Pain part 2a: trigeminal anatomy related to pain

The trigeminal system

The trigeminal nerve supplies general sensory supply to the face, scalp and mouth (Figure 1). A vast proportion of the sensory cortex represents the trigeminal input (over 50%).1

The trigeminal nerve, or 5th cranial nerve, was first described by Galen (200 AD) as being two separate pairs of cranial nerves, owing to its large peripheral branches. It was not until the Italian anatomist and physician Fallopius (1523–1562) discovered that these branches merged as one, that the 5th cranial nerve was created. In 1732, the Danish anatomist Jacques-Bénigne Winslow (1669–1760) ascribed the name ‘nerf trijumeau’, referring to the three peripheral branches of this nerve, and the name ‘trigeminal nerve’ was born meaning ‘three twins’. The trigeminal nerve is the largest of the cranial nerves and the largest sensory nerve. It is a mixed sensory nerve made up of both sensory and motor axons, and it plays a particularly important role in sensations of the face and head regions.

The unique nature of the trigeminal nerve is related to several factors:

The trigeminal nerve or 5th cranial nerve

The trigeminal or 5th cranial nerve is divided into three divisions (Figure 2):

There are three sensory and one motor nuclei. The sensory nuclei (Figure 3) are arranged in a column which spans from the midbrain through the pons and medulla and into the upper cervical cord. The axons of these nuclei cross to the opposite side, ascending in the spinothalamic tract, to relay in the thalamic nuclei; from there, they end in the cerebral cortex. The sensory nucleus of CN V is connected to other motor nuclei of the pons and medulla. In addition, the descending sensory spinal tract receives somatic sensory fibres from other cranial nerves VII, IX and X.

The motor nucleus of V receives cortical fibres for voluntary control of the four muscles of mastication (masseter, temporalis, medial pterygoid, lateral pterygoid and the other four muscles are the tensor veli palatini, the mylohyoid, the anterior belly of the digastrics and the tensor tympani). These fibres are mostly crossed. It also receives input from the mesencephalic and sensory nuclei. The axons emerge anteriorly to the sensory root from the lateral surface of the pons. This motor root joins the semilunar ganglion together with the sensory root.

Extracranial component

The trigeminal nerve exits at the mid pons into the prepontine cistern and passes anteriorly to the Meckel cave where its fibres relay forming Gasserian ganglion.

The semilunar (Gasserian or trigeminal) ganglion is the great sensory ganglion of CN V. It contains the sensory cell bodies of the three branches of the trigeminal nerve (the ophthalmic, mandibular and maxillary divisions). The ophthalmic and maxillary nerves are purely sensory. The mandibular nerve has sensory and motor functions.

The Gasserian ganglion lies in a depression on the petrous apex, within a dural fold called the Meckel cave. The sensory roots of the three branches of CN V are received anteriorly. They then pass from the posterior aspect of the ganglion to the pons. The motor root passes under the ganglion to join the sensory division of the mandibular nerve and exits the skull through foramen ovale. The carotid plexus contributes sympathetic fibres to the Gasserian ganglion.

The extracranial part V then divides into three main branches (Figure 2):

Ophthalmic division (V1)(Figure 4a): While passing at the lateral wall of the cavernous sinus inferior to the trochlear nerve, then through the superior orbital fissure, the ophthalmic nerve divides into the frontal, lacrimal and nasociliary nerves. The frontal nerve divides into the supraorbital and supratrochlear nerves. Nasociliary nerve branches include a communicating branch to the ciliary ganglion, short and long ciliary nerves, the posterior and anterior ethmoidal nerves (the latter divides into internal and external nasal branches) and the infratrochlear nerve (Figure 4a, b).

Maxillary division (V2): This passes in the lateral wall of the cavernous sinus then through the foramen rotundum to exit the skull. Then it crosses the pterygopalatine fossa and enters the orbit through the inferior orbital fissure and the infraorbital canal. It emerges through the infraorbital foramen to become the infraorbital nerve. Hence the orbital blow out fracture is associated with a loss of sensation over the maxilla (Figure 4a, b).

Mandibular division (V3): This passes through the foramen ovale and gives motor supply to the muscles of mastication and sensory supply to the auriculotemporal region, lower face, mouth and dentition.

Pain transmission

Pain signals originating in the orofacial region are carried through the trigeminal (Gasserian) ganglion on to the trigeminal spinal tract where they then synapse within the subnucleus caudalis (Figure 3).6 The subnucleus caudalis (SC), which exhibits functional and morphologic similarities to the spinal cord dorsal horn, relays the signals to the thalamus where they synapse again and move on to higher cortical centres.6 Nociceptive neurons of the subnucleus caudalis converge from the tooth pulp, temporomandiblular joints and muscles of mastication, oral cavity and facial skin. This access of multiple afferent inputs onto a neuron is known as convergence. Convergence is believed to be one of the reasons responsible for the extensive degree of pain referral seen within the orofacial region. While trigeminal system pain has not been studied nearly as extensively as spinal cord mediated pain, it is believed that the mechanisms of pain modulation and conduction pathways are very similar.^7,8

The central axons of the trigeminal nerve terminate in the trigeminal brainstem complex, which ranges from the midbrain to the medulla where it merges seamlessly with the upper cervical spinal cord. The trigeminal brainstem complex is in fact made up of several separate nuclei, including the principal, spinal, paratrigeminal, mesencephalic and supratrigeminal nucleus (Figure 2).^6,7,8

The mesencephalic nucleus is mainly involved in proprioception of the face, and is unique in that it represents the only structure in the CNS to contain cell bodies of primary afferents. All other primary afferent cell bodies are contained in ganglia outside the blood brain barrier. As the paratrigeminal, mesencephalic and supratrigeminal nuclei are mostly involved in integration of motor and sensory signals, proprioception and motor reflexes; they will not be discussed further.^6,7,8

The principal and spinal nuclei of the trigeminal brainstem complex are oriented rostro-caudally to one another, and receive most of the sensory inputs from the trigeminal nerve. As the central axons of the trigeminal nerve enter the brainstem from the ganglia through the sensory root lateral to the pons, they divide and send short ascending axons up to the principal nucleus and long descending axons down to the spinal nucleus. Axons ending in the principal nucleus carry tactile or light pressure information, while axons that descend to the spinal nucleus carry temperature and pain information.8

The subnucleus caudalis represents the major nociceptive input for the facial area. A Swedish physician Carl Sjöqvist, in 1938, showed that surgically lesioning the trigeminal tract at the level of the medulla (correlating with the subnucleus caudalis) relieved the symptoms of patients suffering from chronic pain in the facial area while leaving other sensory functions intact. The subnucleus caudalis is directly adjacent to the cervical spinal cord, and its organization is comparable to the spinal dorsal horn. Projection neurons from the trigeminal brainstem subnucleus caudalis project to the thalamus and parabrachial nucleus via the posterolateral or anterolateral pathways, similar to the dorsal horn. They also project to the periaqueductal grey, dorsal reticular nucleus, the amygdaloid complex, the septal nuclei, and the hypothalamus.9^,10

The peripheral axons of the trigeminal nerve are divided into three distinct branches that innervate non-overlapping dermatomes of the head and face (Figure 4a). The ophthalmic nerve innervates the head, upper eyelid and cornea, the maxillary nerve innervates the lower eyelid, nose, upper lip and upper teeth, and gingiva, and the mandibular branch innervates the temporal mandibular joint, lower lip, gingiva and tongue. Only the mandibular branch carries motor neurons that originate from the separate trigeminal motor ganglia, and mediate mastication and the jaw-opening reflex.

The three branches of the trigeminal nerve converge in the trigeminal ganglion (also named Gasserian or semilunar), where the cell bodies of the sensory axons are found. The trigeminal ganglion is located in the middle cranial fossa (Meckel's Cave) at the base of the skull, and the cell bodies are organized somatotopically, a feature unique to the trigeminal ganglion. Remember the skin over the lower parotid region is supplied with general sensory supply by C2 and C3 cervical sensory nerves (Figure 4a).

Neuropathic mechanism of chronic pain

Recent research has significantly broadened our knowledge into neuroplastic changes that are involved in chronic pain.9^,10 Future research will focus on the question of whether novel neuroimaging techniques can be used in the individual chronic pain patient as a biomarker that would allow for an objective diagnosis of different pain conditions and for the prediction of individual responses to specific therapies.1

Both peripheral and central sensitization may result in increased nociceptive input to the brain and also changes the processing of nociceptive information within the brain. In addition, chronic nociceptive input from the periphery or from lesions within the central nervous system may result in cortical reorganization and maladaptive neuroplasticity within somatosensory and motor systems. There is also increasing evidence for pain-induced changes in large-scale neuronal network connectivity and, in patients with chronic pain, resultant structural brain changes result.^11,12,13

Thus overall the emerging evidence is that, in chronic pain, the endogenous pain-modulatory system may function aberrantly, presenting a distinct disease of the peripheral and central nervous systems.

Peripheral mechanisms

Over the last five years there has been significant progress in understanding the mechanisms involved in trigeminal acute and neuropathic pain. The complexity of the peripheral nervous system and related adaptable systems capable of mediating many of the abnormal pain sensations are becoming recognized mechanisms and are common between spinal and trigeminal neuropathic pain. The unique anatomical and physiological characteristics of the trigeminal nervous system leads to some specific maladaptations that are particular to trigeminal neuropathic pain.

Autonomic sensitivity

The role of the autonomic nervous system in neuropathic pain is becoming more evident. Silas Weir-Mitchell is credited for making the first observations of abnormal sympathetic activity in patients with a traumatic nerve injury. The adjunctive autonomic signs include excessive sweating, oedema, erythema and abnormal hair and nail growth. In many patients, inhibiting sympathetic activity, through sympathectomy or sympathetic blocks, largely relieve the painful symptoms. Injection of norepinephrine into patients treated with a sympathetic block reignited the painful sensations, confirming the sympathetic role. Administration of guanethedine, a pharmacological intervention that depletes norepinephrine from sympathetic terminals, was shown to relieve the painful symptoms in an animal model of rheumatoid arthritis.^14,15,16

Within the orofacial region, sensory and sympathetic fibre innervation is relatively segregated. Most of the sympathetic fibres that innervate the facial area originate from the superior cervical ganglia (SCG), as demonstrated by the fact that bilateral ablation of the SCG results in complete loss of sympathetic fibres in the lower lip skin. Recently, reports of significant sympathetic sprouting into the upper dermis of the skin, an area where they are normally absent, following nerve injury, also correlated well with the pain behaviour of the animal.17 This may be a fundamental mechanism driving many chronic orofacial pain conditions.

Similar to sympathetic fibres, parasympathetic fibres have been shown to sprout into the upper dermis following nerve lesion, where they are found in close relationship. While the parasympathetic fibres do not release norepinephrine like their sympathetic counterparts, they do release acetylcholine (Ach), ATP, enkephalin, VIP and NPY, which could potentially activate surrounding macrophages, mast cells and keratinocytes, as well as directly activating primary afferents, which express nicotinic, muscarinic and purinergic receptors.17 Parasympathetic fibres have also been shown to express the SP receptor, NK1, providing evidence for a bidirectional communication pattern by which sensory afferents may affect parasympathetic activity. Overall, the presence of parasympathetic fibres innervating blood vessels of the trigeminal system and their apparent apposition to sensory fibres under neuropathic conditions suggest parasympathetic activity in the facial skin may represent a unique mechanism involved in trigeminal neuropathic pain.18

Summary

Orofacial pain may be due to various conditions affecting numerous structures local to or distant from the oral cavity including: the meninges, cornea, oral/nasal/sinus mucosa, dentition, musculature, salivary glands and temporomandibular joint.

Without a basic understanding of the sensory supply to the region it is impossible to investigate and diagnose pain conditions successfully.

The region's unique neurophysiologic characteristics, which are different from the spinal nociceptive system, can present diagnostic challenges to clinicians specializing in this area. The region's sensory supply is from both spinal (C2 and 3) and cranial nerves (III, V, VII [nervous intermedius], IX, X), the latter providing both sensory and autonomic supply. The main sensory supply to the orofacial region is from the trigeminal nerve and its large representation in the sensory cortex means that pain in the orofacial region can have significant biopsychosocial impacts: interruption of daily social function such as eating, drinking, speaking, kissing, applying make-up, shaving and sleeping and, in some cases, can compromise a patient's self-identity.4

Overall, our respect for the complexity of pain has increased with recent innovative imaging, genetic and psychological methodologies. The role of the endogenous analgesic systems seem to be of great potential, however, the manipulation of these systems may rekindle memories of a clockwork orange!