Peripheral and Central Anatomy

The trigeminal nerve (cranial nerve V), with its three major branches: ophthalmic nerve (V1), maxillary nerve (V2), and mandibular nerve (V3), is the largest cranial nerve, and is primarily a sensory nerve (with some motor functions). V1 and V2 together innervate the nasal mucosa; V2 and V3 innervate the oral mucosa. From here, they convey both somatosensory and chemosensory information. The three branches converge on the trigeminal ganglion (Gasserian ganglion), where the cell bodies of the incoming sensory fibers are located. This ganglion is analogous to the dorsal root ganglia of the spinal cord.

From the trigeminal ganglion, neurons project to the trigeminal nucleus (extending from the caudal medulla to the rostral pons) and, after synapsing there, project to lateral (e.g., ventrobasal) and medial (e.g., centromedial and parafascicular) thalamic nuclei. From here, neurons project to the somatosensory cortex. In humans, the V1 regions are represented in the inferior portion of the postcentral gyrus, and V3 regions in more superior regions in the central sulcus. In addition to these somatosensory brain regions, chemosensory trigeminal stimuli activate brain regions that are commonly considered olfactory and gustatory regions, such as the insula, the orbitofrontal cortex, and the piriform cortex.1

Somatic and Autonomic Functions

The intranasal trigeminal system has several functions, which may be subdivided into four categories.2 (1) Neurons of the intranasal trigeminal systems release immediate protective mucosal responses by axon response mechanisms.3 (2) The intranasal trigeminal system provides the afferent connections of brainstem reflex circuits such as coughing, sneezing, gagging, and vomiting. These reflexes also include parasympathetically mediated secretions, which are locally active, and systemically acting sympathetic vasoconstrictor reflexes.3 (3) The intranasal trigeminal system modulates breathing parameters.4 (4) The intranasal trigeminal system, together with the olfactory system, monitors inhaled air for quality and composition.5

Trigeminal Role in Local and Remote Reflexes

The myelinated (Aδ) and unmyelinated fibers of the mucous membranes are responsive to a variety of physical and chemical stimuli.6 Stimulation of these nerves (by heat, cold, touch, and chemical irritation) can trigger a variety of local and remote reflexes. Within the nasal mucosa, release of neuropeptides (e.g., substance P) from unmyelinated fibers (the axon reflex) can produce tissue swelling, produce glandular secretion, and facilitate mast cell degranulation.7 Central (autonomic) reflexes also participate in the secretory response in the upper airway.8 Tissue swelling decreases luminal size, thereby increasing nasal airway resistance and the work of nasal breathing. Mucosal swelling also results in decreased patency of upper airway ostia (i.e., the Eustachian tubes and the osteomeatal complex of the paranasal sinuses), and may play a part in the pathogenesis of both otitis media and sinusitis.9

In terms of nasal secretory reflexes, so-called gustatory rhinitis—watery rhinorrhea produced by ingestion of hot or spicy foods, which is very common in the population10—involves trigeminal nerve afferents and facial nerve (cranial nerve VII) parasympathetic efferents. Depending upon the individual, the strength of the stimulus, and the degree of irritation, this response may also include lacrimation. Gustatory rhinitis can be blocked by local application of anticholinergic agents (e.g., atropine or ipratropium bromide).11

Both reflex nasal airflow obstruction and rhinorrhea have been postulated to protect against injurious inhalants. In addition to these purely upper airway reflexes, a variety of nasal reflexes is initiated in the nose but effected at remote sites ( Fig. 12.2 ). Coughing and sneezing are the two best-known protective reflexes triggered by airway irritation. Both involve the musculature of the diaphragm and thoracic cage. These reflexes act to expel noxious substances forcefully, thus protecting the airway. Less well-known autonomic reflexes originating in the upper airway can be parasympathetic (cardiac slowing, bronchoconstriction) or sympathetic (epinephrine release from the adrenal medulla, peripheral vasoconstriction).12

Despite their protective function, when dysregulated, airway reflexes can become pathological. Chronic cough, for example, can arise from a variety of causes, including pharmacological (e.g., ACE [angiotensin-converting enzyme] inhibitors), inflammatory (e.g., asthma), irritant (postnasal drip; gastroesophageal reflux disease [GERD]; cigarette smoke), infectious, intrinsic lung disease, and behavioral factors.13 An exaggerated cough reflex—defined functionally as a heightened response to aerosolized capsaicin—has been termed “sensory hyper-reactivity”.14 This diagnosis may characterize a subset of patients who self-identify as “chemically sensitive” and with impaired ability to cope with a variety of environmental exposures.15

Receptive Structures

Polymodal nociceptors respond to thermal and chemical stimuli. Their receptive structures are located on free trigeminal nerve endings throughout the oral and nasal mucosa. Compared with the olfactory nerve, receptor diversity within the trigeminal system is relatively modest, although their activation leads to diverse perceptions such as cooling, burning, stinging, or tingling. With few exceptions (e.g., vanillin and hydrogen sulfide), most volatile substances activate the trigeminal system, especially at higher concentrations.5 If volatile substances stimulate both the olfactory and the trigeminal system, they are called mixed olfactory–trigeminal stimuli (e.g., benzaldehyde, menthol). At a receptor level, chemical and thermal stimuli activate specific receptors of the trigeminal nerve, most of which are ion channels belonging to the subfamily of transient receptor potential (TRP) receptors. They include TRPV1 (excited by capsaicin,16 eugenol,17 acids,18 and heat16), TRPM8 (excited by menthol, eucalyptol, and cool temperatures19), and TRPA1 (excited by mustard oil, cold temperatures, and a variety of irritant gases20). There is also evidence for non-TRP trigeminal receptors activated by nicotine21 and acids.22

In addition to these receptors on free trigeminal nerve endings, solitary chemoreceptor cells have been described in the nasal cavity, although not yet in humans. These cells reach the surface of the nasal epithelium and form synaptic contacts with trigeminal afferent nerve fibers. They are activated by bitter substances via specific receptors. These cells may add to the repertoire of compounds that can activate the intranasal trigeminal system.23

The low-threshold trigeminal mechanoreceptors responsible for the perception of mechanical stimuli from the nasal mucosa have not yet been identified.24 Some of the TRP channels mentioned above may serve as mechanoreceptors.

Testing the Intranasal Trigeminal System

The major challenge when testing the intranasal trigeminal system is the intimate connection between olfactory and trigeminal sensory systems. Most trigeminal stimuli also activate the olfactory system,5 and do so at lower concentrations than those needed for trigeminal activation. Different methods have been developed to overcome this problem, with their own advantages and disadvantages.

Psychophysical Testing Methods

Psychophysical methods to assess the intranasal trigeminal system include testing of anosmic patients; instructing patients to focus on trigeminal rather than olfactory sensations; or using methods that depend purely or predominantly on trigeminal stimulation.

Anosmic patients can only detect mixed olfactory–trigeminal stimuli by virtue of their trigeminal component. Accordingly, the percentage of patients with anosmia who detect a stimulus correlates to the stimulus’ trigeminal impact.5,25 As patients with anosmia do not perceive olfactory information, the same methods used for measuring an olfactory threshold in subjects with normosmia will result in a trigeminal threshold in subjects with anosmia.26 However, results from anosmic subjects cannot be generalized to the general population, as anosmia per se leads to reduced trigeminal sensitivity.27,28 It is important to note that even though trigeminal thresholds are reduced in anosmic subjects, trigeminal compounds can nevertheless be perceived. In fact, the difference in trigeminal sensitivity between anosmic and normosmic subjects is small, and therefore may not be detected when investigating only a small number of subjects. However, it is a clear limiting factor of this approach.

Methods depending on trigeminal stimulation: Some psychophysical tests depend on information from the trigeminal system. The main such method is the lateralization task, in which patients identify the nostril (i.e., right or left) to which a chemical stimulus is applied monorhinally (i.e., to only one nostril). This task is based upon the fact that humans seem unable to localize pure odorants,29 but can localize mixed olfactory–trigeminal stimuli with high accuracy.29–32 This method is able to establish the sensitivity of the trigeminal system (e.g., when comparing the sensory acuity of subject groups,31,33 or when comparing the trigeminal potency of different chemical compounds).26 In clinical testing, a single concentration of a test compound that is a strong trigeminal stimulus (e.g., menthol) may be used in a semiquantitative screening protocol. The sum of correct identifications is used for further statistical analyses. Alternatively, quantitative thresholds for irritant detection can be generated by employing an ascending concentration series of the test chemical of interest ( Fig. 12.3 ).

Some groups take advantage of the fact that the cornea and conjunctiva of the eye are also innervated by the trigeminal nerve and perceive painful sensations, but do not respond to pure olfactory stimuli. As vaporphase chemical stimuli can evoke sensations of burning or stinging in the cornea, they can be used to assess trigeminal irritation thresholds in the eye if care is taken to avoid costimulation of the nose. Interestingly, for many compounds, irritation thresholds in the eye and nose correlate significantly.34

An alternative is to use patients with normosmia who are instructed and trained to focus on trigeminal sensations and to disregard simultaneous olfactory sensations. Typically, subjects receive instructions such as, “Have you felt any sensation like burning, stinging, cooling, or tickling?” This method allows for the assessment of trigeminal perception thresholds,35 but other applications are also possible. The main disadvantage of the method is that it can never be completely discounted that patients may be influenced by the olfactory input.

There is also the possibility to use “pure” trigeminal stimuli (i.e., stimuli that do not produce an additional chemosensory sensation). However, it is very difficult to exclude a possible concomitant olfactory stimulation. Possible pure trigeminal stimuli include CO₂ and capsaicin. Of note, the CO₂ concentrations necessary to act as an effective trigeminal stimulus are very high (> 100,000 ppm).36 Thus, CO₂ as a nasal trigeminal stimulus can safely be employed only as a brief (< 3-second) stimulus, or, alternatively, with mouth breathing and velopalatine closure (i.e., isolation of the nasal cavity).

Related posts:

The Human Vomeronasal System Sinonasal Olfactory Disorders Assessment of Olfaction and Gustation Functional Anatomy of the Olfactory System II: Central Relays, Pathways, and their Function Miscellaneous Causes of Olfactory Dysfunction Functional Anatomy of the Olfactory System I: From the Nasal Cavity to the Olfactory Bulb

Stay updated, free articles. Join our Telegram channel

Join