Abstract
Structure and distribution of afferent nerve fibres in the rat bladder were studied by fluorescence microscopy after selective staining with antibodies against neuropeptide CGRP. Afferent fibres are very abundant (by comparison with other viscera) and interconnected in all bladder parts: muscle, urothelium, connective tissue, blood vessels, serosa. Their highest concentration is beneath the urothelium in equatorial and caudal regions, where they form a plexus, while individually maintaining a tree-like structure with innumerable branches running without preferential orientation. In cranial regions, mucosal afferent fibres become rare or absent. Abundant fibres are found in the detrusor, within each muscle bundle, with long strings of varicosities parallel to muscle cells. Afferent fibres, invariably varicose over hundreds of micrometres of their terminal parts and while still branching, comprise chains of hundreds of varicosities. Varicosities are irregular in size, frequency and separation, without specialised terminal structures around them, or within or around the fibre’s ending. The possibility that varicosities are transduction points for sensory inputs is discussed, with the implication of a process taking place over considerable length in each branch of each fibre. Interconnectedness of afferent nerves of various bladder tissues, distribution of varicosities over hundreds of micrometres along axonal branches, absence of clear target structures for the fibres, apparent irregularity in the size and sequence of varicosities suggest an innervation that is not rigidly wired with distinct sensory pathways. In fact, the structural evidence suggests extensive afferent integration at the periphery, with wide distribution of source points and broad range of physical detectors.
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References
Alm P, Alumets J, Brodin E, Hakanson R, Nilsson G, Sjöberg N-O, Sundler F (1978) Peptidergic (substance P) nerves in the genito-urinary tract. Neuroscience 3:419–425
Andersson KE, McCloskey KD (2014) Lamina propria: the functional center of the bladder. Neurourol Urodynam 33:9–16
Applebaum AE, Vance WH Coggeshall RE (1980) Segmental localization of sensory cells that innervate the bladder. J Comp Neurol 192:203–209
Apodaca G (2004) The uroepithelium not just a passive barrier. Traffic 5:117–128
Araki I, Du S, Kobayashi H, Sawada N, Mochizuki T, Zakoji H, Takeda M (2008) Roles of mechanosensitive ion channels in bladder sensory transduction and overactive bladder. Int J Urol 15:681–687
Bennett MR (1996) Autonomic neuromuscular transmission at a varicosity. Prog Neurobiol 50:505–532
Birder LA (2014) Nervous network for lower urinary tract function. Int J Urol 20:4–12
Birder L, Andersson KE (2013) Urothelial signaling. Physiol Rev 93:653–680
Burcher E, Zeng X-P, Stigas J, Shang F, Millard RJ, Moore KH (2000) Autoradiographic localization of tachykinin and calcitonin gene-related peptide receptors in adult urinary bladder. J Urol 163:331–337
de Groat WC, Yoshimura N. (2009) Afferent nerve regulation of bladder function in health and disease. Handbook Exp Pharmacol. 2009;194: 91–138. [In: Sensory Nerves, edited by Canning B & Spina D]
Dixon JS, Gilpin CJ (1987) Presumptive sensory axons of the human urinary bladder: a fine structural study. J Anat 151:199–207
Ferguson DR, Kennedy I, Burton TJ (1997) ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes – a possible sensory mechanism? J Physiol 505: 503–11
Franco-Cereceda A, Henke H, Lundberg JM, Petermann JB, Hökfelt T, Fischer JA (1987) Calcitonin gene-related peptide (CGRP) in capsaicin-sensitive substance P-immunoreactive sensory neurons in animals and man: distribution and release by capsaicin. Peptide 8:399–410
Gabella G (1995) The structural relations between nerve fibres and muscle cells in the urinary bladder of the rat. J Neurocytol 24:159–187
Gabella G, Davis C (1998) Distribution of afferent axons in the baldder of rats. J Neurocytol 27:141–155
Gabella G (1999) Structure of the intramural nerves of the rat bladder. J Neurocytol 28:615–637
Gillespie JI, Markeling-van Ittersum M, de Vente J (2006) Sensory collaterals, intramural ganglia and motor nerves in the guinea-pig bladder: evidence for intramural neural circuits. Cell Tissue Res 325:33–45
Gosling JA, Dixon JS (1974) Sensory nerves in the mammalian urinary tract. An evaluation using light and electron microscopy. J Anat 117:133–144
Gulbenkian S, Merighi A, Wharton J, Varndell IM, Polak JM (1986) Ultrastructural evidence for the coexistence of calcitonin gene-related peptide and substance P in secretory vesicles of peripheral nerves in the guinea pig. J Neurocytol 15:535–542
Hirst GDS, Choate JK, Cousins HM, Edwards FR, Klemm MF (1996) Transmission by postganglionic axons of the autonomic nervous system: the importance of the specialized neuroeffector junction. Neuroscience 73:7–23
Hökfelt T, Schultzberg M, Elde R, Nilsson G, Terenius L, Said S, Goldstein M (1978) Peptide neurons in peripheral tissues including the urinary tract: immunohistochemical studies. Acta Pharmacol Toxicol 43(II):78–89
Kanai AJ, Andersson KE (2010) Bladder afferent signaling: recent findings. J Urol 2010(183):1288–1295
Lundberg JM, Franco-Cereceda A, Alving K, Delay-Goyet P, Lou Y-P (1992) Release of calcitonin gene-related peptide from sensory neurons. Ann N Y Acad Sci 657:187–193
Maggi CA, Santicioli P, Abelli L, Parlani M, Capasso M, Conte B, Giuliani S, Meli A (1987) Regional differences in the effects of capsaicin and tachykinins on motor activity and vascular permeability of the rat lower urinary tract. Naunyn Schmiedeberg’s Arch Pharmacol 335:636–645
Masunaga K, Yoshida M, Inadome A, Iwashita H, Miyamae K, Ueda S (2006) Prostaglandin E2 release from isolated bladder strips in rats with spinal cord injury. Int J Urol 13:271–276
Mattiasson A, Ekblad E, Sundler F, Uvelius B (1985) Origin and distribution of neuropeptide Y-, vasoactive intestinal polypeptide- and substance P-containing nerve fibers in the urinary bladder of the rat. Cell Tissue Res 239:141–146
Nakagomi H, Yoshiyama M, Mochizuki T, Miyamoto T, Komatsu R, Imura Y, Moizawa Y, Hiasa M, Miyaji T, Kira S, Araki I, Fujishita K, Shibata K, Shigetomi E, Shinozaki Y, Ichikawa R, Uneyama H, Iwatsuki K, Nomura M, de Groat WC, Moriyama Y, Takeda M, Koizumi S (2016) Urothelial ATP exocytosis: regulation of bladder compliance in the urine storage phase. Scientific Report 6: 1–14
Papka RE, McNeill DL (1992) Is there a synaptic innervation of pelvic neurons by CGRP-immunoreactive sensory nerves. Ann N Y Acad Sci 657:477–480
Papka RE, McNeill DL (1993) Light- and electron-microscopic study of synaptic connections in the paracervical ganglion of the female rat: special reference to calcitonin gene-related peptide-, galanin- and tachykinin (substance P and neurokinin A)-immunoreactive nerve fibers and terminals. Cell Tissue Res 271:417–428
Schueth A, Spronck B, van Zandvoort MAMJ, van Koeveringe GA (2017) Computer-assisted three-dimensional tracking of sensory innervation in the murine bladder mucosa with two-photo microscopy. J Chemical Neuroanat 85:43–49
Senba E, Tohyama M (1988) Calcitonin gene-related peptide containing autonomic efferent pathways to the pelvic ganglia of the rat. Brain Res 449:386–390
Sengupta JN, Gebhart GF (1994) Mechanosensitive properties of pelvic nerve afferent fibers innervating the urinary bladder of the rat. J Neurophysiol 72:2420–2430
Shea VK, Cai R, Crepps B, Mason JL, Perl ER (2000) Sensory fibers of the pelvic nerve innervating the rat’s urinary bladder. J Neurophysiol 84:1924–1933
Smet PJ, Moore KH, Jonavicius J (1997) Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Investig 77:37–49
Su HC, Wharton J, Polak JM, Mulderry PK, Ghatei MA, Gibson SJ, Terenghi G, Morrison JFB, Ballesta J, Bloom SR (1986) Calcitonin gene-related peptide immunoreactivity in afferent neurons supplying the urinary tract: combined retrograde tracing and immunocytochemistry. Neuroscience 18:727–747
Tamaki M, Iwanaga T, Takeda M, Adachi I, Satu S, Fujita T (1992) Calcitonin gene-related peptide (CGRP)-immunoreactive nerve terminals in the whole mount preparations of the dog urethra. Arch Histol Cytol 55:1–11
Vera PL Nadelhaft I (1990) Conduction velocity distribution of afferent fibers innervating the rat urinary bladder. Brain Res 520:83–89
Wakabayashi Y, Tomoyoshi T, Fujimiya M, Arai R, Maeda T (1993) Substance P-containing axon terminals in the mucosa of the human urinary bladder: pre-embedding immunohistochemistry using cryostat sections for electron microscopy. Histochemistry 100:401–407
Yokokawa K, Sakanaka M, Shiosaka S, Toyama M, Shiotani Y, Sonoda T (1985) Three-dimensional distribution of substance P-like immunoreactivity in the urinary bladder of the rat. J Neural Transmission 63:209–222
Yokokawa K, Tahyama M, Shiosaka S, Shiotani Y, Sonoda T, Emson PC, Hillyard CV, Girgis S, MacIntyre I (1986) Distribution of calcitonin gene-related peptide-containing fibers in the urinary bladder of the rat and their origin. Cell Tissue Res 244:271–278
Yoshida M, Inadome A, Maeda Y, Satoji Y, Masunaga K, Sugiyama Y, Murakami S (2006) Non-neuronal cholinergic system in human bladder urothelium. Urology 67:425–430
Zagorodnyuk VP, Gibbins IL, Costa M, Brookes SJ Gregory SJ (2007) Properties of the major classes of mechanoreceptors in the guinea pig bladder. J Physiol 585:147–163
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Gabella, G. Afferent nerve fibres in the wall of the rat urinary bladder. Cell Tissue Res 376, 25–35 (2019). https://doi.org/10.1007/s00441-018-2965-0
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DOI: https://doi.org/10.1007/s00441-018-2965-0