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Translating peripheral bladder afferent mechanosensitivity to neuronal activation within the lumbosacral spinal cord of mice

Grundy, Lukea,b; Harrington, Andrea M.a,b; Caldwell, Ashleea,b; Castro, Joela,b; Staikopoulos, Vasilikic; Zagorodnyuk, Vladimir P.d; Brookes, Simon J.H.d; Spencer, Nick J.d; Brierley, Stuart M.a,b,*

doi: 10.1097/j.pain.0000000000001453
Research Paper
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Primary afferent neurons transduce distension of the bladder wall into action potentials that are relayed into the spinal cord and brain, where autonomic reflexes necessary for maintaining continence are coordinated with pathways involved in sensation. However, the relationship between spinal circuits involved with physiological and nociceptive signalling from the bladder has only been partially characterised. We used ex vivo bladder afferent recordings to characterise mechanosensitive afferent responses to graded distension (0-60 mm Hg) and retrograde tracing from the bladder wall to identify central axon projections within the dorsal horn of the lumbosacral (LS) spinal cord. Labelling of dorsal horn neurons with phosphorylated-MAP-kinase (pERK), combined with labelling for neurochemical markers (calbindin, calretinin, gamma aminobutyric acid, and parvalbumin) after in vivo bladder distension (20-60 mm Hg), was used to identify spinal cord circuits processing bladder afferent input. Ex vivo bladder distension evoked an increase in primary afferent output, and the recruitment of both low- and high-threshold mechanosensitive afferents. Retrograde tracing revealed bladder afferent projections that localised with pERK-immunoreactive dorsal horn neurons within the superficial laminae (superficial dorsal horn), dorsal gray commissure, and lateral collateral tracts of the LS spinal cord. Populations of pERK-immunoreactive neurons colabelled with calbindin, calretinin, or gamma aminobutyric acid, but not parvalbumin. Noxious bladder distension increased the percentage of pERK-immunoreactive neurons colabelled with calretinin. We identified LS spinal circuits supporting autonomic and nociceptive reflexes responsible for maintaining continence and bladder sensations. Our findings show for the first time that low- and high-threshold bladder afferents relay into similar dorsal horn circuits, with nociceptive signalling recruiting a larger number of neurons.

Low- and high-threshold mechanosensitive bladder afferents activate subpopulations of excitatory and inhibitory spinal dorsal horn circuits regulating autonomic function and bladder sensation.

aVisceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia

bCentre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, Adelaide, South Australia, Australia

cARC Centre of Excellence for Nanoscale Biophotonics, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia

dCentre for Neuroscience, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia

Corresponding author. Address: Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia. Tel.: +61 8 8128 4848. E-mail address: stuart.brierley@flinders.edu.au (S.M. Brierley).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

L. Grundy and A.M. Harrington contributed equally to this work.

Received October 04, 2018

Received in revised form November 15, 2018

Accepted November 26, 2018

© 2019 International Association for the Study of Pain
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