18 1 Aδ PAG periaqueductal gray PMC pontine micturition center DRG dorsal root ganglion 3 / NMDA AMPA synergistic NMDA MK-801 AMPA LY i NMDA M
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1 / - I N- methyl-d-aspartate NMDA α-amino-3- hydroxy-5-methylisoxazole-4-propionic acid AMPA metabotropic glutamate II 3 L- 2 NMDA dizocilpine MK-801 AMPA LY NMDA AMPA
2 18 1 Aδ PAG periaqueductal gray PMC pontine micturition center DRG dorsal root ganglion 3 / NMDA AMPA synergistic NMDA MK-801 AMPA LY i NMDA MK-801 AMPA LY NMDA AMPA 4 ii NMDA MK-801 AMPA GYKI52466 NMDA AMPA
3 19 2 periaqueductal gray anterior cingulated gyrus insula PAG periaqueductal gray PMC pontine micturition center DRG dorsal root ganglion 5,6 NMDA AMPA group I/II mglur1, mglur5/mglur2, mglur3 ACPD 7 group I/II MCPG silent 8 mglur1a 71 mglur5 MPEP 9 mglur1a mglur5
4 20 3 NMDA AMPA mglur1 mglur5 mglur1 PAG periaqueductal gray PMC pontine micturition center DRG dorsal root ganglion. MPEP mglur1a mglur1a mglur5 III 3 NMDA MK-801 AMPA GYKI52466 LY NMDA AMPA NMDA AMPA 13 AMPA
5 21 4 i ii iiiiv GYKI52466 LY AMPA GluR-A GluR-B mrna GluR-C GluR-D mrna GluR-C GluR-D mrna GluR-A GluR-B mrna NMDA NR1 NR2A NR2B mrna NR2A NR2B mrna 14 mglur1 mglur5 15 group I/II MCPG 8 mglur1a 1a IV 4 5-Hydroxytryptamine 5-HT 5-HT
6 HT 20 5-HT 7 5-HT 1 5-HT 2 5-HT 3 5-HT 7 5-HT 1 5-HT 1A 8-OH-DPAT 5-HT 1A 21 5-HT 1A 17 5-HT 1A 22 5-HT 1A WAY HT 1A 23 WAY WAY WAY HT 1A 5-HT 1A 2 5-HT 5-HT 5-HT 1A 5-HT 1A 21 silent 5-HT 1A WAY WAY HT 1A HT 1A WAY HT 1A in vitro in vivo 5-HT 1A 5-HT 1A WAY HT 1A - 5-HT 2 5-HT 2A 5-HT 2B 5-HT 2C 3 5-HT 2A 5-HT 2C 5-HT 2C m-chlorophenylpiperazine mcpp 26 5-HT HT 3 zatosetron 5-HT 3 - zatosetron 5-HT 3 2-methyl-5-HT 5-HT 3
7 23 zatosetron 2-methyl- 5-HT 27 5-HT 7 SB HT 7 V 4 5-HT 1A 5-HT HT 2 5-HT 3 19,28 5-HT 2C 29 5-HT 1A 13,30 5-HT 1A 5-HT 2 5-HT 5-methoxy-N,N-dimethyltryptamine 5-MeODMT 32 5-MeODMT 5-HT 1A mcpp 27 5-HT 2 5-HT 2A 27 VI α 1 prazosin 37,38 6-hydroxydopamine α 1 phenylephrine 38 39,40 α 1 Kontani phenylephrine prazosin 41 Ishizuka α 1 doxazosin 42
8 24 5 i ii PMC pontine micturition center PGN preganglionic neurons α i ii - - α 1A α 1B α 1D 44 α 1A- RS α 1A- RS nmol α 1B (+)-cyclazosin 50 nmol α 1A- α 1B- NMDA NMDA α 1A- α 1B- α 1A- 2 α 1- α 1B (+)-cyclazosin α 1B α 1D- BMY 7378 α 1D- 44 α 1A- α 1B- α 1- α 1A- α 1B α 1D- 47 α ,49 α 1 prazosin
9 25 1 mrna α1 α2 1a 3+ 2a 5+ 1b 4+ 2b 7+ 1d 6+ 2c 2+ 1a 0 2a 3+ 1b 0 2b d 0 2c 0 1a 3+ 2a 3+ 1b 3+ 2b 6+ 1d 8+ 2c 0 1a 4+ 2a 3+ 1b 3+ 2b 10+ 1d 10+ 2c 0 α1a mrna α1d α1 mrna α2 mrna α2b Stafford Smith et al., Mol Brain Res 34: , 1995; Stafford Smith et al., Mol Brain Res 63: , 1999 α 1-50,51 α 2- / α 2 clonidine α 2 52,53 α α 2- medetomidine 54 α 2- idazoxan 64 NMDA MK-801 idazoxan MK-801 Idazoxan serotonin-noradrenaline reuptake inhibitor SNRI α 2- α 2- serotonin-noradrenaline reuptake inhibitor SNRI VII NMDA AMPA
10 26 Bladder Bladder afferent pathway GLU α2-ar 5-HT/NE α2-ar GLU External urethral sphincter Soma c motor pathway Onuf s nucleus 6 - α 2- α 2-5HT/NE / GLU α 2-AR α 2- mglur1 mglur5 SNRI / / SNRI 5-HT 5-HT 1A 5-HT 2B α 1 α 2 α 2 - SNRI 1 de Groat WC, Booth AM, Yoshimura N: Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi CA, ed. The Autonomic Nervous System: Nervous Control of the Urogenital System, vol. 3, Harwood Academic Publishers, London, pp , Willette RN, Morrison S, Sapru HN, Reis DJ: Stimulation of opiate receptors in the dorsal pontine tegmentum inhibits reflex contraction of the urinary bladder. J Pharmacol Exp Ther, 244: , Yoshiyama M, de Groat WC: Supraspinal and spinal α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid and N-methyl-D-aspartate glutamatergic control of the micturition reflex in the urethane-anesthetized rat. Neuroscience, 132: , Kakizaki H, Yoshiyama M, Roppolo JR, Booth AM, de Groat WC: Role of spinal glutamatergic transmission in the ascending limb of the micturition reflex pathway in the rat. J Pharmacol Exp
11 27 Ther, 285: 22 27, Matsumoto G, Hisamitsu T, de Groat WC: Role of glutamate and NMDA receptors in the descending limb of the spinobulbospinal micturition reflex pathway of the rat. Neurosci Lett, 183: 58 61, Matsumoto G, Hisamitsu T, de Groat WC: Non- NMDA glutamatergic excitatory transmission in the descending limb of the spinobulbospinal micturition reflex pathway of the rat. Brain Res, 693: , Tanaka H, Kakizaki H, Shibata T, Ameda K, Koyanagi T: Effects of a selective metabotropic glutamate receptor agonist on the micturition reflex pathway in urethane-anesthetized rats. Neurourol Urodyn, 22: , Yoshiyama M, de Groat WC: Role of spinal metabotropic glutamate receptors in regulation of lower urinary tract function in the decerebrate unanesthetized rat. Neurosci Lett, 420: 18 22, Yoshiyama M: Glutamatergic mechanisms controlling lower urinary tract function. LUTS (Lower Urinary Tract Symptoms), 1: S101 S104, Yoshiyama M, Roppolo JR, de Groat WC: Effects of GYKI and CNQX, AMPA/kainate receptor antagonists, on the micturition reflex in the rat. Brain Res, 691: , Yoshiyama M, Roppolo JR, Thor KB, de Groat WC: Effects of LY274614, a competitive NMDA receptor antagonist, on the micturition reflex in the urethane-anaesthetized rat. Br J Pharmacol, 110: 77 86, Yoshiyama M, Roppolo JR, de Groat WC: Effects of LY215490, a competitive α-amino-3-hydroxy- 5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, on the micturition reflex in the rat. J Pharmacol Exp Ther, 280: , Chang HY, Cheng CL, Chen JJ, de Groat WC: Roles of glutamatergic and serotonergic mechanisms in reflex control of the external urethral sphincter in urethane-anesthetized female rats. Am J Physiol Regul Integr Comp Physiol, 291: R224 R234, Shibata T, Watanabe M, Ichikawa R, Inoue Y, Koyanagi T: Different expressions of α-amino- 3-hydroxy-5-methyl-4-isoxazole propionic acid N-methyl-D-aspartate receptor subunit mrnas between visceromotor and somatomotor neurons of the rat lumbosacral spinal cord. J Comp Neurol, 404: , Alvarez FJ, Villalba RM, Carr PA, Grandes P, Somohano PM: Differential distribution of metabotropic glutamate receptors 1a, 1b, and 5 in the rat spinal cord. J Comp Neurol, 422: , Lumb BM: Brainstem control of visceral afferent pathways in the spinal cord. Prog Brain Res, 67: , Lecci A, Giuliani S, Santicioli P, Maggi CA: Involvement of 5-hydroxytryptamine1A receptors in the modulation of micturition reflexes in the anesthetized rat. J Pharmacol Exp Ther, 262: , Steers WD, Albo M, van Asselt E: Effects of serotonergic agonists on micturition and sexual function in the rat. Drug Dev Res, 27: , Espey MJ, Du HJ, Downie JW: Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats. Brain Res, 798: , Thor KB, Nickolaus S, Helke CJ: Autoradiographic localization of 5-hydroxytryptamine 1A, 5-hydroxytryptamine 1B and 5-hydroxytryptamine 1c/2 binding sites in the rat spinal cord. Neuroscience, 55: , Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, et al.: A pharmacological profile of the selective silent 5-HT 1A receptor antagonist, WAY Eur J Pharmacol, 281: 81 88, Testa R, Guarneri L, Poggesi E, Angelico P, Velasco C, et al.: Effects of several 5-hydroxytryptamine 1A receptor ligands on the micturition reflex in rats: comparison with WAY J Pharmacol Exp Ther, 290: , Kakizaki H, Yoshiyama M, Koyanagi T, de Groat WC: Effects of WAY100635, a selective 5-HT 1A - receptor antagonist on the micturition-reflex pathway in the rat. Am J Physiol Regul Integr Comp Physiol, 280: R1407 R1413, Yoshiyama M, Kakizaki H, de Groat WC: Suppression of the micturition reflex in urethaneanesthetized rats by intracerebroventricular injection of WAY100635, a 5-HT 1A receptor antagonist. Brain Res, 980: , Sugaya K, Ogawa Y, Hatano T, Koyama Y, Miyazato T, et al.: Evidence for involvement of the subcoeruleus nucleus and nucleus raphe magnus in urine storage and penile erection in decerebrate rats. J Urol, 159: , Steers WD, de Groat WC: Effects of m-chlorophenylpiperazine on penile and bladder function in rats. Am J Physiol Regul Integr Comp Physiol, 257: R1441 R1449, Ramage AG: The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control
12 28 of micturition. Br J Pharmacol, 147: S120 S131, Danuser H, Thor KB: Spinal 5HT 2 receptormediated facilitation of pudendal nerve reflexes in the anaesthetized cat. Br J Pharmacol, 118: , Conlon K, Miner W, McCleary S, McMurray G: Identification of 5-HT 2C mediated mechanisms involved in urethral sphincter reflexes in a guinea-pig model of urethral function. BJU Int, 110: E113 E117, Thor KB, Katofiasc MA. Danuser H, Springer J. Schaus JM: The role of 5-HT 1A receptors in control of lower urinary tract function in cats. Brain Res, 946: , Thor KB, Hisamitsu T, de Groat WC: Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy- N,N-dimethyltryptamine. Dev Brain Res, 54: 35 42, Dahlstr MA, Fuxe K: The distribution of monoamine terminals in the central nervous system. II. Experimentally induced changes in the interneuronal amine levels of the bulbospinal neuron systems. Acta Physiol Scand, 64 (Suppl. 274): 1 36, Loewy AD, Saper CB, Baker RP: Descending projections from the pontine micturition center. Brain Res, 172, , Satoh K, Tohyama M, Sakumoto T, Yamamoto K, Shimizu N: Descending projection of the nucleus tegmentalis laterodorsalis to the spinal cord: studied by the horseradish peroxidase method following 6-hydroxy-dopa administration. Neurosci Lett, 8, 9 15, Westlund KN, Bowker RM, Ziegler MG, Coulter JD: Descending noradrenergic projections and their spinal terminations. In Progress in Brain Research: Anatomy of Descending Pathways to the Spinal Cord. ed. Kuypers, H.G.J.M. & Martin, G.F. pp Amsterdam: Elsevier, de Groat WC: Nervous control of the urinary bladder of the cat. Brain Res, 87: , Yoshimura N, Sasa M, Ohno Y, Yoshida O, Takaori S: Contraction of urinary bladder by central norepinephrine originating in the locus coeruleus. J Urol, 139, , Yoshimura N, Sasa M, Yoshida O, Takaori S: Mediation of micturition reflex by central norepinephrine from the locus coeruleus in the cat. J Urol, 143, , Downie JW, Bialik GJ, Shefchyk SJ, Fedirchuk B, Song L: Roles for sacral spinal alpha-adrenoreceptors in mediating or modulating bladder and sphincter activity in the cat. Neurourol Urodyn, 10, , Espey MJ, Downie JW, Fine A: Effect of 5-HT receptor and adrenoceptor antagonists on micturition in conscious cats. Eur J Pharmacol, 221: , Kontani H, Maruyama I, Sakai T: Involvement of α 2 -adrenoceptors in the sacral micturition reflex in rats. Japan J Pharmacol, 60: , Ishizuka O, Persson K, Mattiasson A, Naylor A, Wyllie M, Andersson KE: Micturition in conscious rats with and without bladder outlet obstruction: role of spinal α 1 -adrenoceptors. Br J Pharmacol, 117, , Yoshiyama M, Yamamoto T, de Groat WC: Role of spinal α1-adrenergic mechanisms in the control of lower urinary tract in the rat. Brain Res, 882: 36 44, Yoshiyama M, de Groat WC: Role of spinal α1- adrenocepto subtypes in the bladder reflex in anesthetized rats. Am J Physiol Regul Integr Comp Physiol, 280: R1414 R1419, Giardina D, Crucianelli M, Romanelli R, Leonardi A, Poggesi E, Melchiorre C: Synthesis and biological profile of the enantiomers of [4-(4- amino-6,7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin-1-yl]furan-2-ylmethanone (cyclazosin), a potent competitive ( 1B -adrenoceptor antagonist. J Med Chem, 39, , Stam WB, van der Graaf PH, Saxena PR: Functional characterization of the pharmacological profile of the putative ( 1B -adrenoceptor antagonist, (+)-cyclazosin. Eur J Pharmacol, 361, 79 83, Wada T, Otsu T, Hasegawa Y, Mizuchi A, Ono H: Characterization of α 1 -adrenoceptor subtypes in rat spinal cord. Eur J Pharmacol, 312, , Stafford Smith M, Schambra UB, Wilson KH, Page SO, Hulette C, Light AR, Schwinn DA: α 2 -Adrenergic receptors in human spinal cord: specific localized expression of mrna encoding alpha 2-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res, 34: , Stafford Smith M, Schambra UB, Wilson KH, Page SO, Schwinn DA: α1-adrenergic receptors in human spinal cord: specific localized expression of mrna encoding alpha1-adrenergic receptor subtypes at four distinct levels. Brain Res Mol Brain Res, 63: , Gajewski J, Downie JW, Awad SA: Experimental evidence for a central nervous system site of action in the effect of alpha-adrenergic blockers
13 29 on the external urethral sphincter. J Urol, 132: , Danuser H, Thor KB: Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by the α 1 adrenergic receptor antagonist prazosin. J Urol, 153: , Galeano C, Jubelin B, Germain L, Guenette L: Micturition reflexes in chronic spinalized cats: the underactive detrusor and detrusor-sphincter dyssynergia. Neurourol Urodyn, 5: 45 63, Dennys P, Chartier-Kastler E, Azouvi P, Remy- Neris O, Bussel B: Intrathecal clonidine for refractory detrusor hyperreflexia in spinal cord injured patients: a preliminary report. J Urol, 160: , Furuta A, Asano K, Egawa S, de Groat WC, Chancellor MB, Yoshimura N: Role of α2- adrenocepors and glutamate mechanisms in the external uethral sphincter continence reflex in rats. J Urol, 181: , 2009.
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