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Orofacial Pain in Cancer: Part I—Mechanisms
R. Benoliel1,*,
J. Epstein2,
E. Eliav3,
R. Jurevic2 and
S. Elad1
1 Department of Oral Medicine, The Hebrew University, Hadassah Faculty of Dental Medicine, PO Box 12272, Jerusalem 91120, Israel;
2 Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois-Chicago, USA;
3 Universities of Medicine and Dentistry of New Jersey, New Jersey Dental School, 110 Bergen Street, Newark, NJ 07103, USA
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Figure 1. Schematic (simplified) representation of pathways involved in trigeminal nociception. Peripheral nociceptors (1) in muscle, tooth, bone, or soft tissue may be activated by numerous potentially damaging stimuli. The cell bodies of these primary afferent nociceptors reside in the trigeminal ganglion (2). The central projections of these nociceptors synapse in trigeminal nucleus caudalis (3, medullary dorsal horn) on second-order neurons. (See also detail of this area in enlarged box.) The second-order neurons (4) may receive primary afferents from several peripheral sites (5, convergence), accounting for the referral patterns observed in orofacial pain. Primary afferents in the medullary dorsal horn are subject to modulation from higher centers that adjust the central release of neurotransmitters, termed ‘pre-synaptic modulation’ (6). Dorsal horn neurons also synapse with descending modulatory pathways (inhibitory and facilitatory) from higher central nervous system (CNS) centers (6) that adjust the cell’s reaction to peripheral stimuli (post-synaptic modulation). Both the central terminals of primary afferents and second-order neurons are also modulated by local interneurons and synaptic contacts from other primary afferents (mechanosensitive). The modulated message is then transmitted, ultimately reaching the sensory cortex (7). CNS structures involved in pain modulation include the cortex (8), the amygdala (9), the thalamus (10), the hypothalamus (11), and the peri-aqueductal gray (12). Regional tumors (13, primary or metastatic) induce numerous changes involving inflammatory reaction, and damage to major nerve branches (14) and to adjacent tissues such as muscle (15) (Fig. 2 ). Based on Benoliel et al.(2003).
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Figure 2. Pain from regional tumors (1) may be induced via numerous mechanisms. Tumors secrete various agents, such as prostaglandins, cytokines, RANK ligand, and growth factors active in nociception and bone metabolism (see text). The initial response to tumors involves inflammation with recruitment of inflammatory cells (2) that also release prostaglandins and cytokines. Additionally, inflammation and tissue damage are associated with reduced pH, which acts synergistically with inflammatory mediators. Activation of osteoclasts (3) results in bone destruction (also associated with a low pH). Secretion of RANK-ligand by tumor sequesters osteoblast-derived osteoprotegerin, thus removing an important mechanism that modulates osteoclast activation (see text). The tumor may invade deeply and ultimately involve major nerve branches (4). In the case of the mandible, as shown, involvement of the inferior alveolar nerve (4) may induce neuropathic pain or, more commonly, numbness in the distal innervation (5), in this case the lip and chin (‘numb chin’ syndrome). Tumor invasion of adjacent structures, such as the temporomandibular joint or masticatory muscles (6), may cause further pain and dysfunction. Key: IL = interleukin, PG = prostaglandin, ET-1 = endothelin-1, RANK = receptor activator for nuclear factor- B, COX-2 = cyclo-oxygenase 2, TNF- = tumor necrosis factor-.
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Journal of Dental Research, Vol. 86, No. 6,
491-505 (2007)
DOI: 10.1177/154405910708600604
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