Investigations of urethral sphincter activity in mice with bladder hyperalgesia before and after drug administration of gabapentin

Abstract

Purpose: This study investigated the effect of gabapentin on lower urinary tract dysfunction focusing on urethral activities and cystitis-induced hyperalgesia in a mouse model of painful bladder syndrome/interstitial cystitis (PBS/IC). The electromyography (EMG) of external urethral sphincter (EUS) was difficult to obtain, but contained useful information to examine the drug effect in mice.

Methods: Female C57BL/6J mice were intraperitoneally (ip) administration with either saline or 200 mg/kg of cyclophosphamide (CYP) 48 h before experimental evaluation. Cystitis mice were treated with administration of gabapentin (25 or 50 mg/kg, ip). Cystometry and EUS EMG were obtained and analyzed during continuous bladder infusion. The visceral pain-related visceromotor reflex (VMR) was recorded in response to isotonic bladder distension.

Results: Cystitis mice showed shorter inter-contraction intervals and increased occurrence of non-voiding contractions during bladder infusion, with increased VMR during isotonic bladder distension, indicating cystitis-induced bladder hyperalgesia. Gabapentin (50 mg/kg) suppressed effects of CYP on cystometry, but not on EUS EMG activity, during bladder infusion. The effect on urodynamic recordings lasted 4 h. VMR was significantly reduced by gabapentin.

Conclusions: The present study showed that CYP-induced cystitis in mice is a model of visceral hyperalgesia affecting detrusor contractions, not urethral activations. The technique of using EUS EMG to evaluate the drug effects on urethral activities is novel and useful for future investigations. Gabapentin can be as a potential treatment for detrusor overactivity and PBS/IC.

Keywords: Cyclophosphamide; Electromyography; External urethral sphincter; Visceral pain.

Fig. 1:

Representative examples of urodynamic recordings in the control mouse (A) and cystitis mice before (B) and after drug administrations (C-D). In this cystitis mouse, the voiding and non-voiding contractions were more frequent during saline infusion. Urodynamic recordings obtained 4 hours after administrations of gabapentin (ip) of 25 mg/kg (C, cystitis+RX_25) and 50 mg/kg (D, cystitis+RX_50). Asterisks indicate the non-voiding contractions.

Fig. 2:

The effect of gabapentin on VMR during IBD. The bladder was distended by saline from 10 to 50 cmH₂O. In control mice, 25 mg/kg of gabapentin (control+Rx_25) did not suppress VMR AUC at any IVP levels. 50 mg/kg of gabapentin (control+Rx_50) significantly suppressed VMR AUC when the IVP at 40 and 50 cmH₂O in control mice. The cystitis mice showed a significant increase of VMR AUC at each IVP level compared to controls. 25 mg/kg of gabapentin (cystitis+Rx_25) did not suppress VMR AUC. However, 50 mg/kg of gabapentin (cystitis+Rx_50) significantly suppressed VMR AUC when the IVP was higher than 20 cmH₂O. + p<0.05 indicated statistical significance in the group of control+Rx_50 compared to the control mice without drug. # p<0.05 indicated statistical significance between the controls and cystitis mice. * p<0.05 and ** p<0.01 indicated statistical significance in the group of cystitis+Rx_50 compared to the cystitis mice without drug.