Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H₁receptor and TRPV1

Abstract

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. 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 “silent afferents” 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– 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 Ca2+ 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 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 H1 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.

Alterations in histamine responses between juvenile and adult urinary bladder urothelium, lamina propria and detrusor tissues

“…Histamine is known to induce significant increases in both the tension and frequency of spontaneous phasic contractions in both the urothelium with lamina propria and in the underlying detrusor muscle via the activation of the H1 receptors 11 . It also enhances the mechanosensitivity of nearby afferent nerves to bladder distension, resulting in an increased neuronal activation in the spinal cord 40 . In addition, this effect may work in conjunction with other inflammatory-cell released chemicals such as 5-HT 41 to induce or maintain various lower urinary tract disorders.…”

Experimentally Induced Bladder Permeability Evokes Bladder Afferent Hypersensitivity in the Absence of Inflammation

“…Furthermore, analysing this data further shows us that whilst the lowest peak afferent firing in mice 1-day post protamine sulfate is 7 imp/s, in the other experimental cohorts, a large proportion of units exhibit peak firing frequencies between 2-7 imp/s ( Figure 2B). To identify if the transient increases in afferent firing following protamine sulfate treatment were due to the recruitment of an additional cohort of afferents (silent afferents), as has been identified in the presence of inflammatory mediators (Michaelis et al, 1996;Prato et al, 2017;Grundy et al, 2020), we compared the number of individual single units identified by spike waveform analysis per experiment. We found no significant difference in the number of single units per experiments between experimental cohorts ( Figure 2C).…”

“…Briefly, afferent units were deemed 'low threshold' if the pressure required to elicit continuous action potential firing was 16 mmHg or less. In contrast, 'high threshold' afferents exhibited continuous action potential firing only when pressures exceed 18 mmHg (Grundy et al, 2019b;Grundy et al, 2020).…”

“…Bladder afferent nerve recordings were performed using an ex vivo model previously characterised (Grundy et al, 2018b-d;Grundy et al, 2020) on 16 week old mice that either did or didnot (control mice) receive intrabladder infusion of protamine sulfate or vehicle. Mice were humanely killed with CO 2 and dissected under a microscope with continual perfusion of gassed (95% O2, 5% CO2) Krebs-bicarbonate solution (composition in mmol/L: NaCl 118.4, NaHCO 3 24.9, CaCl 2 1.9, MgSO 4 1.2, KCl 4.7, KH2PO 4 1.2, glucose 11.7) at 35 • C. A catheter attached to a syringe pump was inserted into the bladder via the urethra to allow controlled distension at 100 µl/min with saline (0.9%).…”

The five primary prostaglandins stimulate contractions and phasic activity of the urinary bladder urothelium, lamina propria and detrusor

“…Furthermore, significantly increased expression of histamine receptors had been noted in patients with BPS/IC [13]. The actions of inflammatory mediators not only can cause urinary bladder contractions [14][15][16][17] but also are known to sensitise afferent nerve endings resulting in an increased spinal cord neuronal activation [18,19]. Therefore, inflammation and the actions of these pro-inflammatory mediators may contribute to the development of the urinary frequency and urgency symptoms observed in OAB, and pain in IC/BPS.…”