The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) has been known for the processing and transmission of orofacial nociceptive information. Taurine, one of the most plentiful free amino-acids in humans, has proved to be involved in pain modulation. In this study, using whole-cell patch clamp technique, we investigated the direct membrane effects of taurine and the action mechanism behind taurine-mediated responses on the SG neurons of the Vc. Taurine showed non-desensitizing and repeatable membrane depolarizations and inward currents which remained in the presence of amino-acid receptors blocking cocktail (AARBC) with tetrodotoxin, indicating that taurine acts directly on the postsynaptic SG neurons. Further, application of taurine at different doses (10？μM to 3？mM) showed a concentration dependent depolarizations and inward currents with the EC50 of 84.3？μM and 723？μM, respectively. Taurine-mediated responses were partially blocked by picrotoxin (50？μM) and almost completely blocked by strychnine (2？μM), suggesting that taurine-mediated responses are via glycine receptor (GlyR) activation. In addition, taurine (1？mM) activated extrasynaptic GABAA receptor (GABAAR)-mediated currents. Taken together, our results indicate that taurine can be a target molecule for orofacial pain modulation through the activation of GlyRs and/or extrasynaptic GABAARs on the SG neurons. 1. Introduction Taurine (2-amino-ethane sulfonic acid) is one of the most plentiful free amino-acids in humans [1, 2]. In the human body, taurine is distributed with high concentration in various tissues that are excitable and/or prone to generate free radicals in retina, white blood cells, platelets, central nervous system (CNS), heart, skeletal muscles, spleen, and liver [3]. In physiological condition, taurine is accumulated in brain cells at concentration of 5–70？mM [4, 5] and is released in high amounts under various pathological conditions such as anoxaemia or ischemia and seizure [6–8]. Since its first discovery in 1827, a number of studies have been done to find out the various physiological functions and the significance of taurine. It has been reported that taurine has various functions including bile acid production [9–12], antiarrhythmic effects [13–15], and oxidant scavenging effects [16]. In central nervous system, taurine has also been reported to modulate calcium homeostasis [17, 18], neuronal excitabilities [19, 20], and excitotoxic cell death [21, 22]. The pain transmission from the orofacial region to the trigeminal subnucleus caudalis (Vc) is
References
[1]
M. Neuringer and J. Sturman, “Visual acuity loss in rhesus monkey infants fed a taurine-free human infant formula,” The Journal of Neuroscience Research, vol. 18, no. 4, pp. 597–601, 1987.
[2]
M. Neuringer, H. Imaki, J. A. Sturman, R. Moretz, and H. M. Wisniewski, “Abnormal visual acuity and retinal morphology in rhesus monkeys fed a taurine-free diet during the first three postnatal months,” Advances in Experimental Medicine and Biology, vol. 217, pp. 125–134, 1987.
[3]
J. G. Jacobsen and L. H. Smith, “Biochemistry and physiology of taurine and taurine derivatives,” Physiological Reviews, vol. 48, no. 2, pp. 424–511, 1968.
[4]
H. Benrabh, J.-M. Bourre, and J.-M. Lefauconnier, “Taurine transport at the blood-brain barrier: an in vivo brain perfusion study,” Brain Research, vol. 692, no. 1-2, pp. 57–65, 1995.
[5]
N. Del Olmo, M. Galarreta, J. Bustamante, R. Martín Del Río, and J. M. Solís, “Taurine-induced synaptic potentiation: role of calcium and interaction with LTP,” Neuropharmacology, vol. 39, no. 1, pp. 40–54, 2000.
[6]
P. Saransaari and S. S. Oja, “Modulation of the ischemia-induced taurine release by adenosine receptors in the developing and adult mouse hippocampus,” Neuroscience, vol. 97, no. 3, pp. 425–430, 2000.
[7]
J. W. Phillis and M. H. O'Regan, “Characterization of modes of release of amino acids in the ischemic/reperfused rat cerebral cortex,” Neurochemistry International, vol. 43, no. 4-5, pp. 461–467, 2003.
[8]
Z. Li, X. Zhang, X. Lu, M. Zhong, and Y. Ji, “Dynamic release of amino acid transmitters induced by valproate in PTZ-kindled epileptic rat hippocampus,” Neurochemistry International, vol. 44, no. 4, pp. 263–270, 2004.
[9]
F. Guertin, C. C. Roy, G. Lepage et al., “Effect of taurine on total parenteral nutrition-associated cholestasis,” Journal of Parenteral and Enteral Nutrition, vol. 15, no. 3, pp. 247–251, 1991.
[10]
P. Invernizzi, K. D. R. Setchell, A. Crosignani et al., “Differences in the metabolism and disposition of ursodeoxycholic acid and of its taurine-conjugated species in patients with primary biliary cirrhosis,” Hepatology, vol. 29, no. 2, pp. 320–327, 1999.
[11]
S. Caglieris, E. Giannini, G. Dardano, L. Mondello, U. Valente, and R. Testa, “Tauroursodeoxycholic acid administration as adjuvant therapy in cirrhotic patients on transplantation waiting lists,” Hepato-Gastroenterology, vol. 47, no. 34, pp. 1045–1047, 2000.
[12]
Y. Sunami, S. Tazuma, and G. Kajiyama, “Gallbladder dysfunction enhances physical density but not biochemical metastability of biliary vesicles,” Digestive Diseases and Sciences, vol. 45, no. 12, pp. 2382–2391, 2000.
[13]
H. Satoh and N. Sperelakis, “Review of some actions of taurine on ion channels of cardiac muscle cells and others,” General Pharmacology, vol. 30, no. 4, pp. 451–463, 1998.
[14]
L. Niittynen, M. Nurminen, R. Korpela, and H. Vapaatalo, “Role of arginine, taurine and homocysteine in cardiovascular diseases,” Annals of Medicine, vol. 31, no. 5, pp. 318–326, 1999.
[15]
M. J. Sole and K. N. Jeejeebhoy, “Conditioned nutritional requirements and the pathogenesis and treatment of myocardial failure,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 3, no. 6, pp. 417–424, 2000.
[16]
C. Cunningham, K. F. Tipton, and H. B. F. Dixon, “Conversion of taurine into N-chlorotaurine (taurine chloramine) and sulphoacetaldehyde in response to oxidative stress,” Biochemical Journal, vol. 330, no. 2, pp. 939–945, 1998.
[17]
H. Pasantes-Morales and A. Gamboa, “Effect of taurine on 45Ca2+ accumulation in rat brain synaptosomes,” Journal of Neurochemistry, vol. 34, no. 1, pp. 244–246, 1980.
[18]
W. Q. Chen, H. Jin, M. Nguyen et al., “Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons,” The Journal of Neuroscience Research, vol. 66, no. 4, pp. 612–619, 2001.
[19]
F. Wang, C. Xiao, and J. H. Ye, “Taurine activates excitatory non-synaptic glycine receptors on dopamine neurones in ventral tegmental area of young rats,” Journal of Physiology, vol. 565, no. 2, pp. 503–516, 2005.
[20]
H. Xu, W. Wang, Z. Tang, T. Xu, and L. Chen, “Taurine acts as a glycine receptor agonist in slices of rat inferior colliculus,” Hearing Research, vol. 220, no. 1-2, pp. 95–105, 2006.
[21]
P. Saransaari and S. S. Oja, “Taurine and neural cell damage,” Amino Acids, vol. 19, no. 3-4, pp. 509–526, 2000.
[22]
P. R. Louzada, A. C. P. Lima, D. L. Mendon？a-Silva, F. No？l, F. G. De Mello, and S. T. Ferreira, “Taurine prevents the neurotoxicity of β-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer's disease and other neurological disorders,” The FASEB Journal, vol. 18, no. 3, pp. 511–518, 2004.
[23]
A. R. Light and E. R. Perl, “Spinal termination of functionally identified primary afferent neurons with slowly conducting myelinated fibers,” Journal of Comparative Neurology, vol. 186, no. 2, pp. 133–150, 1979.
[24]
Y. Sugiura, C. L. Lee, and E. R. Perl, “Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin,” Science, vol. 234, no. 4774, pp. 358–361, 1986.
[25]
W. D. Willis and K. N. Westlund, “Neuroanatomy of the pain system and of the pathways that modulate pain,” Journal of Clinical Neurophysiology, vol. 14, no. 1, pp. 2–31, 1997.
[26]
L. Lorenzo, M. Ramien, M. St. Louis, Y. De Koninck, and A. Ribeiro-da-Silva, “Postnatal changes in the rexed lamination and markers of nociceptive afferents in the superficial dorsal horn of the rat,” Journal of Comparative Neurology, vol. 508, no. 4, pp. 592–604, 2008.
[27]
B. J. Sessle, “Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates,” Critical Reviews in Oral Biology and Medicine, vol. 11, no. 1, pp. 57–91, 2000.
[28]
S. F. A. Santos, S. Rebelo, V. A. Derkach, and B. V. Safronov, “Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat,” Journal of Physiology, vol. 581, no. 1, pp. 241–254, 2007.
[29]
J. M. Braz, M. A. Nassar, J. N. Wood, and A. I. Basbaum, “Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor,” Neuron, vol. 47, no. 6, pp. 787–793, 2005.
[30]
A. J. Todd and A. C. Sullivan, “Light microscope study of the coexistence of GABA-like and glycine-like immunoreactivities in the spinal cord of the rat,” Journal of Comparative Neurology, vol. 296, no. 3, pp. 496–505, 1990.
[31]
A. J. Todd, C. Watt, R. C. Spike, and W. Sieghart, “Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord,” The Journal of Neuroscience, vol. 16, no. 3, pp. 974–982, 1996.
[32]
R. L. Macdonald and R. W. Olsen, “GABA(A) receptor channels,” Annual Review of Neuroscience, vol. 17, pp. 569–602, 1994.
[33]
T. J. Price, F. Cervero, and Y. de Koninck, “Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia,” Current Topics in Medicinal Chemistry, vol. 5, no. 6, pp. 547–555, 2005.
[34]
J. F. MacDonald, M. F. Jackson, and M. A. Beazely, “Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors,” Critical Reviews in Neurobiology, vol. 18, no. 1-2, pp. 71–84, 2006.
[35]
H. M？hler, U. Rudolph, D. Boison, P. Singer, J. Feldon, and B. K. Yee, “Regulation of cognition and symptoms of psychosis: focus on GABA(A) receptors and glycine transporter 1,” Pharmacology Biochemistry and Behavior, vol. 90, no. 1, pp. 58–64, 2008.
[36]
J. S. Serrano, M. I. Serrano, M. R. Guerrero, R. Ruiz, and J. Polo, “Antinociceptive effect of taurine and its inhibition by naxolone,” General Pharmacology, vol. 21, no. 3, pp. 333–336, 1990.
[37]
C. S. Hornfeldt, D. H. Smullin, C. D. Schamber, X. Sun, and A. A. Larson, “Antinociceptive effects of intrathecal taurine and calcium in the mouse,” Life Sciences, vol. 50, no. 24, pp. 1925–1934, 1992.
[38]
I. Belfer, E. Davidson, A. Ratner, E. Beery, Y. Shir, and Z. Seltzer, “Dietary supplementation with the inhibitory amino acid taurine suppresses autotomy in HA rats,” NeuroReport, vol. 9, no. 13, pp. 3103–3107, 1998.
[39]
I. S. Lee, W. M. Renno, and A. J. Beitz, “A quantitative light and electron microscopic analysis of taurine-like immunoreactivity in the dorsal horn of the rat spinal cord,” Journal of Comparative Neurology, vol. 321, no. 1, pp. 65–82, 1992.
[40]
D. A. Bereiter, S. Shen, and A. P. Benetti, “Sex differences in amino acid release from rostral trigeminal subnucleus caudalis after acute injury to the TMJ region,” Pain, vol. 98, no. 1-2, pp. 89–99, 2002.
[41]
S. A. Park, H. Yin, J. P. Bhattarai et al., “Postnatal change of GluR5 kainate receptor expression in the substantia gelatinosa neuron of the trigeminal subnucleus caudalis in mice,” Brain Research, vol. 1346, pp. 52–61, 2010.
[42]
N. Tokutomi, M. Kaneda, and N. Akaike, “What confers specificity on glycine for its receptor site?” British Journal of Pharmacology, vol. 97, no. 2, pp. 353–360, 1989.
[43]
N. Hussy, C. Deleuze, A. Pantaloni, M. G. Desarménien, and F. Moos, “Agonist action of taurine on glycine receptors in rat supraoptic magnocellular neurones: possible role in osmoregulation,” Journal of Physiology, vol. 502, no. 3, pp. 609–621, 1997.
[44]
Z. Tang, Y. Lu, and L. Chen, “Developmental stability of taurine's activation on glycine receptors in cultured neurons of rat auditory cortex,” Neuroscience Letters, vol. 430, no. 1, pp. 54–59, 2008.
[45]
N. Y. Song, H. B. Shi, C. Y. Li, and S. K. Yin, “Interaction between taurine and GABA(A)/glycine receptors in neurons of the rat anteroventral cochlear nucleus,” Brain Research, vol. 1472, pp. 1–10, 2012.
[46]
M. Puopolo, I. Kratskin, and O. Belluzzi, “Direct inhibitory effect of taurine on relay neurones of the rat olfactory bulb in vitro,” NeuroReport, vol. 9, no. 10, pp. 2319–2323, 1998.
[47]
O. Belluzzi, M. Puopolo, M. Benedusi, and I. Kratskin, “Selective neuroinhibitory effects of taurine in slices of rat main olfactory bulb,” Neuroscience, vol. 124, no. 4, pp. 929–944, 2004.
[48]
Z.-Y. Wu and T. Xu, “Taurine-evoked chloride current and its potentiation by intracellular Ca2+ in immature rat hippocampal CA1 neurons,” Amino Acids, vol. 24, no. 1-2, pp. 155–161, 2003.
[49]
B. M. Stell and I. Mody, “Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons,” The Journal of Neuroscience, vol. 22, no. 10, p. RC223, 2002.
[50]
D. W. Cope, S. W. Hughes, and V. Crunelli, “GABA(A) receptor-mediated tonic inhibition in thalamic neurons,” The Journal of Neuroscience, vol. 25, no. 50, pp. 11553–11563, 2005.
[51]
T. Shirasaki, M. R. Klee, T. Nakaye, and N. Akaike, “Differential blockade of bicuculline and strychnine on GABA- and glycine-induced responses in dissociated rat hippocampal pyramidal cells,” Brain Research, vol. 561, no. 1, pp. 77–83, 1991.
[52]
T. Horikoshi, A. Asanuma, K. Yanagisawa, K. Anzai, and S. Goto, “Taurine and beta-alanine act on both GABA and glycine receptors in Xenopus oocyte injected with mouse brain messenger RNA,” Brain Research, vol. 464, no. 2, pp. 97–105, 1988.
[53]
Z. Jiang, K. Krnjevi？, F. Wang, and J. H. Ye, “Taurine activates strychnine-sensitive glycine receptors in neurons freshly isolated from nucleus accumbens of young rats,” Journal of Neurophysiology, vol. 91, no. 1, pp. 248–257, 2004.
[54]
P. Pfeiffer, D. Graham, and H. Betz, “Purification by affinity chromatography of the glycine receptor of rat spinal cord,” The Journal of Biological Chemistry, vol. 257, no. 16, pp. 9389–9393, 1982.
[55]
P. Legendre, “The glycinergic inhibitory synapse,” Cellular and Molecular Life Sciences, vol. 58, no. 5-6, pp. 760–793, 2001.
[56]
J. Grudzinska, R. Schemm, S. Haeger et al., “The β subunit determines the ligand binding properties of synaptic glycine receptors,” Neuron, vol. 45, no. 5, pp. 727–739, 2005.
[57]
M. H. Cheng, M. Cascio, and R. D. Coalson, “Homology modeling and molecular dynamics simulations of the α1 glycine receptor reveals different states of the channel,” Proteins, vol. 68, no. 2, pp. 581–593, 2007.
[58]
I. Pribilla, T. Takagi, D. Langosch, J. Bormann, and H. Betz, “The atypical M2 segment of the β subunit confers picrotoxinin resistance to inhibitory glycine receptor channels,” The EMBO Journal, vol. 11, no. 12, pp. 4305–4311, 1992.
[59]
P. Jiang, Y. Kong, X. Zhang, W. Wang, C. Liu, and T. Xu, “Glycine receptor in rat hippocampal and spinal cord neurons as a molecular target for rapid actions of 17-β-estradiol,” Molecular Pain, vol. 5, article 2, 2009.
[60]
T. Takazawa and A. B. MacDermott, “Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons,” Journal of Physiology, vol. 588, no. 14, pp. 2571–2587, 2010.
[61]
P. J. Whiting, “GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery?” Drug Discovery Today, vol. 8, no. 10, pp. 445–450, 2003.
[62]
E. R. Korpi, R. M. Mihalek, S. T. Sinkkonen et al., “Altered receptor subtypes in the forebrain of GABA(A) receptor δ subunit-deficient mice: recruitment of γ2 subunits,” Neuroscience, vol. 109, no. 4, pp. 733–743, 2002.
[63]
W. Sieghart and G. Sperk, “Subunit composition, distribution and function of GABA(A) receptor subtypes,” Current Topics in Medicinal Chemistry, vol. 2, no. 8, pp. 795–816, 2002.
[64]
P. Somogyi, J.-M. Fritschy, D. Benke, J. D. B. Roberts, and W. Sieghart, “The γ2 subunit of the GABA(A) receptor is concentrated in synaptic junctions containing the α1 and β2/3 subunits in hippocampus, cerebellum and globus pallidus,” Neuropharmacology, vol. 35, no. 9-10, pp. 1425–1444, 1996.
[65]
W. Wei, N. Zhang, Z. Peng, C. R. Houser, and I. Mody, “Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus,” The Journal of Neuroscience, vol. 23, no. 33, pp. 10650–10661, 2003.
[66]
A. Semyanov, M. C. Walker, D. M. Kullmann, and R. A. Silver, “Tonically active GABA(A) receptors: modulating gain and maintaining the tone,” Trends in Neurosciences, vol. 27, no. 5, pp. 262–269, 2004.
[67]
M. Farrant and Z. Nusser, “Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors,” Nature Reviews Neuroscience, vol. 6, no. 3, pp. 215–229, 2005.
[68]
J. P. Bhattarai, S. A. Park, J. B. Park et al., “Tonic extrasynaptic GABA(A) receptor currents control gonadotropin-releasing hormone neuron excitability in the mouse,” Endocrinology, vol. 152, no. 4, pp. 1551–1561, 2011.
[69]
C. J. A. Game and D. Lodge, “The pharmacology of the inhibition of dorsal horn neurones by impulses in myelinated cutaneous afferents in the cat,” Experimental Brain Research, vol. 23, no. 1, pp. 75–84, 1975.
[70]
M. Yoshimura and S. Nishi, “Blind patch-clamp recordings from substantia gelatinosa neurons in adult rat spinal cord slices: pharmacological properties of synaptic currents,” Neuroscience, vol. 53, no. 2, pp. 519–526, 1993.
[71]
H. Ripps and W. Shen, “Review: taurine: a “very essential” amino acid,” Molecular Vision, vol. 18, pp. 2673–2686, 2012.
[72]
K. Matsumoto, E. H. Lo, A. R. Pierce, E. F. Halpern, and R. Newcomb, “Secondary elevation of extracellular neurotransmitter amino acids in the reperfusion phase following focal cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 16, no. 1, pp. 114–124, 1996.
[73]
Y. Uchiyama-Tsuyuki, H. Araki, T. Yae, and S. Otomo, “Changes in the extracellular concentrations of amino acids in the rat striatum during transient focal cerebral ischemia,” Journal of Neurochemistry, vol. 62, no. 3, pp. 1074–1078, 1994.
[74]
M. A. M. Silva, G. M. A. Cunha, G. S. B. Viana, and V. S. N. Rao, “Taurine modulates chemical nociception in mice,” Brazilian Journal of Medical and Biological Research, vol. 26, no. 12, pp. 1319–1324, 1993.
