Temporal Changes in Inflammatory Mediator Concentrations in an Adjuvant Model of Temporomandibular Joint Inflammation

Aims: To determine temporal changes in the concentrations found in the temporomandibular joint (TMJ) and trigeminal ganglion of 3 specific classes of inflammatory mediators commonly linked with conditions of joint inflammation. The intent was to deter-mine whether concentrations of the neuropeptide calcitonin gene–related peptide (CGRP), the neurotrophin nerve growth fac-tor (NGF), and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are altered in the trigem-inal ganglion and TMJ tissues during various stages of adjuvant-induced inflammation of the rat TMJ. Methods: Adult male rats received bilateral TMJ injection of complete Freund’s adjuvant (CFA), while control rats did not receive CFA treatment. The trigeminal ganglion and TMJ tissues were collected at 2 days, and 2, 4, and 6 weeks postinjection and analyzed using either radioimmunoassay or enzyme-linked immunosorbent assay. Results: In the trigeminal ganglion, both CGRP and NGF concen-trations were significantly elevated in comparison to controls from 2 days to 4 weeks; however, the patterns of increase differed. Concentrations of each inflammatory mediator were significantly elevated in the TMJ tissues of CFA-injected animals at 2 days and continued to be significantly elevated throughout the 6-week period. CGRP content remained at peak levels from 2 days through 6 weeks, while peak content for NGF, IL-1β, and TNF-α was found at 2 days through 2 weeks. Conclusion: The results suggest that the development of CFA-induced inflammation of the TMJ was accompanied by a variable increase in the concentration of different classes of inflammatory mediators in both the trigemi-nal ganglion and TMJ tissues, which implies that each class of inflammatory mediator may play a significant role during different stages in the onset and exacerbation of the inflammatory process.

calcitonin gene-related peptide; inflammation; inter-leukin-1β; nerve growth factor; temporomandibular joint; trigeminal ganglion; tumor necrosis factor-α

1. Hanesch U, Pfrommer U, Grubb BD, Schaible H. Acute and chronic phases of unilateral inflammation in rat’s ankles are associated with an increase in the proportion of calcitonin gene-related peptide-immunoreactive dorsal root ganglion cells. Euro J Neurosci 1993;5:154–161.

2. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14: 397–440.

3. Wimalawansa SJ. Calcitonin gene-related peptide and its receptors: Molecular genetics, physiology, pathophysiology, and therapeutic potentials. Endocr Rev 1996;17: 533–585.

4. Kilo S, Harding-Rose C, Hargreaves KM, Flores CM. Peripheral CGRP release as a marker for a neurogenic inflammation: A model system for the study of neuropeptide secretion in rat paw skin. Pain 1997;73:201–207.

5. Cruwys SC, Kidd BL, Mapp PI, Walsh DA, Blake DR. The effects of calcitonin gene-related peptide on formation of intra-articular oedema by inflammatory mediators. Brit J Pharmacol 1992;107:116–119.

6. Averbeck B, Izydorczyk I, Kress M. Inflammatory media-tors release calcitonin gene-related peptide from dorsal root ganglion neurons of the rat. Neuroscience 2000; 98:135–140.

7. Konttinen YT, Rees R, Hukkanen M, et al. Nerves in inflammatory synovium: Immunohistochemical observations on the adjuvant arthritis rat model. J Rheumatol 1990;17:1586–1591.

8. Pereria da Silva A, Carmo-Fonseca M. Peptide containing nerves in human synovium: Immunohistochemical evidence for decreased innervation in rheumatoid arthritis. J Rheumatol 1990;17:1592–1599.

9. Mapp PI, Kidd BL, Gibson SJ, et al. Substance P-, calcitonin gene-related peptide- and C-flanking peptide of neuropeptide Y-immunoreactive fibres are present in normal synovium but depleted in patients with rheumatoid arthritis. Neuroscience 1990;37:143–153.

10. Ahmed M, Bjurholm A, Schultzberg M, Theodorsson E, Kreicbergs A. Increased concentration of substance P and calcitonin gene-related peptide in rat adjuvant-induced arthritis. A combined immunohistochemical and radioim-munoassay analysis. Arthrit Rheum 1995;38:699–709.

11. Ichikawa H, Matsuo S, Wakisaka S, Akai M. Fine structure of calcitonin gene-related peptide-immunoreactive nerve fibres in the rat temporomandibular joint. Arch Oral Biol 1990;35:727–730.

12. Kido MA, Kiyoshima T, Kondo T, et al. Distribution of substance P and calcitonin gene-related peptide-like immunoreactive nerve fibers in the rat temporomandibular joint. J Dent Res 1993;72:592–598.

13. Carleson J, Bileviciute I, Theodorsson E, et al. Effects of adjuvant on neuropeptide-like immunoreactivity in the temporomandibular joint and trigeminal ganglia. J Orofac Pain 1997;11:195–199.

14. Shimizu S, Kido MA, Kiyoshima T, Tanaka T. Postnatal development of protein gene product 9.5- and calcitonin gene-related peptide-like immunoreactive nerve fibers in the rat temporomandibular joint. Anat Rec 1996;245: 568–576.

15. Holmlund A, Ekblom A, Hansson P, Lind J, Lundeberg T, Theodorsson E. Concentrations of neuropeptides substance P, neurokinin A, calcitonin gene-related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid of the human temporomandibular joint. A correlation with symptoms, signs and arthroscopic find-ings. Int J Oral Maxillofac Surg 1991;20:228–231.

16. Alstergren P, Appelgren A, Appelgren B, Kopp S, Lunde-berg T, Theodorsson E. Co-variation of neuropeptide Y, calcitonin gene-related peptide, substance P and neurokinin A in joint fluid from patients with temporomandibular joint arthritis. Arch Oral Biol 1995;40:127–135.

17. Thoenen H, Barde YA. Physiology of nerve growth factor. Physiol Rev 1980;60:1284–1335.

18. Lindsay RM, Lockett C, Sternberg J, Winter J. Neuro-peptide expression in cultures of adult sensory neurons: Modulation of substance P and calcitonin gene-related peptide concentration by nerve growth factor. Neurosci 1989;33:53–65.

19. Verge VM, Richardson PM, Wiesenfeld-Hallin Z, Hökfelt T. Differential influence of nerve growth factor on neuropeptide expression in vivo: A novel role in peptide suppression in adult sensory neurons. J Neurosci 1995;15: 2081–2096.

20. Donnerer J, Amann R, Schuligoi R, Skofitsch G. Complete recovery by nerve growth factor of neuropeptide content and function in capsaicin-impaired sensory neurons. Brain Res 1996;741:103–108.

21. Donnerer J, Schuligoi R, Stein C. Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: Evidence for a regulatory function of nerve growth factor in vivo. Neuroscience 1992;49:693–698.

22. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 1994;62:327–331.

23. Pezet S, Onteniente B, Jullien J, et al. Differential regula-tion of NGF receptors in primary sensory neurons by adjuvant-induced arthritis in the rat. Pain 2001;90:113–125.

24. Wu Z, Nagata K, Iijima T. Immunohistochemical study of NGF and its receptors in the synovial membrane of the ankle joint of adjuvant-induced arthritic rats. Histochem Cell Biol 2000;114:453–459.

25. Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum 1995;38:151–160.

26. Deleuran BW. Cytokines in rheumatoid arthritis. Localization in arthritic joint tissue and regulation in vitro. Scand J Rheumatol 1996;25(suppl 104):1–34.

27. Starkebaum G. Role of cytokines in rheumatoid arthritis. Sci Med 1998;5:6–15.

28. Takahashi T, Kondoh T, Fukuda M, Yamazaki Y, Toyosaki T, Suzuki R. Proinflammatory cytokines detectable in synovial fluids from patients with temporo-mandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endol 1998;85:135–141.

29. Alstergren P, Ernberg M, Kopp S, Lundeberg T, Theo-dorsson E. TMJ pain in relation to circulating neuropeptide Y, serotonin, and interleukin-1 beta in rheumatoid arthritis. J Orofac Pain 1999;13:49–55.

30. Brennan FM, Field M, Chu CQ, Feldmann M, Maini RN. Cytokine expression in rheumatoid arthritis. Br J Rheumatol 1991;30(suppl 1):76–80.

31. Howson P, Shepard N, Mitchell N. The antigen induced arthritis model: The relevance of the method of induction to its use as a model of human disease. J Rheumatol 1986;13:379–390.

32. Donaldson LF, Seckl JR, McQueen DS. A discrete adjuvant-induced monoarthritis in the rat: Effects of adjuvant dose. J Neurosci Methods 1993;49:5–10.

33. Cannon GW, Openshaw S, Clayton F, Sawitzke AD, Griffiths MM. Adjuvant arthritis in rats: susceptibility to arthritis induced by Mycobacterium butyricum and Mycobacterium tuberculosis. Transplant Proc 1999;31: 1590–1591.

34. Kuraishi Y, Nanayama T, Ohno H, et al. Calcitonin gene-related peptide increases in the dorsal root ganglia of adjuvant arthritic rat. Peptides 1989;10:447–452.

35. Smith GD, Harmar AJ, McQueen DS, Seckl JR. Increases in substance P and CGRP but not somatostatin content of innervating dorsal root ganglia in adjuvant monoarthritis in the rat. Neurosci Lett 1992;137:257–260.

36. Kapila S, Lee C, Tavakkoli Jou MR, Miller AJ, Richards DW. Development and histologic characterizations of an animal model of antigen-induced arthritis of the juvenile rabbit temporomandibular joint. J Dent Res 1995;74: 1870–1879.

37. Hutchins B, Spears R, Hinton RJ, Harper RP. Calcitonin gene-related peptide and substance P immunoreactivity in rat trigeminal ganglia and brainstem following adjuvant-induced inflammation of the temporomandibular joint. Arch Oral Biol 2000;45:335–345.

38. Harper RP, Kerins CA, McIntosh JE, Spears R, Bellinger LL. Modulation of the inflammatory response in the rat TMJ with increasing doses of complete Freund’s adjuvant. Osteoarthritis Cartilage 2001;9:619–624.

39. Carleson J, Alstergren P, Appelgren A, et al. Effects of adjuvant on neuropeptide-like immunoreactivity in experimentally induced temporomandibular arthritis in rats. Arch Oral Biol 1996;41:705–712.

40. Harper RP, Kerins CA, Talwar R, et al. Meal pattern analysis in response to temporomandibular joint inflammation in the rat. J Dent Res 2000;79:1704–1711.

41. Reinert A, Kaske A, Mense S. Inflammation-induced increase in the density of neuropeptide-immunoreactive nerve endings in rat skeletal muscle. Exper Brain Res 1998;121:174–180.