Vanilloid Receptor 1 Expression in Human Tooth Pulp in Relation to Caries and Pain

Aims: To investigate the presence of vanilloid receptor 1 (TRPV1) in human dental pulp and to correlate any expression with caries and pain. Methods: Permanent mandibular first molars were col-lected and categorized as intact or grossly carious. Grossly carious teeth were further categorized as carious asymptomatic or carious painful samples. Coronal pulps were removed and processed for indirect immunofluorescence using antibodies raised against TRPV1 and a neuronal marker, either protein gene product 9.5 or alpha-smooth muscle actin, in conjunction with Ulex europaeus agglutinin 1 lectin to fully label the pulp vasculature. Results: Analysis revealed that TRPV1 labeling was not confined to pulpal nerve fibers. TRPV1 was also consistently expressed within pulp microvasculature. Expression of neuronal TRPV1 was signifi-cantly increased throughout the pulp in grossly carious samples (P < .05). No significant differences were found between carious asymptomatic and carious painful samples. A significant increase in vascular TRPV1 expression was observed in arterioles present in the midcoronal pulp in carious painful compared with carious asymptomatic samples (mean area ± SEM [%] of TRPV1 to vascu-lar labeling; 6.48% ± 4.5% for carious asymptomatic teeth, n = 9; 31.21% ± 9.6% for carious painful teeth, n = 9; P = .02). Conclusion: Expression of TRPV1 in pulpal nerve fibers under-goes marked changes with caries. This may be of relevance in the development of pulpal inflammation, but its relationship to dental pain is still unclear. However, vascular TRPV1 expression does appear to be positively correlated with dental pain, thus providing new insights into symptomatic pulpitis.

blood vessels; inflammation; pain, tooth pulp; vanilloid receptor 1

1. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 1997;389:816–824.

2. Ikeda H, Tokita Y, Suda H. Capsaicin-sensitive A delta fibers in cat tooth pulp. J Dent Res 1997;76:1341–1349.

3. Chaudhary P, Martenson ME, Baumann TK. Vanilloid receptor expression and capsaicin excitation of rat dental primary afferent neurons. J Dent Res 2001;80:1518–1523.

4. Mezey E, Toth ZE, Cortright DN, et al. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci USA 2000;97:3655–3660.

5. Birder LA, Kanai AJ, de Groat WC, et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 2001;98:13396–13401.

6. Biro T, Maurer M, Modarres, et al. Characterization of functional vanilloid receptors expressed by mast cells. Blood 1998;91:1332–1340.

7. Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 1999;398:436–441.

8. Di Marzo V, Blumberg PM, Szallasi A. Endovanilloid signaling in pain. Curr Opin Neurobiol 2002;12:372–379.

9. Tominaga M, Caterina MJ, Malmberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998;21:531–543.

10. Premkumar LS, Ahern GP. Induction of vanilloid receptor channel activity by protein kinase C. Nature 2000;408:985–990.

11. Lopshire JC, Nicol GD. The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: Whole cell and single-channel studies. J Neurosci 1998;18: 6081–6092.

12. McVey DC, Vigna SR. The capsaicin VR1 receptor medi-ates substance P release in toxin A-induced enteritis in rats. Peptides 2001;22:1439–1446.

13. Nathan JD, Patel AA, McVey DC, et al. Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. Am J Physiol Gastrointest Liver Physiol 2001;281:G1322–G1328.

14. Hou M, Uddman R, Tajti J, Kanje M, Edvinsson L. Capsaicin receptor immunoreactivity in the human trigeminal ganglion. Neurosci Lett 2002;330:223–226.

15. Chan CLH, Facer P, Davis JB, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 2003;361:385–391.

16. Yiangou Y, Facer P, Dyer NH, et al. Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet 2001;357:1338–1339.

17. Ichikawa H, Sugimoto T. Vanilloid receptor 1-like receptor-immunoreactive primary sensory neurons in the rat trigeminal nervous system. Neuroscience 2000;101: 719–725.

18. Ichikawa H, Sugimoto T. VR1-immunoreactive primary sensory neurons in the rat trigeminal ganglion. Brain Res 2001;890:184–188.

19. Stenholm E, Bongenhielm U, Ahlquist M, Fried K. VR1-and VRL-1-like immunoreactivity in normal and injured trigeminal dental primary sensory neurons of the rat. Acta Odontol Scand 2002;60:72–79.

20. Renton T, Yiangou Y, Baecker PA, Ford AP, Anand P. Capsaicin receptor VR1 and ATP purinoceptor P2X3 in painful and nonpainful human tooth pulp. J Orofac Pain 2003;17:245–250.

21. Ramieri G, Anselmetti GC, Baracchi F, et al. The innervation of human teeth and gingival epithelium as revealed by means of an antiserum for protein gene product 9.5 (PGP 9.5). Am J Anat 1990;189:146–154.

22. Ordóñez NG, Brooks T, Thompson S, Batsakis JG. Use of Ulex europaeus agglutinin I in the identification of lymphatic and blood vessel invasion in previously stained microscopic slides. Am J Surg Pathol 1987;11:543–550.

23. Skalli O, Ropraz P, Trzeciak A. A monoclonal antibody against α-smooth muscle actin: A new probe for smooth muscle differentiation. J Cell Biol 1986;103:2787–2796.

24. Altschul SF, Madden TL, Schäffer AA, et al. Gapped BLAST and PSI-BLAST: A new generation of protein database search programs. Nucleic Acids Res 1997;25:3389–3402.

25. Rodd HD, Boissonade FM. Immunocytochemical investigation of neurovascular relationships in human tooth pulp. J Anat 2003;202:195–203.

26. Rodd HD, Boissonade FM. Innervation of human tooth pulp in relation to caries and dentition type. J Dent Res 2001;80:389–393.

27. Rodd HD, Boissonade FM. Vascular status in human primary and permanent teeth in health and disease. Eur J Oral Sci 2005;113:128–134.

28. 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.

29. Byers MR, Wheeler EF, Bothwell M. Altered expression of NGF and P75 NGF-receptor by fibroblasts in injured teeth precedes sensory nerve sprouting. Growth Factors 1992;6:41–52.

30. Winston J, Toma H, Shenoy M, Pasricha PJ. Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons. Pain 2001;89:181–186.

31. Tohda C, Sasaki M, Konemura T, Sasamura T, Itoh M, Kuraishi Y. Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. J Neurochem 2001;76:1628–1635.

32. Ross RA, Gibson TM, Brockie HC, et al. Structure-activity relationship for the endogenous cannabinoid, anandamide, and certain of its analogues at vanilloid receptors in transfected cells and vas deferens. Br J Pharmacol 2001;132:631–640.

33. Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999;400:452–457.

34. Tognetto M, Amadesi S, Harrison S, et al. Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation. J Neurosci 2001;21:1104–1109.

35. Heyeraas KJ, Kvinnsland I. Tissue pressure and blood flow in pulpal inflammation. Proc Finn Dent Soc 1992;88(suppl 1):393–401.

36. Caterina MJ, Leffler A, Malmberg AB, et al. Impaired nociception and pain in mice lacking the capsaicin receptor. Science 2000;288:306–313.

37. Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000;405:183–187.

38. Bevan S, Hothi S, Hughes G, et al. Capsazepine: A com-petitive antagonist of the sensory neurone excitant capsaicin. Br J Pharmacol 1992;107:544–552.

39. Lou YP, Lundberg JM. Inhibition of low pH evoked activation of airway sensory nerves by capsazepine, a novel capsaicin-receptor antagonist. Biochem Biophys Res Commun 1992;189:537–544.

40. Fox AJ, Urban L, Barnes PJ, Dray A. Effects of cap-sazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig. Neuroscience 1995;67:741–752.

41. Baumann TK, Chaudhary P, Martenson ME. Background potassium channel block and TRPv1 activation contribute to proton depolarization of sensory neurons from humans with neuropathic pain. Eur J Neurosci 2004;19: 1343–1351.

42. McIntyre P, McLatchie L, Chambers A, et al. Pharmacological differences between the human and rat vanilloid receptor 1 (VR1). Br J Pharmacol 2001;132:1084–1094.

43. Walker KM, Urban L, Medhurst SJ, et al. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003;304:56–62.