Histamine is reported to contract mouse bladder strips through H1 receptors [1]. However, roles of brain histamine in regulation of the micturition reflex are unknown. In previous reports, intracerebroventricularly (icv) administered histamine activated the rat sympatho-adrenomedullary system [2], which can induce urine storage. In this study, therefore, we investigated effects of icv administered histamine on the rat micturition reflex.

In urethane-anesthetized (0.8 g/kg, ip) male Wistar rats (300-450 g), a catheter was inserted into the bladder to perform cystometry. Two hours after the surgery, continuous cystometry (saline instillation at 12 ml/h) was started to evaluate intercontraction interval (ICI) and maximal voiding pressure (MVP). One hour after the start, histamine (1 or 3 µg/rat) or vehicle was icv administered. Evaluations of these parameters were continued 2 h after the administration. In some rats, three hours after the surgery described above, single cystometry (saline instillation at 12 ml/h) was performed. After 4-5 times of single cystometry, histamine (3 µg/rat) or vehicle was icv administered, then single cystometry was performed during 0-60 min after the administration. When using receptor antagonists, olopatadine (H1 antagonist, 3 or 10 nmol/rat), zolantidine (H2 antagonist, 10 or 30 nmol/rat) or DNQX [an antagonist of AMPA type glutamate receptors (AMPA receptors), 0.3 or 1 nmol/rat] was icv pretreated 30 min before histamine administration (3 µg/rat, icv).

Histamine dose-dependently shortened ICI without changing MVP (Fig. 1). In single cystometry, histamine significantly reduced single-voided volume (Vv) and bladder capacity (BC) without affecting post-voided residual volume (Rv) or voiding efficiency (VE) compared to the vehicle-treated control group (Table 1). The histamine-induced ICI shortening was significantly attenuated by icv pretreated olopatadine, zolantidine or DNQX (Fig. 2).

In this study, icv administered histamine induced ICI shortening and reductions in Vv and BC without changing MVP, Rv or VE. In response to histamine, parameters related to bladder efferent activity such as MVP, Rv and VE were not changed, therefore, histamine in the brain might induce the micturition reflex through facilitation of sensory inputs to the micturition center. Icv administered histamine at 5 µg/rat activated the sympatho-adrenomedullary system [2], while at a lower dose 3 µg/rat, icv administered histamine facilitated the micturition reflex. Therefore, the histamine-induced facilitation might be independent of activation of the system. The histamine-induced ICI shortening was attenuated by olopatadine or zolantidine, suggesting that histamine induced facilitation of the micturition reflex via brain H1 and H2 receptors. 
Since brain histamine can modulate excitation of the glutamatergic nervous system [3], which is essential for voiding function in the central nervous system, we investigated effects of icv pretreated glutamate receptor antagonists on the histamine-induced ICI shortening. Icv pretreated DNQX attenuated the histamine-induced shortening, but we preliminary found that icv pretreated MK-801 [an antagonist of NMDA type glutamate receptors (NMDA receptors)] showed no effect on the histamine-induced responses. Therefore, brain histamine might facilitate the micturition reflex through brain AMPA, but not NMDA, receptor-mediated activation of the glutamatergic nervous system.

Centrally administered histamine facilitates the rat micturition reflex via brain H1, H2 and AMPA receptors. These findings suggest that brain histamine receptors could be novel therapeutic targets for patients with lower urinary tract dysfunctions attributed to neurogenic bladder overactivity.

Jones BM, Mingin GC, Tykocki NR. Histamine receptors rapidly desensitize without altering nerve-evoked contractions in murine urinary bladder smooth muscle. Am J Physiol Renal Physiol. 2022; 322: F268-F279.
Shimizu T, Okada S, Yamaguchi N, et al. Centrally administered histamine evokes the adrenal secretion of noradrenaline and adrenaline by brain cyclooxygenase-1- and thromboxane A2-mediated mechanisms in rats. Eur J Pharmacol. 2006; 541: 152-157.
Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008; 88: 1183-1241.