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The inflammatory mast cell mediator histamine has long been implicated in IC\/BPS, yet the direct interactions between histamine and bladder afferents remain unclear. In the present study, we show, using a mouse ex vivo bladder afferent preparation, that intravesical histamine enhanced the mechanosensitivity of subpopulations of afferents to bladder distension. Histamine also recruited \u201csilent afferents\u201d that 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 in the central nervous system. Quantitative RT-PCR revealed significant expression of histamine receptor subtypes ( Hrh1\u2013 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 Ca<jats:sup>2+<\/jats:sup>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 H<jats:sub>1<\/jats:sub>receptor antagonist pyrilamine and was not present in preparations from mice lacking transient receptor potential vanilloid 1 (TRPV1). Together, these results indicate that histamine enhances the sensitivity of bladder afferents to distension via interactions with histamine H<jats:sub>1<\/jats:sub>receptor 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.<\/jats:p>","DOI":"10.1152\/ajprenal.00435.2019","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T17:55:05Z","timestamp":1575309305000},"page":"F298-F314","source":"Crossref","is-referenced-by-count":61,"title":["Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H<sub>1<\/sub>receptor and TRPV1"],"prefix":"10.1152","volume":"318","author":[{"given":"Luke","family":"Grundy","sequence":"first","affiliation":[{"name":"Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, South Australia, Australia"},{"name":"Hopwood Centre for Neurobiology, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, 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