5-ht Induces Temporomandibular Joint Nociception In Rats Through The Local Release Of Inflammatory Mediators And Activation Of Local β Adrenoceptors

The 5-hydroxytryptamine (serotonin, 5-HT) is an important inflammatory mediator found in high levels in the synovial fluid of the temporomandibular joint (TMJ) of patients with inflammatory pain. In this study, we used the nociceptive behavior responses, measured as flinching the head and rubbing the orofacial region, as a nociceptive assay. We demonstrated that the local blockade of the 5-HT3 receptor and β1 or β2-adrenoceptors, the depletion of norepinephrine in the sympathetic terminals and the local inhibition of cyclooxygenase significantly reduced 5-HT-induced TMJ nociception. These results demonstrated that 5-HT induces nociception in the TMJ region by the activation of β1 and β2 adrenoceptors located in the TMJ region and local release of sympathetic amines and prostaglandins. Therefore, the high levels of 5-HT in the synovial fluid of patients with TMJ inflammatory pain may contribute to TMJ pain by similar mechanisms. © 2012 Elsevier Inc.1023458464Aley, K.O., Levine, J.D., Role of protein kinase A in the maintenance of inflammatory pain (1999) Journal of Neuroscience, 19 (6), pp. 2181-2186Alstergren, P., Kopp, S., Pain and synovial fluid concentration of serotonin in arthritic temporomandibular joints (1997) Pain, 72 (1-2), pp. 137-143. , DOI 10.1016/S0304-3959(97)00022-5, PII S0304395997000225Baker, J.G., The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors (2005) British Journal of Pharmacology, 144 (3), pp. 317-322. , DOI 10.1038/sj.bjp.0706048Bakke, M., Hu, J.W., Sessle, B.J., Involvement of NK-1 and NK-2 tachykinin receptor mechanisms in jaw muscle activity reflexly evoked by inflammatory irritant application to the rat temporomandibular joint (1998) Pain, 75 (2-3), pp. 219-227. , DOI 10.1016/S0304-3959(97)00223-6, PII S0304395997002236Barnes, P.J., β-Adrenoceptors on smooth muscle, nerves and inflammatory cells (1993) Life Sciences, 52 (26), pp. 2101-2109. , DOI 10.1016/0024-3205(93)90725-IBicego, K.C., Steiner, A.A., Antunes-Rodrigues, J., Branco, L.G.S., Indomethacin impairs LPS-induced behavioral fever in toads (2002) Journal of Applied Physiology, 93 (2), pp. 512-516Bradley, P.P., Priebat, D.A., Christensen, R.D., Rothstein, G., Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker (1982) Journal of Investigative Dermatology, 78 (3), pp. 206-209Chen, Y., Palm, F., Lesch, K.P., Gerlach, M., Moessner, R., Sommer, C., 5-Hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice (2011) Mol Pain, 7, p. 2Christidis, 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 (2007) Clinical Journal of Pain, 23 (6), pp. 467-472. , DOI 10.1097/AJP.0b013e318058abb1, PII 0000250820070700000001Christidis, N., Ioannidou, K., Milosevic, M., Segerdahl, M., Ernberg, M., Changes of hypertonic saline-induced masseter muscle pain characterisitcs, by an infusion of the serotonin receptor type 3 antagonist granisetron (2008) J Pain, 10, pp. 892-901Claria, J., Romano, M., Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer (2005) Current Pharmaceutical Design, 11 (26), pp. 3431-3447. , DOI 10.2174/138161205774370753Cunha, T.M., Verri Jr., W.A., Schivo, I.R., Napimoga, M.H., Parada, C.A., Poole, S., Teixeira, M.M., Cunha, F.Q., Crucial role of neutrophils in the development of mechanical inflammatory hypernociception (2008) Journal of Leukocyte Biology, 83 (4), pp. 824-832. , http://www.jleukbio.org/cgi/reprint/83/4/824, DOI 10.1189/jlb.0907654Dworkin, S.F., Leresche, L., Research diagnostic criteria for temporomandibular disorders: Review, criteria, examinations and specifications, critique (1992) J Craniomandib Disord, 6, pp. 301-355Ernberg, M., Hedenberg-Magnusson, B., Alstergren, P., Lundeberg, T., Kopp, S., Pain, allodynia, and serum serotonin level in orofacial pain of muscular origin (1999) J Orofac Pain, 13, pp. 56-62Ernberg, M., Hedenberg-Magnusson, B., Kurita, H., Kopp, S., Effects of local serotonin administration on pain and microcirculation in the human masseter muscle (2006) Journal of Orofacial Pain, 20 (3), pp. 241-248Fasano, M.B., Wells, J.D., McCall, C.E., Human neutrophils express the prostaglandin G/H synthase 2 gene when stimulated with bacterial lipopolysaccharide (1998) Clinical Immunology and Immunopathology, 87 (3), pp. 304-308. , DOI 10.1006/clin.1998.4545Fávaro-Moreira, N.C., Parada, C.A., Tambeli, C.H., Blockade of β(1)-, β(2)- and β(3)-adrenoceptors in the temporomandibular joint induces antinociception especially in female rats (2012) Eur J Pain, , 10.1002/j.1532-2149.2012.00132.xFerreira, S.H., Nakamura, M., De Abreu Castro, M.S., The hyperalgesic effects of prostacyclin and prostaglandin E2 (1978) Prostaglandins, 16, pp. 31-37Fischer, L., Tambeli, C.H., Parada, C.A., TRPA1-mediated nociception (2008) Neuroscience, 155, pp. 337-338Green, P.G., Luo, J., Heller, P.H., Levine, J.D., Further substantiation of a significant role for the sympathetic nervous system in inflammation (1993) Neuroscience, 55 (4), pp. 1037-1043. , DOI 10.1016/0306-4522(93)90317-9Hong, Y., Abbott, F.V., Behavioural effects of intraplantar injection of inflammatory mediators in the rat (1994) Neuroscience, 63 (3), pp. 827-836. , DOI 10.1016/0306-4522(94)90527-4Hu, W.P., Guan, B.C., Ru, L.Q., Chen, J.G., Li, Z.W., Potentiation of 5-HT3 receptor function by the activation of coexistent 5-HT2 receptors in trigeminal ganglion neurons of rats (2004) Neuropharmacology, 47, pp. 833-840Hu, W.-P., Li, X.-M., Wu, J.-L., Zheng, M., Li, Z.-W., Bradykinin potentiates 5-HT3 receptor-mediated current in rat trigeminal ganglion neurons (2005) Acta Pharmacologica Sinica, 26 (4), pp. 428-434. , DOI 10.1111/j.1745-7254.2005.00074.xInoue, M., Rashid, Md.H., Kawashima, T., Matsumoto, M., Maeda, T., Kishioka, S., Ueda, H., The algogenic-induced nociceptive flexion test in mice: Studies on sensitivity of the test and stress on animals (2003) Brain Research Bulletin, 60 (3), pp. 275-281. , DOI 10.1016/S0361-9230(03)00045-5Khasar, S.G., Mccarter, G., Levine, J.D., Epinephrine produces a β-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors (1999) Journal of Neurophysiology, 81 (3), pp. 1104-1112Kido, M.A., Zhang, J.-Q., Muroya, H., Yamaza, T., Terada, Y., Tanaka, T., Topography and distribution of sympathetic nerve fibers in the rat temporomandibular joint: Immunocytochemistry and ultrastructure (2001) Anatomy and Embryology, 203 (5), pp. 357-366. , DOI 10.1007/s004290100163Kim, H.Y., Kim, K., Li, H.Y., Chung, G., Park, C.K., Kim, J.S., Selectively targeting pain in the trigeminal system (2010) Pain, 150, pp. 29-40Levine, J.D., Dardick, S.J., Roizen, M.F., Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis (1986) Journal of Neuroscience, 6 (12), pp. 3423-3429Morales, M., Wang, S.-D., Differential composition of 5-hydroxytryptamine3 receptors synthesized in the rat CNS and peripheral nervous system (2002) Journal of Neuroscience, 22 (15), pp. 6732-6741Nakamura, M., Ferreira, S.H., A peripheral sympathetic component in inflammatory hyperalgesia (1987) European Journal of Pharmacology, 135 (2), pp. 145-153. , DOI 10.1016/0014-2999(87)90606-6Nebigil, C., Malik, K.U., Prostaglandin synthesis elicited by adrenergic stimuli in rabbit aorta is mediated via alpha-1 and alpha-2 adrenergic receptors (1990) Journal of Pharmacology and Experimental Therapeutics, 254 (2), pp. 633-640Nicholson, R., Dixon, A.K., Spanswick, D., Lee, K., Noradrenergic receptor mRNA expression in adult rat superficial dorsal horn and dorsal root ganglion neurons (2005) Neuroscience Letters, 380 (3), pp. 316-321. , DOI 10.1016/j.neulet.2005.01.079Nuttall, S.L., Routledge, H.C., Kendall, M.J., A comparison of the β1-selectivity of three β1-selective β-blockers (2003) Journal of Clinical Pharmacy and Therapeutics, 28 (3), pp. 179-186. , DOI 10.1046/j.1365-2710.2003.00477.xOjeda, S.R., Negro-Vilar, A., McCann, S.M., Evidence for involvement of α-adrenergic receptors in norepinephrine-induced prostaglandin E2 and luteinizing hormone-releasing hormone release from the median eminence (1982) Endocrinology, 110 (2), pp. 409-412Okamoto, K., Imbe, H., Tashiro, A., Kumabe, S., Senba, E., Blockade of peripheral 5HT3 receptor attenuates the formalin-induced nocifensive behavior in persistent temporomandibular joint inflammation of rat (2004) Neuroscience Letters, 367 (2), pp. 259-263. , DOI 10.1016/j.neulet.2004.06.017, PII S0304394004007529Oliveira, M.C.G., Parada, C.A., Veiga, M.C.F.A., Rodrigues, L.R., Barros, S.P., Tambeli, C.H., Evidence for the involvement of endogenous ATP and P2X receptors in TMJ pain (2005) European Journal of Pain, 9 (1), pp. 87-93. , DOI 10.1016/j.ejpain.2004.04.006, PII S1090380104000527Oliveira, M.C.G., Pelegrini-Da-Silva, A., Parada, C.A., Tambeli, C.H., 5-HT acts on nociceptive primary afferents through an indirect mechanism to induce hyperalgesia in the subcutaneous tissue (2007) Neuroscience, 145 (2), pp. 708-714. , DOI 10.1016/j.neuroscience.2006.12.021, PII S0306452206016757Oliveira, M.C., Pelegrini-Da-Silva, A., Tambeli, C.H., Parada, C.A., Peripheral mechanisms underlying the essential role of P2X3,2/3 receptors in the development of inflammatory hyperalgesia (2009) Pain, 141, pp. 127-134Parada, C.A., Tambeli, C.H., Cunha, F.Q., Ferreira, S.H., The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception (2001) Neuroscience, 102 (4), pp. 937-944. , DOI 10.1016/S0306-4522(00)00523-6, PII S0306452200005236Parada, C.A., Yeh, J.J., Joseph, E.K., Levine, J.D., Tumor necrosis factor receptor type-1 in sensory neurons contributes to induction of chronic enhancement of inflammatory hyperalgesia in rat (2003) European Journal of Neuroscience, 17 (9), pp. 1847-1852. , DOI 10.1046/j.1460-9568.2003.02626.xPelegrini-Da-Silva, A., Oliveira, M.C., Parada, C.A., Tambeli, C.H., Nerve growth factor acts with the beta2-adrenoceptor to induce spontaneous nociceptive behavior during temporomandibular joint inflammatory hyperalgesia (2008) Life Sci, 83, pp. 780-785Pierce, P.A., Xie, G.X., Levine, J.D., Peroutka, S.J., 5-Hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: A polymerase chain reaction study (1996) Neuroscience, 70, pp. 553-559Ritta, M.N., Cardinali, D.P., Involvement of α-adrenoceptors in norepinephrine-induced prostaglandin E2 release by rat pineal gland in vitro (1982) Neuroscience Letters, 31 (3), pp. 307-311. , DOI 10.1016/0304-3940(82)90038-6Rodrigues, L.L.F.R., Oliveira, M.C.G., Pelegrini-Da-Silva, A., De Arruda Veiga, M.C.F., Parada, C.A., Tambeli, C.H., Peripheral Sympathetic Component of the Temporomandibular Joint Inflammatory Pain in Rats (2006) Journal of Pain, 7 (12), pp. 929-936. , DOI 10.1016/j.jpain.2006.05.006, PII S1526590006007905Rosenberg, M., Pie, B., Cooper, E., Developing neonatal rat sympathetic and sensory neurons differ in their regulation of 5-HT3 receptor expression (1997) Journal of Neuroscience, 17 (17), pp. 6629-6638Rosland, J.H., The formalin test in mice: The influence of ambient temperature (1991) Pain, 45, pp. 211-216Roveroni, R.C., Parada, C.A., Cecilia, M., Veiga, F.A., Tambeli, C.H., Development of a behavioral model of TMJ pain in rats: The TMJ formalin test (2001) Pain, 94 (2), pp. 185-191. , DOI 10.1016/S0304-3959(01)00357-8, PII S0304395901003578Sasaki, M., Obata, H., Kawahara, K., Saito, S., Goto, F., Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats (2006) Pain, 122, pp. 130-136Secco, D.D., Paron, J.A., De Oliveira, S.H.P., Ferreira, S.H., Silva, J.S., Cunha, F.D.Q., Neutrophil migration in inflammation: Nitric oxide inhibits rolling, adhesion and induces apoptosis (2003) Nitric Oxide - Biology and Chemistry, 9 (3), pp. 153-164. , DOI 10.1016/j.niox.2003.11.001Seide, M.F., Ulrich-Merzenich, G., Fiebich, B., Candelario-Jalil, E., Koch, F.W., Vetter, H., Tropisetron inhibits serotonin-induced PGE2 release from macrophage-like synovial cells in serum-free tissue culture (2004) Scand J Rheumatol Suppl, 33Smith, J.A., Davis, C.L., Burgess, G.M., Prostaglandin E2-induced sensitization of bradykinin-evoked responses in rat dorsal root ganglion neurons is mediated by cAMP-dependent protein kinase A (2000) Eur J Neurosci, 12, pp. 3250-3258Sun, J., Sung, J.K., Min, K.P., Hye, J.K., Tsoy, I., Young, J.K., Young, S.L., Chang, K.C., Selective activation of adrenergic β1 receptors induces heme oxygenase 1 production in RAW264.7 cells (2005) FEBS Letters, 579 (25), pp. 5494-5500. , DOI 10.1016/j.febslet.2005.08.080, PII S0014579305011063Sung, D., Dong, X., Ernberg, M., Kumar, U., Cairns, B.E., Serotonin (5-HT) excites rat masticatory muscle afferent fibers through activation of peripheral 5-HT3 receptors (2008) Pain, 134 (1-2), pp. 41-50. , DOI 10.1016/j.pain.2007.03.034, PII S0304395907001625Taiwo, Y.O., Levine, J.D., Serotonin is a directly-acting hyperalgesic agent in the rat (1992) Neuroscience, 48, pp. 485-490Tambeli, C.H., Seo, K., Sessle, B.J., Hu, J.W., Central μ opioid receptor mechanisms modulate mustard oil-evoked jaw muscle activity (2001) Brain Research, 913 (1), pp. 90-94. , DOI 10.1016/S0006-8993(01)02742-1, PII S0006899301027421Tambeli, C.H., Oliveira, M.C.G., Clemente, J.T., Pelegrini-Da-Silva, A., Parada, C.A., A novel mechanism involved in 5-hydroxytryptamine-induced nociception: The indirect activation of primary afferents (2006) Neuroscience, 141 (3), pp. 1517-1524. , DOI 10.1016/j.neuroscience.2006.04.030, PII S0306452206005355Vivancos, G.G., Parada, C.A., Ferreira, S.H., Opposite nociceptive effects of the arginine/NO/cGMP pathway stimulation in dermal and subcutaneous tissues (2003) British Journal of Pharmacology, 138 (7), pp. 1351-1357. , DOI 10.1038/sj.bjp.0705181Voog, U., Alstergren, P., Leibur, E., Kallikorm, R., Kopp, S., Influence of serotonin on the analgesic effect of granisetron on temporomandibular joint arthritis (2004) Mediators of Inflammation, 13 (5-6), pp. 373-376. , DOI 10.1080/09629350400014123Waldron, J.B., Sawynok, J., Peripheral P2X receptors and nociception: Interactions with biogenic amine systems (2004) Pain, 110 (1-2), pp. 79-89. , DOI 10.1016/j.pain.2004.03.012, PII S030439590400137XWeissmann, G., The biochemistry of inflammation: Rheumatoid arthritis and anti-inflammatory drugs (1982) J Miss State Med Assoc, 23, pp. 66-73Widenfalk, B., Wiberg, M., Origin of sympathetic and sensory innervation of the temporo-mandibular joint. A retrograde axonal tracing study in the rat (1990) Neuroscience Letters, 109 (1-2), pp. 30-35. , DOI 10.1016/0304-3940(90)90533-FYang, J., Mathie, A., Hille, B., 5-HT3 receptor channels in dissociated rat superior cervical ganglion neurons (1992) J Physiol, 448, pp. 237-256Yoshino, K., Kawagishi, S., Amano, N., Morphological characteristics of primary sensory and postsynaptic sympathetic neurones supplying the temporomandibular joint in the cat (1998) Archives of Oral Biology, 43 (9), pp. 679-686. , DOI 10.1016/S0003-9969(98)00058-2, PII S0003996998000582Sardar, Y.K., Yousufzai, Y.K., Abdel-Latif, A.A., The effects of alphasub 1-adrenergic and muscarinic cholinergic stimulation on prostaglandin release by rabbit iris (1984) Prostaglandins, 28 (3), pp. 399-415. , DOI 10.1016/0090-6980(84)90025-XYu, X.-M., Sessle, B.J., Haas, D.A., Izzo, A., Vernon, H., Hu, J.W., Involvement of NMDA receptor mechanisms in jaw electromyographic activity and plasma extravasation induced by inflammatory irritant application to temporomandibular joint region of rats (1996) Pain, 68 (1), pp. 169-178. , DOI 10.1016/S0304-3959(96)03181-8, PII S0304395996031818Zeitz, K.P., Guy, N., Malmberg, A.B., Dirajlal, S., Martin, W.J., Sun, L., Bonhaus, D.W., Basbaum, A.I., The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors (2002) Journal of Neuroscience, 22 (3), pp. 1010-101