PK2/PKR1 Signaling Regulates Bladder Function and Sensation in Rats with Cyclophosphamide-Induced Cystitis

Abstract

Prokineticin 2 (PK2) is a novel chemokine-like peptide with multiple proinflammatory and nociception-related activities. This study aimed to explore the potential role of PK2 in modulating bladder activity and sensation in rats with cyclophosphamide- (CYP-) induced cystitis. Changes of PK2 and prokineticin receptors (PKRs) in normal and inflamed urinary bladders were determined at several time points (4 h, 48 h, and 8 d) after CYP treatment. Combining a nonselective antagonist of prokineticin receptors (PKRA), we further evaluated the regulatory role of PK2 in modulating bladder function and visceral pain sensation via conscious cystometry and pain behavioral scoring. PK2 and prokineticin receptor 1 (PKR1), but not prokineticin receptor 2, were detected in normal and upregulated in CYP-treated rat bladders at several levels. Immunohistochemistry staining localized PKR1 primarily in the urothelium. Blocking PKRs with PKRA showed no effect on micturition reflex activity and bladder sensation in control rats while it increased the voiding volume, prolonged voiding interval, and ameliorated visceral hyperalgesia in rats suffering from CYP-induced cystitis. In conclusion, PK2/PKR1 signaling pathway contributes to the modulation of inflammation-mediated voiding dysfunction and spontaneous visceral pain. Local blockade of PKRs may represent a novel and promising therapeutic strategy for the clinical management of inflammation-related bladder diseases.

Blocking PAR2 alleviates bladder pain and hyperactivity via TRPA1 signal

“…injected with CYP (75 mg/kg, in the concentration of 75 mM, Sigma-Aldrich, St. Louis, MO, USA) every 3 days to induce chronic cystitis [12, 13]. On the eighth day experiments were performed.…”

“…Thus, in this study we determined the role played by PAR2 at this level of lumbar superficial dorsal horn in regulating bladder hypersensitivity and mechanical hyperalgesia in rats following cystitis induced by systemic administration of cyclophosphamide (CYP). In a cystitis model of CYP, the rats' bladders appear to be hyperactive with an elevated voiding pressure, which leads to mechanical pain [12, 13]. In general, mechanical paw withdrawal threshold (PWT) of a rat's hind paw in response to the stimulation of von Frey filaments was employed to assess mechanical pain under pathophysiological conditions [14].…”

“…A recent study has demonstrated that PAR2 appears in the superficial dorsal horn and is involved with neuropathic pain [6]. Prior findings suggest that PAR2 signaling plays a critical role in regulating TRPA1 and thereby leads to mechanical allodynia and thermal hyperalgesia [12]. …”

Blocking mammalian target of rapamycin alleviates bladder hyperactivity and pain in rats with cystitis

“…injected with CYP (75 mg/kg, in the concentration of 75 mM, Sigma-Aldrich) every three days to induce chronic cystitis. 16,17 On the eighth day, experiments were performed. Control rats received saline injections.…”

“…In a cystitis model of CYP, rats' bladder appears to be hyperactive with an elevated voiding pressure and thereby leads to mechanical pain. 16,17 In general, mechanical paw withdrawal threshold (PWT) of rat hind paw in response to the stimulation of von Frey filaments was employed to assess mechanical pain under pathophysiological conditions. 4,18 On the basis of these previous findings, we suspected that mTOR in the superficial dorsal horn of the lumbar spinal cord is likely changed in CYP-rats.…”