Abstract
This chapter focuses on the potential role of biomarkers for masticatory muscle pain, i.e., myalgia. To date, no biomarkers have been identified that can be used clinically for diagnosis or treatment of myalgia of jaw muscles. There is evidence from microdialysis studies that intramuscular levels of glutamate and serotonin are elevated in patients with chronic myalgia, including myalgia of jaw muscles. High muscle levels of glutamate and serotonin correlate to pain intensity and mechanical allodynia, and both glutamate and serotonin have been shown to induce pain and mechanical hyperalgesia when injected into jaw muscles. This pain, consequently, can be blocked with specific receptor antagonists, indicating that glutamate and serotonin may be promising biomarker candidates. However, muscle levels of glutamate and serotonin do not correlate to plasma levels, which is a disadvantage since measuring intramuscular biomarker levels with currently available techniques is too complicated to be clinically useful. Nerve growth factor (NGF) has also been shown to cause long-lasting hyperalgesia, albeit with no pain, when injected into jaw muscles, but muscle biopsies did not show any differences in NGF levels between patients with jaw myalgia and pain-free controls. Additionally, muscle levels of prostaglandins, bradykinin, or substance P, commonly characterized pain mediators, do not seem to be elevated in myalgic jaw muscles. Because pain mediation and peripheral sensitization are complex events that involve many substances, future research should focus on investigating intramuscular profiles of multiple biomarkers. This, in turn, is possible with newly developed methods, such as proteomics and metabolomics.
The author declares no conflict of interest.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for clinical and research applications: recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache. 2014;28:6–27.
Mense S. Muscle pain: mechanisms and clinical significance. Dtsch Arztebl Int. 2008;105(12):214–9.
Kamper SJ, Maher CG, Hush JM, Pedler A, Sterling M. Relationship between pressure pain thresholds and pain ratings in patients with whiplash-associated disorders. Clin J Pain. 2011;27(6):495–501.
Atkinson AJJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, et al. Biomarkers Definition Working Group-Bethesda. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.
Huang W, Sowa G. Biomarker development for musculoskeletal diseases. PM R J Injury Function Rehabil. 2011;3(6 Suppl 1):S39–44.
Larsson B, Bjork J, Henriksson KG, Gerdle B, Lindman R. The prevalences of cytochrome C oxidase-negative and superpositive fibres and ragged-red fibres in the trapezius muscle of female cleaners with and without myalgia and of female healthy controls. Pain. 2000;84:379–87.
McMahon SB, Bennet DLH, Bevan S. Inflammatory mediators and modulators of pain. In: Koltzenburg M, McMahon SB, editors. Wall and Melzack’s textbook of pain. 5th ed. Philadelphia: Elsevier/Churchill Livingstone; 2005. p. 49–72.
Miller KE, Hoffman EM, Sutharshan M, Schechter R. Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. Pharmacol Ther. 2011;130(3):283–309.
Ernberg M. Serotonin receptors. In: Cairns BE, editor. Peripheral receptor targets for analgesia. Hoboken: John Wiley & Sons, Inc; 2009. p. 243–74.
McKelvey L, Shorten GD, O'Keeffe GW. Nerve growth factor-mediated regulation of pain signaling and proposed new intervention strategies in clinical pain management. J Neurochem. 2013;124(3):276–89.
Boix F, Roe C, Rosenborg L, Knardahl S. Kinin peptides in human trapezius muscle during sustained isometric contraction and their relation to pain. J Appl Physiol (1985). 2005;98(2):534–40.
Trevisani M, Szallasi A. Vanilloid (TRPV1) and other transient receptor potential channels. In: Cairns BE, editor. Peripheral receptor targets for analgesia: novel approaches to pain management. Hoboken: John Wiley & Sons, Inc.; 2009. p. 175–213.
Hoyer D, Bartfai T. Neuropeptides and neuropeptide receptors: drug targets, and peptide and non-peptide ligands: a tribute to Prof. Dieter Seebach Chem Biodiversity. 2012;9(11):2367–87.
Alstergren P. Cytokines (tumor necrosis factor, interleukins) and prostaglandins. In: Cairns BE, editor. Peripheral receptor targets for analgesia. Hoboken: John Wiley & Sons, Inc.; 2009. p. 419–54.
Tegeder L, Zimmermann J, Meller ST, Geisslinger G. Release of algesic substances in human experimental muscle pain. Inflammation Res Off J Eur Histamine Res Soc [et al.]. 2002;51(8):393–402.
Graven-Nielsen T. Fundamentals of muscle pain, referred pain, and deep tissue hyperalgesia. Scand J Rheumatol Suppl. 2006;122:1–43.
Rosendal L, Blangsted AK, Kristiansen J, Sogaard K, Langberg H, Sjogaard G, et al. Interstitial muscle lactate, pyruvate and potassium dynamics in the trapezius muscle during repetitive low-force arm movements, measured with microdialysis. Acta Physiol Scand. 2004;182(4):379–88.
Svensson P, Cairns BE, Wang K, Hu JW, Graven-Nielsen T, Arendt-Nielsen L, et al. Glutamate-evoked pain and mechanical allodynia in the human masseter muscle. Pain. 2003;101(3):221–7.
Cairns BE, Hu JW, Arendt-Nielsen L, Sessle BJ, Svensson P. Sex-related differences in human pain and rat afferent discharge evoked by injection of glutamate into the masseter muscle. J Neurophysiol. 2001;86(2):782–91.
Castrillon EE, Cairns BE, Wang K, Arendt-Nielsen L, Svensson P. Comparison of glutamate-evoked pain between the temporalis and masseter muscles in men and women. Pain. 2012;153(4):823–9.
Castroflorio T, Falla D, Wang K, Svensson P, Farina D. Effect of experimental jaw-muscle pain on the spatial distribution of surface EMG activity of the human masseter muscle during tooth clenching. J Oral Rehabil. 2012;39(2):81–92.
Castrillon EE, Cairns BE, Ernberg M, Wang K, Sessle B, Arendt-Nielsen L, et al. Glutamate-evoked jaw muscle pain as a model of persistent myofascial TMD pain? Arch Oral Biol. 2008;53(7):666–76.
Svensson P, Wang K, Arendt-Nielsen L, Cairns BE, Sessle BJ. Pain effects of glutamate injections into human jaw or neck muscles. J Orofac Pain. 2005;19(2):109–18.
Wang C, Ge HY, Ibarra JM, Yue SW, Madeleine P, Arendt-Nielsen L. Spatial pain propagation over time following painful glutamate activation of latent myofascial trigger points in humans. J Pain. 2012;13(6):537–45.
Svensson P, Wang K, Arendt-Nielsen L, Cairns BE. Effects of NGF-induced muscle sensitization on proprioception and nociception. Exp Brain Res. 2008;189(1):1–10.
Wang K, Svensson P, Sessle BJ, Cairns BE, Arendt-Nielsen L. Interactions of glutamate and capsaicin-evoked muscle pain on jaw motor functions of men. Clin Neurophysiol. 2010;121(6):950–6.
Arendt-Nielsen L, Svensson P, Sessle BJ, Cairns BE, Wang K. Interactions between glutamate and capsaicin in inducing muscle pain and sensitization in humans. Eur J Pain. 2008;12(5):661–70.
Cairns BE, Svensson P, Wang K, Castrillon E, Hupfeld S, Sessle BJ, et al. Ketamine attenuates glutamate-induced mechanical sensitization of the masseter muscle in human males. Exp Brain Res. 2006;169(4):467–72.
Castrillon EE, Cairns BE, Ernberg M, Wang K, Sessle BJ, Arendt-Nielsen L, et al. Effect of peripheral NMDA receptor blockade with ketamine on chronic myofascial pain in temporomandibular disorder patients: a randomized, double-blinded, placebo-controlled trial. J Orofac Pain. 2008;22(2):122–30.
Ernberg M, Lundeberg T, Kopp S. Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain. 2000;85(1–2):31–9.
Babenko V, Graven-Nielsen T, Svensson P, Drewes AM, Jensen TS, Arendt-Nielsen L. Experimental human muscle pain induced by intramuscular injections of bradykinin, serotonin, and substance P. Eur J Pain. 1999;3(2):93–102.
Babenko V, Svensson P, Graven-Nielsen T, Drewes AM, Jensen TS, Arendt-Nielsen L. Duration and distribution of experimental muscle hyperalgesia in humans following combined infusions of serotonin and bradykinin. Brain Res. 2000;853(2):275–81.
Jensen K, Tuxen C, Pedersen-Bjergaard U, Jansen I, Edvinsson L, Olesen J. Pain and tenderness in human temporal muscle induced by bradykinin and 5-hydroxytryptamine. Peptides. 1990;11:1127–32.
Ernberg M, Lundeberg T, Kopp S. Effect of propranolol and granisetron on experimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonin into the human masseter muscle. Pain. 2000;84(2–3):339–46.
Christidis N, Ioannidou K, Milosevic M, Segerdahl M, Ernberg M. Changes of hypertonic saline-induced masseter muscle pain characteristics, by an infusion of the serotonin receptor type 3 antagonist granisetron. J Pain. 2008;9(10):892–901.
Louca S, Ernberg M, Christidis N. Influence of intramuscular granisetron on experimentally induced muscle pain by acidic saline. J Oral Rehabil. 2013;40(6):403–12.
Christidis N, Nilsson A, Kopp S, Ernberg M. Intramuscular injection of granisetron into the masseter muscle increases the pressure pain threshold in healthy participants and patients with localized myalgia. Clin J Pain. 2007;23(6):467–72.
Christidis N, Kopp S, Ernberg M. The effect on mechanical pain threshold over human muscles by oral administration of granisetron and diclofenac-sodium. Pain. 2005;113(3):265–70.
Muller W, Stratz T. Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron. Scand J Rheumatol Suppl. 2004;119:44–8.
Farber L, Stratz TH, Bruckle W, Spath M, Pongratz D, Lautenschlager J, et al. Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients. Int J Clin Pharmacol Res. 2001;21(1):1–13.
Svensson P, Cairns BE, Wang K, Arendt-Nielsen L. Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain. 2003;104(1–2):241–7.
Svensson P, Castrillon E, Cairns BE. Nerve growth factor-evoked masseter muscle sensitization and perturbation of jaw motor function in healthy women. J Orofac Pain. 2008;22(4):340–8.
Andersen H, Arendt-Nielsen L, Svensson P, Danneskiold-Samsoe B, Graven-Nielsen T. Spatial and temporal aspects of muscle hyperalgesia induced by nerve growth factor in humans. Exp Brain Res. 2008;191(3):371–82.
Arima T, Svensson P, Arendt-Nielsen L. Capsaicin-induced muscle hyperalgesia in the exercised and non-exercised human masseter muscle. J Orofac Pain. 2000;14(3):213–23.
Sohn MK, Graven-Nielsen T, Arendt-Nielsen L, Svensson P. Inhibition of motor unit firing during experimental muscle pain in humans. Muscle Nerve. 2000;23(8):1219–26.
Wang K, Arendt-Nielsen L, Svensson P. Capsaicin-induced muscle pain alters the excitability of the human jaw-stretch reflex. J Dent Res. 2002;81(9):650–4.
Arima T, Arendt-Nielsen L, Minagi S, Svensson P. Effect of capsaicin-evoked jaw-muscle pain on intramuscular blood-flow. Arch Oral Biol. 2009;54(3):241–9.
Pedersen-Bjergaard U, Nielsen LB, Jensen K, Edvinsson L, Jansen I, Olesen J. Algesia and local responses induced by neurokinin A and substance P in human skin and temporal muscle. Peptides. 1989;10(6):1147–52.
Jensen K, Norup M. Experimental pain in human temporal muscle induced by hypertonic saline, potassium and acidity. Cephalalgia. 1992;12:101–6.
Mork H, Ashina M, Bendtsen L, Olesen J, Jensen R. Induction of prolonged tenderness in patients with tension-type headache by means of a new experimental model of myofascial pain. Eur J Neurol. 2003;10(3):249–56.
McGregor NR, Zerbes M, Niblett SH, Dunstan RH, Roberts TK, Butt HL, et al. Pain intensity, illness duration, and protein catabolism in temporomandibular disorder patients with chronic muscle pain. J Orofac Pain. 2003;17(2):112–24.
Dawson A, Ghafouri B, Gerdle B, List T, Svensson P, Ernberg M. Effects of experimental tooth clenching on pain and intramuscular release of 5-HT and glutamate in patients with myofascial TMD. Clin J Pain. 2015;31:9–740.
Castrillon EE, Ernberg M, Cairns BE, Wang K, Sessle BJ, Arendt-Nielsen L, et al. Interstitial glutamate concentration is elevated in the masseter muscle of myofascial temporomandibular disorder patients. J Orofac Pain. 2010;24(4):350–60.
Rosendal L, Larsson B, Kristiansen J, Peolsson M, Sogaard K, Kjaer M, et al. Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: microdialysis in rest and during exercise. Pain. 2004;112(3):324–34.
Gerdle B, Larsson B, Forsberg F, Ghafouri N, Karlsson L, Stensson N, et al. Chronic widespread pain: increased glutamate and lactate concentrations in the trapezius muscle and plasma. Clin J Pain. 2014;30(5):409–20.
Larsson B, Rosendal L, Kristiansen J, Sjogaard G, Sogaard K, Ghafouri B, et al. Responses of algesic and metabolic substances to 8 h of repetitive manual work in myalgic human trapezius muscle. Pain. 2008;140(3):479–90.
Flodgren GM, Crenshaw AG, Alfredson H, Fahlstrom M, Hellstrom FB, Bronemo L, et al. Glutamate and prostaglandin E2 in the trapezius muscle of female subjects with chronic muscle pain and controls determined by microdialysis. Eur J Pain. 2005;9(5):511–5.
Gerdle B, Lemming D, Kristiansen J, Larsson B, Peolsson M, Rosendal L. Biochemical alterations in the trapezius muscle of patients with chronic whiplash associated disorders (WAD)--a microdialysis study. Eur J Pain. 2008;12(1):82–93.
Gerdle B, Soderberg K, Salvador Puigvert L, Rosendal L, Larsson B. Increased interstitial concentrations of pyruvate and lactate in the trapezius muscle of patients with fibromyalgia: a microdialysis study. J Rehabil Med. 2010;42(7):679–87.
Ashina M, Stallknecht B, Bendtsen L, Pedersen JF, Schifter S, Galbo H, et al. Tender points are not sites of ongoing inflammation -in vivo evidence in patients with chronic tension-type headache. Cephalalgia. 2003;23(2):109–16.
Ernberg M, Hedenberg-Magnusson B, Alstergren P, Lundeberg T, Kopp S. Pain, allodynia, and serum serotonin level in orofacial pain of muscular origin. J Orofac Pain. 1999;13(1):56–62.
Ernberg M, Hedenberg-Magnusson B, Alstergren P, Kopp S. The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia. Life Sci. 1999;65(3):313–25.
Ghafouri B, Larsson BK, Sjors A, Leandersson P, Gerdle BU. Interstitial concentration of serotonin is increased in myalgic human trapezius muscle during rest, repetitive work and mental stress – an in vivo microdialysis study. Scand J Clin Lab Invest. 2010;70(7):478–86.
Shah JP, Phillips TM, Danoff JV, Gerber LH. An in vivo microanalytical technique for measuring the local biochemical milieu of human skeletal muscle. J Appl Physiol. 2005;99(5):1977–84.
Christidis N, Cairns BE, Kumar U, Dong X, Rosén A, Kopp S, Ernberg M. Expression of 5-HT3 receptors and TTX insensitive sodium channels (NaV1.8) by masseter muscle nerve fibers in healthy subjects compared to patients with local myalgia. J Headache Pain. 2014;15(1):63.
Hedenberg-Magnusson B, Ernberg M, Alstergren P, Kopp S. Pain mediation by prostaglandin E2 and leukotriene B4 in the human masseter muscle. Acta Odontol Scand. 2001;59(6):348–55.
Basi DL, Velly AM, Schiffman EL, Lenton PA, Besspiata DA, Rankin AM, et al. Human temporomandibular joint and myofascial pain biochemical profiles: a case-control study. J Oral Rehabil. 2012;39(5):326–37.
Sjogaard G, Rosendal L, Kristiansen J, Blangsted AK, Skotte J, Larsson B, et al. Muscle oxygenation and glycolysis in females with trapezius myalgia during stress and repetitive work using microdialysis and NIRS. Eur J Appl Physiol. 2010;108(4):657–69.
Shah JP, Danoff JV, Desai MJ, Parikh S, Nakamura LY, Phillips TM, et al. Biochemicals associated with pain and inflammation are elevated in sites near to and remote from active myofascial trigger points. Arch Phys Med Rehabil. 2008;89(1):16–23.
Rosendal L, Kristiansen J, Gerdle B, Sogaard K, Peolsson M, Kjaer M, et al. Increased levels of interstitial potassium but normal levels of muscle IL-6 and LDH in patients with trapezius myalgia. Pain. 2005;119(1–3):201–9.
Slade GD, Conrad MS, Diatchenko L, Rashid NU, Zhong S, Smith S, et al. Cytokine biomarkers and chronic pain: Association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness. Pain. 2011;152(12):2802–12.
Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E. Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol. 2012;242(1–2):33–8.
Linnman C, Appel L, Fredrikson M, Gordh T, Soderlund A, Langstrom B, et al. Elevated [11C]-D-deprenyl uptake in chronic Whiplash Associated Disorder suggests persistent musculoskeletal inflammation. PLoS One. 2011;6(4):e19182.
Hedenberg-Magnusson B, Brodda Jansen G, Ernberg M, Kopp S. Effects of isometric contraction on intramuscular level of neuropeptide Y and local pain perception. Acta Odontol Scand. 2006;64(6):360–7.
McIver KL, Evans C, Kraus RM, Ispas L, Sciotti VM, Hickner RC. NO-mediated alterations in skeletal muscle nutritive blood flow and lactate metabolism in fibromyalgia. Pain. 2006;120(1–2):161–9.
Louca S, Christidis N, Ghafouri B, Gerdle B, Svensson P, List T, Ernberg M. Serotonin, glutamate and glycerol are released after the injection of hypertonic saline into the human masseter muscles – a microdialysis study. J Headache Pain. 2014;15(1):89.
Sluka KA, Rohlwing JJ, Bussey RA, Eikenberry SA, Wilken JM. Chronic muscle pain induced by repeated acid Injection is reversed by spinally administered mu- and delta-, but not kappa-, opioid receptor agonists. J Pharmacol Exp Ther. 2002;302(3):1146–50.
Walder RY, Benson CJ, Sluka KA. Acid-sensing ion channels and pain. In: Cairns BE, editor. Peripheral receptor targets for analgesia. Hoboken: John Wiley & Sons, Inc.; 2009. p. 153–74.
Castrillon EE, Cairns B, List T, Svensson P, Ernberg M. Acidic saline-induced pain as a model for experimental masseter myalgia in healthy subjects. Eur J Pain. 2013;17(10):1438–46.
Ernberg M, Castrillon EE, Ghafouri B, Larsson B, Gerdle B, List T, et al. Experimental myalgia induced by repeated infusion of acidic saline into the human masseter muscle does not cause the release of algesic substances. Eur J Pain. 2013;17(4):539–50.
Ashina M, Jorgensen M, Stallknecht B, Mork H, Bendtsen L, Pedersen JF, et al. No release of interstitial glutamate in experimental human model of muscle pain. Eur J Pain. 2005;9(3):337–43.
Additional Reading
Christidis N, Omrani S, Fredriksson L, Gjelset M, Louca S, Hedenberg-Magnusson B, Ernberg M. Repeated tender point injections of granisetron alleviate chronic myofascial pain – a randomized, controlled, double-blinded trial. J Headache Pain 2015;16(1):104.
Christidis N, Cairns BE, Kumar U, Dong X, Rosén A, Kopp S, Ernberg M. Expression of 5-HT3 receptors and TTX insensitive sodium channels (NaV1.8) by masseter muscle nerve fibers in healthy subjects compared to patients with local myalgia. J Headache Pain. 2014;15(1):63.
Gerdle B, Ghafouri B, Ernberg M, Larsson B. Chronic musculoskeletal pain: review of mechanisms and biochemical biomarkers as assessed by the microdialysis technique. J Pain Res. 2014;7:313–26.
Shimada A, Castrillon E, Baad-Hansen L, Ghafouri B, Gerdle B, Wåhlén K, Ernberg M, Cairns B, Svensson P. Increased pain and muscle glutamate concentration after single ingestion of monosodium glutamate by myofascial temporomandibular disorders patients. Eur J Pain. 2016;20:1502–12.
Simonic-Kocijan S, Zhao X, Liu W, Wu Y, Uhac I, Wang K. TRPV1 channel-mediated bilateral allodynia induced by unilateral masseter muscle inflammation in rats. Mol Pain 2013;9:68. doi: 10.1186/1744-8069-9-68.
Wong H, Kang I, Dong XD, Christidis N, Ernberg M, Svensson P, Cairns BE. NGF-induced mechanical sensitization of the masseter muscle is mediated through peripheral NMDA receptors. Neuroscience. 2014;269:232–44.
Xu XX, Cao Y, Ding TT, Fu KY, Li Y, Xie QF. Role of TRPV1 and ASIC3 channels in experimental occlusal interference-induced hyperalgesia in rat masseter muscle. Eur J Pain. 2016;20(4):552–63.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer-Verlag GmbH Germany
About this chapter
Cite this chapter
Ernberg, M. (2017). Masticatory Muscle Pain Biomarkers. In: Goulet, JP., Velly, A. (eds) Orofacial Pain Biomarkers. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-53994-1_6
Download citation
DOI: https://doi.org/10.1007/978-3-662-53994-1_6
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-53992-7
Online ISBN: 978-3-662-53994-1
eBook Packages: MedicineMedicine (R0)