Home About NIMESULIDE Evidence of efficacy Appropriate use About inflammatory pain Expert's view Q&A
About inflammatory pain Orofacial inflammatory pain
 

Prof. Luca Levrini
Professor of Dentistry
Dental Clinic, University of Insubria
Varese, Italy

The face, mouth, and jaws are common locations for pain, and epidemiological investigations have documented the high prevalence rates for several orofacial pain conditions.
These pain conditions may present inflammation of orofacial tissues, may be associated with the activation of trigeminal nociceptive primary afferents and neurons in the trigeminal nociceptive pathways, and can also produce a sustained hyperexcitability (sensitization) of these neural elements. This sensitization contributes to the allodynia, hyperalgesia, spontaneous pain, and pain spread or referral that are characteristic of many of these conditions. A variety of chemical mediators are involved in these sensitization processes.
The use of pharmacological agents that act on the consequences of the increased afferent excitability associated with inflammation can be regarded to as a promising way to effectively control orofacial inflammatory pain.
This paper shortly summarizes current understanding of the peripheral mechanisms underlying acute orofacial inflammatory pain conditions.

Anatomy and physiology of orofacial inflammatory pain
The trigeminal nerve is the fifth cranial nerve and provides the principal sensory innervation of the face and mouth. Many trigeminal primary afferent fibers terminate in the orofacial tissues as free nerve endings. They are considered nociceptors since they are activated by noxious stimuli like surgical incisions of the facial skin or oral mucosa, tooth extractions, bacterial toxins accessing an exposed dental pulp, action of inflammatory mediators and exposure to chemical irritants (e.g. hot pepper, mustard) or excessively hot or cold liquids. The activation of the nociceptive endings by a noxious stimulus can result in the activation of their parent small-diameter, slowly conducting primary afferent fibers (A-delta and C-fiber) which have their primary afferent cell bodies in the trigeminal ganglion. These nociceptive afferent fibers conduct nerve impulses to the central nervous system (CNS) and provide the brain with sensory-discriminative information about the quality, location, intensity, and duration of the stimulus.
Several mediators are involved in the activation of the nociceptors, after their release due to the damage or inflammation of the tissue innervated by nociceptive endings.

Effects of inflammatory mediators on trigeminal nociceptors
Inflammation of peripheral tissues is associated with the release of chemical mediators from either tissue cells (e.g., mast cells, macrophages, and immune cells) or from the nociceptive afferent endings themselves (e.g., substance P). Many of these mediators increase the excitability of the nociceptive endings at the site of injury. As a result, the endings may show an enhanced response to subsequent noxious stimuli, and even respond to stimuli that were innocuous before the tissue damage or inflammation, thus reflecting a decreased activation threshold; a spontaneous activity may also develop. As mediators spread through the tissues, these changes may also occur in nociceptive endings adjacent to the injury site. This enhanced excitability is known as peripheral sensitization of the nociceptive endings, and can result in enhanced signal conducted along the nociceptive afferents into the CNS.
Table 1 outlines the effects of different inflammatory mediators on nociceptors.

Table 1. Effects of different inflammatory mediators on nociceptors. 
Mediator  Effect
Bradykinin  Activation
Histamine  Activation
Interleukin-1  Sensitization
Leukotrienes  Sensitization
Nerve Growth Factor (NGF)  Sensitization
Potassium  Activation
Prostaglandins  Sensitization
Proteases  Activation
Serotonin  Activation
Substance P  Sensitization
Tumor necrosis factor α (TNF)  Sensitization

Increased responsiveness to noxious stimuli, decreased activation threshold, spontaneous activity, and involvement of adjacent afferents all contribute to peripheral sensitization, which in turn leads to the hyperalgesia, allodynia, spontaneous pain and pain diffusion characteristic of most acute or chronic inflammatory pain conditions. Tissue injury or inflammation may also lead to axonal sprouting or abnormal discharges of the nociceptive afferents, an additional pathophysiological process underlying some painful conditions.

Mechanisms of inflammatory dental pain
The tooth pulp and periodontium are extensively innervated. Several studies have investigated the properties of nerve fibers afferent to the tooth pulp, which is a common site of pain. The dentine encasing the pulp is also very sensitive despite its relatively sparse innervation. The activation of intradentinal afferents appears to be mainly due to a hydrodynamic mechanism, although the odontoblast (the dentine-forming cell) may play an important role in local inflammation.
A special feature of the pulp that should be noted is its very low compliance, due to its encasement in hard tissues. This feature can contribute to the exquisite sensitivity of the tooth in some inflammatory states. In addition, the clinical outcome of dental caries reflects an orchestrated process which involves bacterial invasion, immune cells, a number of inflammatory mediators, and other chemical processes within the pulp. These processes may also include the action of growth factors which lead to morphological and phenotypic changes in the pulp afferent endings - including sprouting. Moreover, growth factors can induce changes in neuropeptide expression, that may determine an increased receptive field size of the afferents, and therefore an enhancement of spatial summation. Collectively, these phenomena result in an increased pain sensitivity.
Many of the peripheral chemical processes, mediators, receptors, and ion channels that contribute to the activation and sensitization of intradental afferents appear to be similar to those identified in other tissues, including intraneural neuropeptides (e.g. substance P, calcitonin gene-related peptide [CGRP]), and a number of other chemical mediators (e.g. histamine, serotonin, prostaglandins, cytokines) released from pulp tissue cells. Several of these mediators also contribute to pulp inflammatory, repair, and regenerative processes. Novel approaches to study these mediators or effects of inflammatory irritants have been explored, such as pulpal perfusion and microdialysis techniques. The in situ application of these methods to human pulps showed that, when compared to normal healthy teeth, an inflamed pulp presents increased levels of substance P, a neuropeptide produced in neuron cell bodies localized in dorsal root and trigeminal ganglia which largely contributes to the transmission and maintenance of noxious stimuli and inflammatory processes. Of note, the major role of substance P in the onset of dental pain and inflammation is increasingly being recognized. .

Inflammation in headache
Cranial vessels and the meninges are supplied by small-diameter afferents activated by noxious stimuli that may be associated with the subsequent development of vasodilatation related to neurogenic inflammation. Experimentally, they can also be activated or sensitized by the application to these tissues of an "inflammatory soup" containing several inflammatory mediators like bradykinin, 5-HT, histamine and prostaglandin E2. The activation of these afferents by inflammation and related peripheral neurochemical processes - like those activated by serotonin or substance P) are thought to be important factors in the initiation and maintenance of some types of headache, including migraine.

Essential references
Hucho T, Levine JD (2007). Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 55, 365-376.
Magloire H, Maurin JC, Couble ML, Shibukawa Y, Tsumura M, Thivichon-Prince B, Bleicher F (2010). Topical Review. Dental pain and odontoblasts: Facts and hypotheses. J. Orofac. Pain 24, 335-349.
Messlinger K. (2009). Migraine: where and how does the pain originate? Exp. Brain Res. 196,
179-193.
Sacerdote P, Levrini L. (2012). Peripheral mechanisms of dental pain: the role of Substance P. Mediators Inflamm. 2012, 951920..
Sessle BJ. (2011). Peripheral and central mechanisms of orofacial inflammatory pain. Int. Rev. Neurobiol. 97, 179-206.

Distributors
Download
Links
Contacts
 
HELSINN Last Update: 22.02.2013
Sitemap Privacy Policy Terms of Use