Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a common chronic pelvic disorder with sensory symptoms of urinary urgency, frequency, and pain, indicating a key role for hypersensitivity of bladder-innervating sensory neurons. The inflammatory mast cell mediator histamine has long been implicated in IC/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. Here we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of sub-populations of afferents to bladder distension. Histamine also recruited 'silent afferents', which were previously unresponsive to bladder distension. Furthermore, in vivo intravesical histamine enhanced activation of dorsal horn neurons within the lumbosacral spinal cord, indicating increased afferent signaling into the central nervous system. qRT-PCR revealed significant expression of histamine receptor subtypes (Hrh1-Hrh3) in mouse lumbosacral dorsal root ganglia (DRG), bladder detrusor smooth muscle, mucosa, and isolated urothelial cells. In DRG, Hrh1 was the most abundantly expressed. Acute histamine exposure evoked calcium influx in select populations of DRG neurons but did not elicit calcium transients in isolated primary urothelial cells. Histamine-induced mechanical hypersensitivity ex vivo was abolished in the presence of the histamine H1 receptor (H1R) antagonist pyrilamine and was not present in preparations from mice lacking the TRPV1 receptor. Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with H1R and TRPV1. This hypersensitivity translates to increased sensory input and activation in the spinal cord, which may underlie the symptoms of bladder hypersensitivity and pain experienced in IC/BPS.

American journal of physiology. Renal physiology. 2019 Dec 02 [Epub ahead of print]

Luke Grundy, Ashlee Caldwell, Sonia Garcia Caraballo, Andelain Erickson, Gudrun Schober, Joel Castro, Andrea M Harrington, Stuart M Brierley

College of Medicine and Public Health, Flinders University, Australia., Flinders University.

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