Suppression of detrusor-sphincter dysynergia by GABA-receptor activation in the lumbosacral spinal cord in spinal cord-injured rats

Abstract

We investigated the effects of intrathecal application of GABAA- or GABAB-receptor agonists on detrusor-sphincter dyssynergia (DSD) in spinal cord transection (SCT) rats. Adult female Sprague-Dawley rats were used. At 4 wk after Th9-10 SCT, simultaneous recordings of intravesical pressure and urethral pressure were performed under an awake condition to examine the effect of intrathecal application of GABAA and GABAB agonists (muscimol and baclofen, respectively) or GABAA and GABAB antagonists (bicuculline and saclofen, respectively) at the level of L6-S1 spinal cord. In spinal-intact rats, the effects of bicuculline and saclofen on bladder and urethral activity were also examined. During urethral pressure measurements, DSD characterized by urethral pressure increases during isovolumetric bladder contractions were observed in 95% of SCT rats. However, after intrathecal application of muscimol or baclofen, urethral pressure showed urethral relaxation during isovolumetric bladder contractions. The effective dose to induce inhibition of urethral activity was lower compared with the dose that inhibited bladder contractions. The effect of muscimol and baclofen was antagonized by intrathecal bicuculline and saclofen, respectively. In spinal-intact rats, intrathecal application of bicuculline induced DSD-like changes. These results indicate that GABAA- and GABAB-receptor activation in the spinal cord exerts the inhibitory effects on DSD after SCT. Decreased activation of GABAA receptors due to hypofunction of GABAergic mechanisms in the spinal cord might be responsible, at least in part, for the development of DSD after SCT.

Fig. 1.

Isovolumetric cystometry and urethral pressure in a spinal cord transection (SCT) rat before (A) and after intrathecal application of 0.1 μg (B) and 1 μg of muscimol (C). A: increases in urethral pressure during bladder contractions indicative of detrusor-sphincter dyssynergia (DSD) were recorded before drug application. B: after intrathecal muscimol (0.l μg), urethral pressure responses during bladder contraction were changed to a synergic pattern, as evidenced by a negative shift of urethral pressure during bladder contractions. C: after intrathecal muscimol (1 μg), bladder contraction amplitude was decreased, and changes in urethral pressure became negligible.

Fig. 2.

Isovolumetric cystometry and urethral pressure in a SCT rat before (A) and after intrathecal application of 0.1 μg (B) and 1 μg of baclofen (C). A: increases in urethral pressure during bladder contractions indicative of DSD were recorded before drug application. B: after intrathecal baclofen (0.l μg), urethral pressure responses during bladder contractions were changed to a synergic pattern, as evidenced by a negative shift of urethral pressure during bladder contractions. C: after intrathecal baclofen (1 μg), bladder contraction amplitude was decreased, and changes in urethral pressure became negligible.

Fig. 3.

Isovolumetric cystometry and urethral pressure in a SCT rat before (A) and after intrathecal application of bicuculline (0.01 μg) followed by muscimol (0.01 μg) (B). A: increases in urethral pressure during bladder contractions indicative of DSD were recorded before drug application. B: after intrathecal application of bicuculline (0.0l μg) followed by muscimol (0.01 μg), the DSD pattern of urethral pressure during bladder contractions was not changed.

Fig. 4.

Isovolumetric cystometry and urethral pressure in a SCT rat before (A) and after intrathecal application of saclofen (1 μg) followed by baclofen (0.01 μg) (B). A: increases in urethral pressure during bladder contractions indicative of DSD were recorded during isovolumetric bladder contractions. B: after intrathecal application of 1 μg of saclofen followed by baclofen (0.0l μg), the DSD pattern of urethral pressure during bladder contractions was still observed.

Fig. 5.

Simultaneous recordings of isovolumetric bladder contractions and urethral pressure before (A) and after intrathecal injection of bicuculline (B) in a spinal-intact rat. A: urethral relaxation during bladder contractions also exhibits small amplitude of high-frequency oscillations (HFOs). B: after intrathecal application of 0.l μg of bicuculline, urethral relaxation at the peak of bladder contractions was decreased. During incomplete urethral relaxation, the amplitude of HFOs was also increased.