Trigeminal Mechanisms of Nociception

Introduction

The trigeminal system is involved in processing nociceptive information from the oral, facial, and cranial territories. Although the input from tissue-damaging events transduced by skin nociceptors is similar to that throughout the rest of the body, trigeminal mechanisms of nociception have some specific features that merit special consideration. For example, craniofacial structures such as the cornea, meninges, and tooth pulp give rise mainly to pain sensations in humans. Curiously, the most commonly experienced types of pain, such as toothache, are often difficult to localize, and some headaches may occur even in the absence of an identifiable external tissue-damaging event.

The sensory pathways that convey craniofacial nociceptive input to higher levels of the brain originate in trigeminal ganglion nociceptors and their associated nuclei within the trigeminal brain stem sensory complex and upper cervical spinal cord. These structures are simultaneously collecting basic somesthetic activities from many sources that are not only relevant for pain but could also have a role in the continual transmission of crucial information to maintain the integrity of the craniofacial regions. This information is constantly being selected and modulated in the context of an appropriate response. Endogenous modulation networks originating from several central nervous system (CNS) structures can act at many levels to specifically enhance or diminish the incoming messages. Some of the particular features of trigeminal nociception could thus result not only from the unique anatomical–functional organization of trigeminal brain stem nuclei but also from the interaction between bottom-up and top-down central mechanisms.

This chapter outlines the more relevant features of the central processing mechanisms of trigeminal nociception by using animal studies, which provide valuable models in our understanding of human oro- and craniofacial pain disorders.

Trigeminal Primary Afferents from Oro- and Craniofacial Tissues That Convey Nociceptive Input

The fine primary afferents responding to noxious stimuli from the outside world and from intraoral and intracranial tissues are made up almost exclusively of the three branches of the trigeminal nerve, the ophthalmic (V1), maxillary (V2), and mandibular (V3) divisions ( Fig. 56-1 ), although some parts of the head receive their sensory innervation from branches of the upper cervical nerves. Each division supplies one of the three different dermatomes of the face and the underlying deeper mucosal, vascular, muscular, and meningeal tissues. In all mammals, the ophthalmic branch supplies the cornea, neighboring conjunctiva, skin of the dorsum and tip of the nose, intranasal mucosa, dorsum of the head, upper eyelid, and supraorbital skin. Trigeminal afferents from the ophthalmic branch also supply the supratentorial dural and pial tissues, whereas the upper cervical nerves innervate the ear pinna, caudal head, and infratentorial structures. The maxillary division includes the infraorbital and postorbital skin, upper lip, lateral aspect of the nose, intraoral maxillary mucosa, and upper teeth. The mandibular branch supplies the temporomandibular joint, lower lip skin, intraoral mandibular mucosa, lower teeth, and anterior part of the tongue. Transmission of acute pain involves the activation of different groups of sensory receptors on peripheral Aδ and C fibers, the nociceptors, which respond to noxious mechanical, thermal, and chemical stimuli. The roles of these receptors in nociceptive signaling are covered in Chapter 1, Chapter 2, Chapter 3, Chapter 4 .

Trigeminal Brain Stem Sensory Nuclei Integrate Nociceptive Input from Oro- and Craniofacial Primary Afferents

Noxious input from receptors in peripheral terminals of the fifth nerve that innervate craniofacial tissues is conveyed through trigeminal (gasserian) ganglion neurons located in the base of the skull. An approximate somatotopic organization exists in the trigeminal ganglion of mammals, with ophthalmic cells lying anteromedially, mandibular cells lying posterolaterally, and maxillary cells in between. Central processes of these primary afferents enter the brain stem via the trigeminal tract in a dorsal and lateral position, adjacent to the trigeminal motor root. After entering the tract, most afferents pass caudally while giving off collaterals that terminate in the subdivisions of the spinal trigeminal nucleus and upper cervical cord to activate second-order neurons. Some root fibers give rise to an ascending branch toward the principal sensory trigeminal nucleus (Pr5), which is mainly involved in non-nociceptive processes and thus is not considered here.

As shown in Figure 56-2 , the spinal trigeminal sensory nucleus (Sp5) consists of three subnuclei (oralis, Sp5O; interpolaris, Sp5I; and caudalis, Sp5C). Aδ and C primary afferent fibers terminate somatotopically in a dorsal–ventral fashion, with mandibular afferents ending dorsally, maxillary fibers projecting centrally, and ophthalmic fibers innervating the ventral-most aspect of Sp5. In addition, a mediolateral organization is also present in Sp5O and Sp5I, in which midline regions such as the nose and medial peri- and intraoral areas project medially and the posterior skin and intraoral areas are represented more laterally ( ). In Sp5C this pattern changes and becomes a segmental “onion skin” arrangement, with input from the nose and rostral part of the face ending rostrally and the posterior craniofacial areas terminating gradually at more caudal levels. Sp5C is the only portion that has a laminated structure and a morphological and functional organization comparable to the spinal dorsal horn. The great majority of nociceptive primary afferents terminates in superficial layers (laminae I and II), although some Aδ fibers terminate in lamina V of Sp5C. Recent studies have shown the existence of a different distribution of two subsets of fine primary afferents: (1) Aδ and C peptidergic fibers contacting lamina I neurons at the origin of ascending projections and local interneurons in the outer part of lamina II and (2) non-peptidergic nociceptive primary afferents that terminate in the inner part of lamina II. In contrast, large myelinated Aβ fibers that convey innocuous input contact lamina V projection neurons and local protein kinase C-γ (PKC-γ) interneurons in the inner lamina II ( ).

In contrast to hair afferents, which have more compact, circumscribed arbors, those of nociceptors from the skin, cranial blood vessels, dura, mucosa, temporomandibular joint, or tooth pulp have a widespread termination. Small-diameter fibers extend within the trigeminal tract and then terminate mainly in the Sp5I–Sp5C junction and Sp5C, where they often provide collaterals that contact the dendrites and somata of many hundreds of trigeminal neurons. In addition to this widespread distribution of nociceptive input, the phenomenon of convergence onto a single central neuron receiving input from different primary afferents is a feature that distinguishes the trigeminal complex and has been proposed to explain referral of pain and the difficulty sometimes encountered in precise localization of a painful focus. This is the case with toothache since patients are often unable to localize the tooth as the origin of the pain, and sometimes it is even difficult to determine whether the pulpitis originates in the maxillary or mandibular territories. Moreover, toothache often radiates to the neighboring facial and neck regions, whereas muscle, cervical, auricular, and even cardiac pain may project to the orofacial regions. As stated below, this phenomenon of pain referral is amplified following peripheral and subsequent central sensitization.

Trigeminal Brain Stem Second-Order Neurons: A Widespread Convergence Locus from Oro- and Craniofacial Input

A number of clinical and preclinical findings support the involvement of trigeminal brain stem neurons in oro- and craniofacial nociceptive processing. In the last century, neurosurgical procedures have shown that transection of the trigeminal descending tract at the level of the rostral pole of Sp5C produces thermal analgesia of the face without significantly affecting tactile sensations ( ). However, painful sensations from the oral cavity were partially preserved following tractotomy, thus suggesting that craniofacial noxious input is also conveyed by neurons located more rostrally. Animal studies have confirmed that orofacial tissues have multiple representations in Sp5C, in the transition zone between Sp5C and Sp5I, and in Sp5O ( ).

Numerous electrophysiological studies have shown that Sp5C contains neurons activated specifically by nociceptive input (“nociceptive specific” [NS]), which are found mainly in laminae I–II; however this area also contains “wide–dynamic range” (WDR) cells and neurons that respond specifically to cooling or light touch ( ). The restricted cutaneous receptive fields and the somatotopic organization indicate that NS and WDR neurons are suitable for signaling the spatial and temporal features of nociceptive information. NS and WDR cells have small cutaneous receptive fields and are also activated by Aδ and C fibers originating in a variety of non-cutaneous tissues. They thus show convergence of exteroceptive (cutaneous) and interoceptive (meningeal, muscle, dental pulp) input ( ). A great number of WDR cells in Sp5C are concentrated in lamina V. Their receptive fields show a gradient of sizes: the lateral-most aspect of Sp5C contains WDR cells with small fields, and another population of neurons with larger receptive fields is found in the adjacent reticular formation (laminae V–VI) ( ). Studies in both anesthetized and awake animals have shown that WDR neurons have a greater ability to encode noxious stimuli with a wider range of responses than do NS neurons ( ). WDR neurons receive Aβ-, Aδ-, and C-fiber input and respond to a large range of mechanical stimuli from innocuous up to strong nociceptive stimuli. They also respond to a variety of other stimuli (innocuous thermal and/or noxious and chemical stimuli) and exhibit cutaneous and deep tissue convergence ( ). WDR neurons usually have excitatory peripheral fields that are larger than those of NS cells, although their properties are still compatible with their playing a role in stimulus location.

Trigeminal Brain Stem Interneurons: A Substrate for Central Sensitization Phenomena

It has been shown that Sp5C trigeminovascular neurons receiving convergent input from the dura and periorbital area not only increase their responses following the application of inflammatory agents to the dura but also become sensitized for several hours. Sp5C sensitized neurons have lower thresholds to both dural and peri-ocular skin stimulation and show a significant increase in the size of their dural and cutaneous receptive fields. Based on these findings, it was proposed that the referred, cutaneous allodynia observed in migraine patients is due to central sensitization of Sp5C neurons following peripheral sensitization of meningeal nociceptors ( ). Moreover, the ophthalmic region of Sp5C, which contains neurons that receive convergent input from the dura and peri-orbital skin, sends projections to the ophthalmic primary afferent projection area of the contralateral trigeminal brain stem sensory complex. These projections are somatotopically organized and extend rostrocaudally from the caudal spinal trigeminal nucleus to the upper cervical dorsal horn C2–3 segments ( ). Contralateral projections could provide input that specifically modulates the activity of medullary and spinal dorsal horn cells driven from the ophthalmic division of the trigeminal nerve. Such input could become effective following long-lasting noxious stimulation of meningeal nociceptors and thus contribute to the central sensitization that occurs after long-lasting migraine attacks ( ). In patients it could elicit the cutaneous allodynia that extends outside the referred pain area to the skin over the contralateral head and forearm ( ). Sp5C also projects to the ipsilateral junction of Sp5C and Sp5I, Sp5O, and Pr5 nuclei over their whole caudal–rostral extent ( ). Such intratrigeminal connections are somatotopically organized, as observed in both animals ( ) and humans ( ); however, the functional significance of these topographically organized, intratrigeminal connections has not been fully elucidated. Ipsilateral input from Sp5C neurons to rostral trigeminal nuclei could contribute to the amplification of nociceptive output to supramedullary structures via the interpolar, oral, and principal subdivisions since these regions convey orofacial input to the brain stem and thalamic areas ( ).

As in spinal nociceptive processing, glutamatergic transmission is very important in Sp5C since local application of glutamate activates nociceptive neurons ( ). In addition, systemic or local application of N -methyl- d -aspartate (NMDA) antagonists in the Sp5C inhibits c-fos expression following corneal stimulation ( ). There is also strong evidence that rostral trigeminal nuclei, especially Sp5O, convey both extra- and intra-oral nociceptive input, which is dependent on glutamatergic input from Sp5C ( ). Recent studies have shown that following intense noxious stimulation or nerve injury, fine primary afferents release glutamate and several other peptides and neuromodulators onto lamina I neurons. Normally silent NMDA receptors become activated, thereby leading to a cascade of calcium-dependent and second-messenger signaling that increases the excitability of lamina I neurons and thus facilitates the transmission of noxious messages to the brain. Under such circumstances, lamina I nociceptive neurons could also be activated by Aβ non-nociceptive primary afferents that usually drive inhibitory interneurons. Following injury, Aβ fibers could activate PKC-γ–expressing interneurons in inner lamina II, which become disinhibited and in turn activate lamina I neurons ( ).

Spinal Trigeminal Complex Neurons Convey Craniofacial Nociceptive Input To Several Brain Regions