Glutamate-induced Temporomandibular Joint Pain in Healthy Individuals Is Partially Mediated by Peripheral NMDA Receptors

Aim: To determine if glutamate injected into the healthy temporomandibular joint (TMJ) evokes pain through peripheral N-methyl-D-aspartate (NMDA) receptors and if such pain is influenced by sex or sex steroid hormones. Methods: Sixteen healthy men and 36 healthy women were included and subjected to two randomized and double-blind intra-articular injections of the TMJ. Experimental TMJ pain was induced by injection of glutamate(1.0 mol/L) and NMDA block was achieved by co-injection of the NMDA antagonist ketamine (10 mmol/L). The TMJ pain intensity in the joint before and during a 25-minute postinjection period was continuously recorded on an electronic visual analog scale(0 to 10). Estradiol, progesterone, and testosterone levels in serum were analyzed. Results: Glutamate-induced pain showed a median (25/75 percentile) duration of 8.3 (5.2/12.2) minutes. The peak pain intensity was 6.1 (4.2/8.2), the time to peak was 50 (30/95) seconds, and the area under the curve was 59 (29/115) arbitrary units. The women reported higher maximum pain intensity than the men and shorter time to peak. The sex hormone levels were not significantly related to the glutamate-induced TMJ pain. NMDA block significantly reduced the glutamate-induced TMJ pain, mainly in the women. There were no significant correlations between sex hormone levels and the effects of NMDA block for any pain variable. Conclusion: Glutamate evokes immediate pain in the healthy human TMJ that is partly mediated by peripheral NMDA receptors in the TMJ.

glutamate;NMDA;pain;sex hormones;temporomandibular joint

1. Cairns BE, Svensson P, Wang K, et al. Ketamine attenu-ates glutamate-induced mechanical sensitization of the masseter muscle in human males. Exp Brain Res 2006;169:467–472.

2. Lawand NB, Willis WD, Westlund KN. Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 1997;324:169–177.

3. Alfredson H, Thorsen K, Lorentzon R. In situ microdialysis in tendon tissue: High levels of glutamate, but not prostaglandin E2 in chronic Achilles tendon pain. Knee Surg Sports Traumatol Arthrosc 1999;7:378–381.

4. Alfredson H, Forsgren S, Thorsen K, Lorentzon R. In vivo microdialysis and immunohistochemical analyses of tendon tissue demonstrated high amounts of free glutamate and glutamate NMDAR1 receptors, but no signs of inflammation, in Jumper’s knee. J Orthop Res 2001;19: 881–886.

5. Castrillon EE, Cairns BE, Ernberg M, et al. Glutamate-evoked jaw muscle pain as a model of persistent myofascial TMD pain? Arch Oral Biol 2008;53:666 –676.

6. McNearney T, Baethge BA, Cao S, Alam R, Lisse JR, Westlund KN. Excitatory amino acids, TNF-alpha, and chemokine levels in synovial fluids of patients with active arthropathies. Clin Exp Immunol 2004;137:621–627.

7. Parpura V, Liu F, Jeftinija KV, Haydon PG, Jeftinija SD. Neuroligand-evoked calcium-dependent release of excitatory amino acids from Schwann cells. J Neurosci 1995; 15:5831–5839.

8. Omote K, Kawamata T, Kawamata M, Namiki A. Formalin-induced release of excitatory amino acids in the skin of the rat hindpaw. Brain Res 1998;787:161–164.

9. Dong XD, Mann MK, Kumar U, et al. Sex-related differ-ences in NMDA-evoked rat masseter muscle afferent discharge result from estrogen-mediated modulation of peripheral NMDA receptor activity. Neuroscience 2007; 146:822–832.

10. Cairns BE, Sessle BJ, Hu JW. Evidence that excitatory amino acid receptors within the temporomandibular joint region are involved in the reflex activation of the jaw mus-cles. J Neurosci 1998;18:8056–8064.

11. Carlton SM. Peripheral excitatory amino acids. Curr Opin Pharmacol 2001;1:52–56.

12. deGroot J, Zhou S, Carlton SM. Peripheral glutamate release in the hindpaw following low and high intensity sciatic stimulation. Neuroreport 2000;11:497–502.

13. Lam DK, Sessle BJ, Cairns BE, Hu JW. Neural mechanisms of temporomandibular joint and masticatory muscle pain: A possible role for peripheral glutamate receptor mechanisms. Pain Res Manag 2005;10:145–152.

14. Cairns BE, Sessle BJ, Hu JW. Characteristics of glutamate-evoked temporomandibular joint afferent activity in the rat. J Neurophysiol 2001;85:2446–2454.

15. Cairns BE, Sessle BJ, Hu JW. Temporomandibular-evoked jaw muscle reflex: Role of brain stem NMDA and non-NMDA receptors. Neuroreport 2001;12:1875–1878.

16. Lam DK, Sessle BJ, Hu JW. Glutamate and capsaicin effects on trigeminal nociception I: Activation and peripheral sensitization of deep craniofacial nociceptive affer-ents. Brain Res 2009;1251:130–139.

17. Cairns BE, Svensson P, Wang K, et al. Activation of peripheral NMDA receptors contributes to human pain and rat afferent discharges evoked by injection of glutamate into the masseter muscle. J Neurophysiol 2003;90: 2098–2105.

18. Dong XD, Mann MK, Sessle BJ, Arendt-Nielsen L, Svensson P, Cairns BE. Sensitivity of rat temporalis muscle afferent fibers to peripheral N-methyl-D-aspartate recep-tor activation. Neuroscience 2006;141:939–945.

19. Svensson P, Cairns BE, Wang K, et al. Glutamate-evoked pain and mechanical allodynia in the human masseter muscle. Pain 2003;101:221–227.

20. 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;19:109 –118.

21. Wang K, Sessle BJ, Svensson P, Arendt-Nielsen L. Glutamate evoked neck and jaw muscle pain facilitate the human jaw stretch reflex. Clin Neurophysiol 2004;115: 1288–1295.

22. Castrillon EE, Cairns BE, Ernberg M, et al. Effect of a peripheral NMDA receptor antagonist on glutamate-evoked masseter muscle pain and mechanical sensitization in women. J Orofac Pain 2007;21:216 –224.

23. Gazerani P, Wang K, Cairns BE, Svensson P, Arendt-Nielsen L. Effects of subcutaneous administration of glutamate on pain, sensitization and vasomotor responses in healthy men and women. Pain 2006;124:338–348.

24. Bereiter DA, Barker DJ. Hormone-induced enlargement of receptive fields in trigeminal mechanoreceptive neurons. I. Time course, hormone, sex and modality specificity. Brain Res 1980;184:395–410.

25. Bereiter DA, Barker DJ. Facial receptive fields of trigeminal neurons: Increased size following estrogen treatment in female rats. Neuroendocrinology 1975;18:115–124.

26. Puri V, Cui L, Liverman CS, et al. Ovarian steroids regulate neuropeptides in the trigeminal ganglion. Neuropeptides 2005;39:409–417.

27. 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;86:782–791.

28. Fredriksson L, Alstergren P, Kopp S. Absolute and relative facial pressure-pain thresholds in healthy individuals. J Orofac Pain 2000;14:98–104.

29. Isselee H, De Laat A, Bogaerts K, Lysens R. Short-term reproducibility of pressure pain thresholds in masticatory muscles measured with a new algometer. J Orofac Pain 1998;12:203–209.

30. Fredriksson L, Alstergren P, Kopp S. Pressure pain thresh-olds in the craniofacial region of female patients with rheumatoid arthritis. J Orofac Pain 2003;17:326–332.

31. Cairns BE, Sim Y, Bereiter DA, Sessle BJ, Hu JW. Influence of sex on reflex jaw muscle activity evoked from the rat temporomandibular joint. Brain Res 2002;957: 338–344.

32. Cairns BE, Wang K, Hu JW, Sessle BJ, Arendt-Nielsen L, Svensson P. The effect of glutamate-evoked masseter muscle pain on the human jaw-stretch reflex differs in men and women. J Orofac Pain 2003;17:317–325.

33. Alstergren P, Fredriksson L, Kopp S. Temporomandibular joint pressure pain threshold is systemically modulated in rheumatoid arthritis. J Orofac Pain 2008;22:231–238.

34. Alstergren P, Kopp S. Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints. Pain 1997;72:137–143.

35. Ayesh EE, Jensen TS, Svensson P. Effects of intra-articular ketamine on pain and somatosensory function in temporomandibular joint arthralgia patients. Pain 2008;137: 286–294.