Prolonged Jaw Opening Promotes Nociception and Enhanced Cytokine Expression

Aims: To test the hypothesis that prolonged jaw opening, as can occur during routine dental procedures, increases nociceptive sensitivity of the masseter muscle and increases cytokine expression. Methods: Sprague-Dawley rats were used to investigate behavioral and cellular changes in response to prolonged jaw opening. A surgical retractor was placed around the maxillary and mandibular incisors, and the jaw was held at near maximal opening for 20 minutes. Head-withdrawal responses to mechanical stimuli applied to the facial skin overlying the left and right masseter muscles were determined following jaw opening. Cytokine levels in the upper cervical spinal cord containing the caudal part of the spinal trigeminal nucleus were evaluated using protein antibody microarrays (n = 3). Statistical analysis was performed using a nonparametric Mann-Whitney U test. Results: Prolonged jaw opening significantly increased nocifensive head withdrawal to mechanical stimuli at 2 hours, and days 3 and 7 postinduction (P < .05). The increase in nociceptive response resolved after 14 days. Sustained jaw opening also stimulated differential cytokine expression in the trigeminal ganglion and upper cervical spinal cord that persisted 14 days postprocedure (P < .05). Conclusion: These findings provide evidence that near maximal jaw opening can lead to activation and prolonged sensitization of trigeminal neurons that results in nociceptive behavior evoked by stimulation of the masseter muscle, a physiologic event often associated with temporomandibular disorders (TMD). Results from this study may provide a plausible explanation for why some patients develop TMD after routine dental procedures that involve prolonged jaw opening.

central sensitization; nociception; spinal trigeminal nucleus; temporomandibular disorders; trigeminal ganglion

1. Tjakkes GH, Reinders JJ, Tenvergert EM, Stegenga B. TMD pain: The effect on health related quality of life and the influenceof pain duration. Health Qual Life Outcomes 2010;8:46.

2. Sessle BJ, Lavigne GJ, Lund JP, Dubner R. Orofacial Pain: From Basic Science to Clinical Management. The Transfer of Knowledge in Pain Research to Education. Chicago: Quintessence, 2008.

3. Greene CS, Lerman MD, Sutcher HD, Laskin DM. The TMJ pain-dysfunction syndrome: Heterogeneity of the patient population. J Am Dent Assoc 1969;79:1168–1172.

4. Hillier CD. Temporomandibular joint dysfunction: A dental overview. Can Fam Physician 1985;31:549–555.

5. Ohrbach R, Fillingim RB, Mulkey F, et al. Clinical findings and pain symptoms as potential risk factors for chronic TMD: Descriptive data and empirically identified domains from the OPPERA case-control study. J Pain 2011;12:T27–T45.

6. Bereiter DA, Okamoto K, Bereiter DF. Effect of persistent monoarthritis of the temporomandibular joint region on acute mustard oil-induced excitation of trigeminal subnucleus caudalis neurons in male and female rats. Pain 2005;117:58–67.

7. Shimizu K, Guo W, Wang H, et al. Differential involvement of trigeminal transition zone and laminated subnucleus caudalisin orofacial deep and cutaneous hyperalgesia: The effects of interleukin-10 and glial inhibitors. Mol Pain 2009;5:75.

8. Sessle BJ. Peripheral and central mechanisms of orofacial inflammatory pain. Int Rev Neurobiol 2011;97:179–206.

9. Shankland WE 2nd. The trigeminal nerve. Part IV: The mandibular division. Cranio 2001;19:153–161.

10. Vause CV, Durham PL. CGRP stimulation of iNOS and NO release from trigeminal ganglion glial cells involves mitogen-activated protein kinase pathways. J Neurochem 2009; 110:811–821.

11. Durham PL, Garrett FG. Emerging importance of neuron-satellite glia interactions within trigeminal ganglia in craniofacial pain. Open Pain J 2010;3:3–13.

12. Ambalavanar R, Dessem D, Moutanni A, et al. Muscle inflammation induces a rapid increase in calcitonin gene-related peptide (CGRP) mRNA that temporally relates to CGRP immunoreactivity and nociceptive behavior. Neuroscience 2006; 143:875–884.

13. Cady RJ, Glenn JR, Smith KM, Durham PL. Calcitonin gene-related peptide promotes cellular changes in trigeminal neurons and glia implicated in peripheral and central sensitization. Mol Pain 2011;7:94.

14. Ren K, Dubner R. Neuron-glia crosstalk gets serious: Role in pain hypersensitivity. Curr Opin Anaesthesiol 2008;21:570–579.

15. Seybold VS. The role of peptides in central sensitization. Handb Exp Pharmacol 2009;451–491.

16. Garrett FG, Hawkins JL, Overmyer AE, Hayden JB, Durham PL. Validation of a novel rat-holding device for studying heat- and mechanical-evoked trigeminal nocifensive behavioral responses. J Orofac Pain 2012;26:337–344.

17. Noma N, Tsuboi Y, Kondo M, et al. Organization of pERK-immunoreactive cells in trigeminal spinal nucleus caudalis and upper cervical cord following capsaicin injection into oral and craniofacial regions in rats. J Comp Neurol 2008;507:1428–1440.

18. Lam DK, Sessle BJ, Cairns BE, Hu JW. Peripheral NMDA receptor modulation of jaw muscle electromyographic activity induced by capsaicin injection into the temporomandibular joint of rats. Brain Res 2005;1046:68–76.

19. Bellinger LL, Spears R, King CM, et al. Capsaicin sensitive neurons role in the inflamed TMJ acute nociceptive response of female and male rats. Physiol Behav 2007;90:782–789.

20. Imbe H, Iwata K, Zhou QQ, Zou S, Dubner R, Ren K. Orofacial deep and cutaneous tissue inflammation and trigeminal neuronal activation. Implications for persistent temporomandibular pain. Cells Tissues Organs 2001;169:238–247.

21. Iwata K, Tashiro A, Tsuboi Y, et al. Medullary dorsal horn neuronal activity in rats with persistent temporomandibular joint and perioral inflammation. J Neurophysiol 1999;82:1244–1253.

22. Watanabe M, Guo W, Zou S, Sugiyo S, Dubner R, Ren K. Antibody array analysis of peripheral and blood cytokine levels in rats after masseter inflammation. Neurosci Lett 2005; 382:128–133.

23. Guo W, Wang H, Watanabe M, et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 2007;27:6006–6018.

24. Greenspan JD, Slade GD, Bair E, et al. Pain sensitivity risk factors for chronic TMD: Descriptive data and empirically identified domains from the OPPERA case control study. J Pain 2011; 12:T61–T74.

25. Uçeyler N, Schäfers M, Sommer C. Mode of action of cytokines on nociceptive neurons. Exp Brain Res 2009;196:67–78.

26. Gao YJ, Ji RR. Targeting astrocyte signaling for chronic pain. Neurotherapeutics 2010;7:482–493.

27. Gosselin RD, Suter MR, Ji RR, Decosterd I. Glial cells and chronic pain. Neuroscientist 2010;16:519–531.

28. Watkins LR, Maier SF. Beyond neurons: Evidence that immune and glial cells contribute to pathological pain states. PhysiolRev 2002;82:981–1011.

29. Taylor BK, Corder G. Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci 2014;20: 283–325.

30. Hucho T, Levine JD. Signaling pathways in sensitization: Toward a nociceptor cell biology. Neuron 2007;55:365–376.

31. Reichling DB, Levine JD. Critical role of nociceptor plasticity in chronic pain. Trends Neurosci 2009;32:611–618.

32. Le Roy C, Laboureyras E, Gavello-Baudy S, Chateauraynaud J, Laulin JP, Simonnet G. Endogenous opioids released during non-nociceptive environmental stress induce latent pain sensitization Via a NMDA-dependent process. J Pain 2011;12: 1069–1079.

33. Asiedu MN, Tillu DV, Melemedjian OK, et al. Spinal protein kinase M zeta underlies the maintenance mechanism of persistent nociceptive sensitization. J Neurosci 2011;31:6646–6653.

34. Melemedjian OK, Tillu DV, Asiedu MN, et al. BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state. Mol Pain 2013;9:12.

35. Melemedjian OK, Tillu DV, Moy JK, et al. Local translation and retrograde axonal transport of CREB regulates IL-6-induced nociceptive plasticity. Mol Pain 2014;10:45.