functional organization of cutaneous afferents resident microglia-like macrophages (17). A functional within the TG is quite well-known from lesion crosstalk between neurons and macrophages via Messlinger and