agonists, depresses reflex bladder contractions

Experiments using conscious and anesthe-

and increases the bladder volume threshold for

tized rats demonstrated that exogenous GABA,

inducing micturition.128 5-HT1A receptors are

muscimol (GABAA

receptor agonist) and

involved in multiple inhibitory mechanisms

baclofen (GABAB receptor agonist) given i.v., i.t.

controlling the spinobulbospinal micturition

or intracerebroventricularly (i.c.v.) inhibit mic-

reflex pathway. The regulation of the frequency

turition.137,138 Baclofen given i.t. attenuated oxy-

of bladder reflexes is presumably mediated by a

hemoglobin induced DO in rats, suggesting that

suppression of afferent input to the micturition

the inhibitory actions of GABAB receptor ago-

switching circuitry in the pons, whereas the reg-

nists in the spinal cord may be useful for con-

ulation of bladder contraction amplitude may

trolling micturition disorders caused by C-fiber

be related to an inhibition of the output from

activation in the urothelium and/or suburothe-

the pons to the parasympathetic nuclei in the

lium.137 Beneficial effects of baclofen have also

spinal cord.

been documented in humans with DO.141

Duloxetine is a combined noradrenaline and

serotonin reuptake inhibitor, which has been

Gabapentin

shown to significantly increase sphincteric

Gabapentin was originally designed as an anti-

muscle activity during the filling/storage phase

of micturition in the cat acetic acid model of

convulsant GABA mimetic capable of crossing

irritated bladder function.131,132 Bladder capac-

the blood-brain barrier.142 However, its effects

ity was also increased in this model, both effects

do not appear to be mediated through interac-

mediated centrally through both motor effer-

tion with GABA receptors, and its mechanism of

ent and sensory afferent modulation.133 The

action is still controversial.142 Gabapentin is also

effects of duloxetine was studied in a placebo-

widely used not only for seizures and neuro-

controlled study comprising women with

pathic pain, but for many other indications such

OAB134 and was, compared to placebo, shown to

as anxiety and sleep disorders due to its appar-

cause significant improvements or decreases in

ent lack of toxicity.

voiding and incontinence episodes,for increases

In a pilot study, Carbone et al.143 reported on

in the daytime voiding intervals, and for

the effect of gabapentin on neurogenic detrusor

improvements in quality of life (I-QoL) scores.

activity. They found a positive effect on symp-

Urodynamic studies showed no significant

toms and a significant improvement of urody-

increases in maximum cystometric capacity or

namic parameters after treatment,and suggested

in the volume threshold for DO. However,

that the effects of the drug should be explored in

adverse effects were common with nausea, dry

further controlled studies in both neurogenic

mouth, dizziness, constipation, insomnia, and

and non-neurogenic DO. Kim et al.144 found that

fatigue, limiting its tolerability.

14 of 31 patients with OAB and nocturia, refrac-

tory to antimuscarinic treatment, improved with

g-Amino Butyric Acid (GABA) Mechanisms

oral gabapentin. The drug was generally well

tolerated and was considered to be an option in

GABA has been identified as a main inhibitory

selective patients when conventional treatment

modalities have failed.

transmitter in the brain and spinal cord. GABA

functions appear to be triggered by binding of

GABA to its ionotropic receptors, GABAA and

Neurokinin and Neurokinin Receptors

GABAC, which are ligand-gated chloride chan-

nels, and its metabotropic receptor, GABAB.135

The main endogenous tachykinins, substance P

Since blockade of GABAA and GABAB receptors

(SP), neurokinin A (NKA) and neurokinin B

in the spinal cord136,137 and brain137,138 stimulated

(NKB), and their preferred receptors, NK1, NK2,

rat micturition, an endogenous activation of

and NK3, respectively, have been demonstrated

GABAA+B receptors may be responsible for con-

in various CNS regions, including those involved

tinuous inhibition of the micturition reflex

in micturition control.145–147 NK1 receptor

within the CNS. In the spinal cord GABAA recep-

expressing neurons in the dorsal horn of the

tors are more numerous than GABAB receptors,

spinal cord may play an important role in DO,

except for the dorsal horn where GABAB recep-

and tachykinin involvement via NK1 receptors

tors predominate.139,140

in the micturition reflex induced by bladder