Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment

Abstract

The oral cavity is a portal into the digestive system, which exhibits unique sensory properties. Like facial skin, the oral mucosa needs to be exquisitely sensitive and selective, in order to detect harmful toxins versus edible food. Chemosensation and somatosensation by multiple receptors, including transient receptor potential channels, are well-developed to meet these needs. In contrast to facial skin, however, the oral mucosa rarely exhibits itch responses. Like the gut, the oral cavity performs mechanical and chemical digestion. Therefore, the oral mucosa needs to be insensitive, to some degree, in order to endure noxious irritation. Persistent pain from the oral mucosa is often due to ulcers, involving both tissue injury and infection. Trigeminal nerve injury and trigeminal neuralgia produce intractable pain in the orofacial skin and the oral mucosa, through mechanisms distinct from those seen in the spinal area, which is particularly difficult to predict or treat. The diagnosis and treatment of idiopathic chronic pain, such as atypical odontalgia (idiopathic painful trigeminal neuropathy or post-traumatic trigeminal neuropathy) and burning mouth syndrome, remain especially challenging. The central integration of gustatory inputs might modulate chronic oral and facial pain. A lack of pain in chronic inflammation inside the oral cavity, such as chronic periodontitis, involves the specialized functioning of oral bacteria. A more detailed understanding of the unique neurobiology of pain from the orofacial skin and the oral mucosa should help us develop novel methods for better treating persistent orofacial pain.

Keywords: chronic pain; mucosa pain; orofacial pain.

Figure 1

Innervation of the craniofacial sensory nerves, and the sources of persistent orofacial pain from tissue or nerve injuries. The trigeminal nerve is the fifth cranial nerve. The trigeminal ganglia (TG) contain neuronal cell bodies of sensory neurons projecting to the orofacial structures. The first branch (V1) projects to the forehead skin and dura through the ophthalmic nerve. The second branch (V2) projects to the skin, mucosa, and teeth of the upper jaw through the maxillary nerve. The third branch (V3) projects to the skin, mucosa, and teeth of the lower jaw, including the tongue mucosa. The central branches of the trigeminal sensory neurons project to the trigeminal nucleus complex in the brainstem and make synaptic connections with second-order neurons. The pain-sensing nociceptors from the orofacial area are highly connected with the caudal region of the trigeminal nucleus complex (trigeminal subnucleus caudalis; Vc). The Vc neurons relay signals to various ascending pain pathways within the brain. The tongue mucosa is also innervated by gustatory nerves, such as the chorda tympani nerve (Ch tym n), which is a part of the facial nerve (the seventh cranial nerve). Taste signals are transmitted through the chorda tympani nerve, relayed in the nucleus tract solitarius in the brainstem, and transmitted to the central taste pathways. Persistent pain from the orofacial area can be derived from multiple etiologies of injuries to the tissue or nerves. Irradiation or chemotherapy can cause oral mucositis. Oral cancer often causes pain from the oral mucosa. The direct injury of peripheral nerves due to facial trauma or tooth extraction can lead to the development of painful post-traumatic trigeminal neuropathy (PTTN). Trigeminal neuralgia [8] is a distinct entity of chronic pain, derived from compression of the central root of the trigeminal nerve. Some idiopathic chronic orofacial pain, such as burning mouth syndrome (BMS) or persistent idiopathic dentoalveolar pain, are regarded to be of neuropathic origin.

Figure 2

Different sensations of intraoral mucosa and extraoral skin. Results of quantitative sensory testing (QST) in 21 healthy subjects (13 women and 8 men; mean 40.4 years) on the cheek, tip of the tongue, and gingival mucosa of the upper premolar region. Mean ± SD; * p < 0.05, ** p < 0.01, and *** p < 0.001; paired t-test following Bonferroni correction for multiple comparisons. Plots were redrawn using previously published data from Pigg et al. [9], with kind permission.

Figure 3

Lack of histamine-induced itch response from the tongue mucosa. The number of behavioral responses assessed 5 min before and after the injection of capsaicin (10 µg/10 µl (A)) or histamine (20 µg/10 µl (B)) into the facial skin or tongue of C57BL/6 mice. Under isoflurane anesthesia, capsaicin or histamine was injected into the facial skin subcutaneously or into the submucosa of the dorsum of the tongue. Before and after the injection of capsaicin into the facial skin, the number of wipings of the injected skin using the ipsilateral hind paw was counted. Before and after histamine injection into the facial skin, the number of scratchings of the injected site using the ipsilateral forepaw was counted. Upon the injection of capsaicin or histamine into the tongue, the number of instances of wiping, scratching, and grooming of the face using the bilateral forepaws was counted. n = 4 in each group. * p < 0.05 in post-test following two-way repeated measures ANOVA.

Figure 4

Mechanistic contribution of the nociceptive primary afferents to chronic orofacial neuropathic pain. Chronic constriction nerve injury (CCI) of the infraorbital nerve (ION), a part of V2, induces widespread unique transcriptomic changes in TG. The spreading of a nociceptive signal between the V2 and V3 neurons within TG may contribute to extraterritorial hyperalgesia. Central terminals of trigeminal afferents within the trigeminal subnucleus caudalis (Vc) are sensitized by descending facilitatory inputs from the rostral ventromedial medulla (RVM). A subset of trigeminal afferents directly projects to the parabrachial nucleus (PBN), which is a hub of affective pain pathways, without relaying at the Vc. The localized administration of capsaicin—which selectively defunctionalizes nociceptive afferents—to orofacial tissues attenuates long-lasting orofacial neuropathic pain, both in humans and rodents.

Figure 5

Functional plasticity changes of the trigeminal nociceptors following a craniofacial neuropathic injury. (A,B) Representative GCaMP3 imaging of TG explants from Pirt-GCaMP3 mice. TG neurons of V2 (A) or V3 (B) division after CCI-ION were activated by capsaicin (1 µM) or KCl (100 mM). Upper panels show ipsilateral a V2 (A) or V3 (B) division of TG. Lower panels show a contralateral V2 (A) or V3 (B) division of TG. Scale bar, 50 µm (for both). Arrowheads in red indicate TG neurons that are over 30 µm in diameter and activated by capsaicin. Arrowheads in yellow indicate coupled TG activation by capsaicin; that is, adjacent neurons activated together—simultaneously or in a very short time window (<1 sec). (C,D) Population data for V2 shown in (C) or for V3 shown in (D), expressed as the percentage of KCl-sensitive TG neurons. ipsi., ipsilateral; cont., contralateral. * p < 0.05; ** p < 0.01; and *** p < 0.001. Data are presented as the mean ± SEM. (E) Schematic diagram of a mouse Vc. Black dashed lines indicate the border of three large divisions (V1, V2, and V3) in Vc. White square dash lines indicate where the region of the nerve fibers and terminals [74] was selected and analyzed, in order to measure the Ca²⁺ transient at different lamina (yellow dash lines). (F,G) Representative GCaMP3 imaging of Vc slices from Pirt-GCaMP3 mice. Central fibers and terminals in the V2 (F) or V3 (G) division of Vc after CCI-ION were activated by capsaicin (1 µM) or 20-mM KCl. The upper panels show the ipsilateral V2 (F) or V3 (G) division of Vc. The lower panels show the contralateral V2 (F) or V3 (G) division of Vc. Scale bar, 50 µm. (H–J) Time course of the amplitude of the Ca²⁺ transient evoked by capsaicin (1 µM and 10 µM) or KCl (20 mM) applications at different lamina (lamina I/IIo, IIi, and III/IV) of V2 and V3 of the Vc. Capsaicin was applied in a bath from 0 to 60 s during the time course. The Ca²⁺ transient (∆F/F₀) was normalized to the value imaged at the baseline. Ipsi., ipsilateral; cont., contralateral. * p < 0.05, ** p < 0.01, and *** p < 0.001. Data are presented as the mean ± SEM. The data and images were redrawn using previously published data from Kim et al. [70].