Nalini Vadivelu, Amarender Vadivelu and Alan David Kaye (eds.)Orofacial Pain2014A Clinician’s Guide10.1007/978-3-319-01875-1_4
© Springer International Publishing Switzerland 2014 2014
4. Nociceptive Chemical Mediators in Oral Inflammation
Nalini Vadivelu1 , Anusha Manje Gowda2, Stephen Thorp1, Alice Kai3 , Amarender Vadivelu4 and Susan Dabu-Bondoc1
Department of Anesthesiology, Yale University School of Medicine and Yale-New Haven Hospital, 333 Cedar Street, 208051, New Haven, CT 06520-8051, USA
Bangalore Medical college and research institute, Bangalore, 560003, Karnataka, India
Neuroplasticity Unit, National Institutes of Health, Bethesda, MD, USA
Annoor Dental College and Hospital, Muvattupuzha, Kerala, 686673, India
Pain is detected by nociceptors, which are unmyelinated nerve endings. Inflammatory processes result in the release of chemical mediators that are released at different levels in the pain pathways. This chapter discusses the pain pathways as well as the several nociceptive mediators that play a role in the inflammatory states in the mouth. The innervation of the orofacial region is also discussed.
Orofacial pain is commonly due to inflammation. It is extremely important to understand the chemical mediators of oral inflammation and the pathways of orofacial pain for its effective treatment. This chapter focuses on the pain pathways traversed by impulses causing orofacial pain and the many nociceptive chemical mediators that play a role in oral inflammation.
Nociceptors, the receptors for pain, are unmyelinated nerve endings that are located in bone, skin, muscle, and visceral tissues, the activation of which generates a Ca2+ current that depolarizes the distal axonal segment and initiates a self-propagating action potential and an inward current of Na+. The nociceptors of sensory afferent fibers are activated following tissue injury by the release of prostaglandins mainly the prostaglandin (PGE), which is synthesized by the enzyme cyclooxygenase-2 from the damaged cells, bradykinin from damaged vessels, and cellular mediators including hydrogen and potassium ions. Orthodromic transmission in sensitized afferents initiates the release of peptides like substance P (sP), calcitonin gene-related peptide (CGRP), and cholecystokinin (CCK) within and around the site of tissue damage. Substance P further enhances nociceptor excitability through the release of bradykinin, histamine from mast cells, and serotonin (5HT) from platelets. The above factors combine with other mediators such as cytokines and 5HT which results in the inflammatory response and recruits neighboring nociceptors, leading to primary hyperalgesia. Reflex sympathetic efferent responses cause further release of BK and sP which excite nociceptors by the release of noradrenaline, which also results in peripheral vasoconstriction and trophic changes .
Pathophysiology of Orofacial Pain
There are three types of primary peripheral afferents: Ab fibers, Ad fibers, and C fibers. Ab fibers are the quickest conducting fibers due to their myelinated quality. Ad fibers are slightly slower, comprising thinner myelinated axons. The slowest conducting fibers are the C fibers consisting of the thinnest and unmyelinated fibers .
Trigeminal nerve mostly innervates the orofacial region, and its primary afferent cell bodies are found within the trigeminal ganglion which consists mostly of Ad fibers and C fibers . The Ab fibers of the trigeminal region respond to pressure and light touch, while pain acts as a stimulus to the less conducting Ad fibers and C fibers, which are jointly termed nociceptors, the excitation of which causes considerable release of sP, which activates neurokinin-1 receptors and thereby modulates sensitivity to pain . These nociceptors can be further classified into mechano-nociceptors, thermo-nociceptors, and chemo-nociceptors. Thermo-nociceptors contain vanilloid receptor 1-like receptors that contribute to the pain due to extreme temperatures . Mechano-nociceptors, which are sensitive to mechanical stimuli, are located in the root pulp and are lined with epithelial Na+ channels that contribute to sharp pain produced by liquid motion in the dentinal tubules . Chemo-nociceptors are sensitive to chemicals.
The modulation of these nociceptors is either mechanical or chemical. Canine studies have shown that the threshold for mechano-nociception can increase sensitization because it may be lowered by periodontal inflammation . It is possible that this is due to the hydrodynamic mechanism (which activates the nociceptors by increasing pressure on the pulp ) of inflammation in the noncompliant environment in the dentine-encased pulp. In addition, there is substantial peripheral and central modulation due to the various neuropeptides released following tissue damage, and it is localized within the trigeminal ganglia. Peptides such as sP and calcitonin-related peptide are crucial in sensitizing the nociceptors: this leads to allodynia, the pain to innocuous stimuli, and hyperalgesia, increased sensitivity to painful stimuli .
The primary afferent neurons terminate in the trigeminal spinal tract nucleus in the brain stem. The trigeminal spinal tract nucleus is made up of three subnuclei: the subnucleus oralis, subnucleus interpolaris, and subnucleus caudalis. The subnucleus caudalis is structurally comparable to the spinal dorsal horn and hence often called the trigeminal dorsal horn . This subnucleus functions as the main brain stem relay and is a critical central structure for the modulation of nociception. The subnucleus oralis and subnucleus interpolaris both receive a versatile input from all three types of fibers, particularly from the quickly conducting Ab fibers. The central neurons found within these subnuclei are further subdivided into nociceptive specific neurons. This consists of either Ad fibers and C fibers that respond only to noxious stimuli or all the three fiber types that respond to both noxious and innocuous stimuli . Deep pain is attributed to the convergence of various types of receptors into a central nociceptive neuron. The intricacy of this convergence results in the misreading of the original sensation, leading to allodynia or hyperalgesia . In addition, various other studies have also found that the transition zone between the subnuclei caudalis and the subnuclei interpolaris also contributes to the central processing of deep orofacial nociception .
From the brain stem, the orofacial impulses are conducted through the thalamus to the cortex. In the thalamus, mainly the posterior nucleus, ventral posterior nucleus, and intralaminar nucleus, nociceptive specific neurons and wide dynamic range neurons are located. The ventral posterior nucleus is involved in localization of pain to a region, and the intralaminar nucleus is responsible for the affective and motivational dimension to pain and identification of stimuli as pain is caused by the posterior nucleus. In effect, the lateral thalamus projects to the somatosensory cerebral cortex to narrow down and identify the location of the pain, and the medial thalamus projects to neighboring areas such as the hypothalamus and the cingulated gyrus in order to associate the pain with their relevant emotions .
Transduction, Conduction, and Transmission of Nociceptors
The activity of nociceptors can be classified into that of transduction, conduction, and transmission. Transduction  is the response of peripheral nociceptors to noxious impulses caused by traumatic, mechanical, chemical, or thermal stimuli that are converted within the distal nociceptors into a depolarization current mediated by Ca2. Cellular damage and neurohormonal response to the injury in the skin, fascia, bone, muscle, and ligaments cause the release of intracellular H+ and K+ ions, in addition to arachidonic acid (AA) from cell membranes that have been lysed and other noxious mediators. The accumulated AA activates and up regulates the cyclooxygenase-2 enzyme isoform (COX-2), which leads to conversion of AA into biologically active metabolites like prostaglandin E2 (PGE2) and prostaglandin G2 (PGG2), followed by prostaglandin H2 (PGH2). These metabolites and the intracellular H+ and K+ ions cause the sensitization of peripheral nociceptors that initiates inflammatory responses leading to pain and an increase in the swelling of the tissue at the site of injury .
Other important primary and secondary noxious sensitizers that are released following tissue injury are 5-hydroxytryptamine (5-HT) , bradykinin (BK) , and histamine . The 5-HT released in response to thermal stimuli activates peripheral 5-HT2a receptors causing sensitization of primary afferent neurons leading to mechanical allodynia and thermal hyperalgesia . G-protein-coupled receptors  B1 and B2, which are located in the primary nociceptors, mediate bradykinin’s role in peripheral sensitization. The receptor–G-protein complex, when activated by BK and kallidin, leads to increase of nociceptor excitability by causing inward Na+ flux and reduced outward K+ currents. The resulting primary hyperalgesia is due to the increase in nociceptor irritability, increase in vascular permeability, initiation of neurogenic edema, and activation of adjacent nociceptor endings caused by these locally released substances. In addition, bradykinin, 5-HT, and other primary mediators excite orthodromic transmission in sensitized nerve endings and initiate the release of various peptides and neurokinins like CGRP , sP , and CCK  in and around the injury site.
Substance P enhances sensitization of peripheral nociceptors by inducing further release of histamine from mast cells, bradykinin, and 5-HT through a feedback loop mechanism. Calcitonin gene-related protein, a 37 amino acid peptide, is present in the central and peripheral terminals of greater than 35 % of Ad fibers and 50 % of C fibers . Similar to sP, CGRP  produced in the cell bodies of primary nociceptors found in the dorsal root ganglion initiates mechanical and thermal hyperalgesia. CGRP released at peripheral endings has several effects including the inhibition of its peripheral metabolic breakdown, which prolongs the effect of sP  and histamine-induced vasodilation and inflammatory extravasation.