GABAergic control of micturition within the periaqueductal grey matter of the male rat

Abstract

Non-technical summary Even when the bladder is full, emptying can be deferred voluntarily until individuals find themselves in a socially appropriate environment. This indicates that the brain is important in the control of bladder function. This study used drugs that either mimic or block the effects of the neurotransmitter chemicals involved in communication between nerve cells to investigate the brain nerve circuits that govern the control of the bladder. A small region in the midbrain was shown to be critical for normal bladder emptying to occur. Normally the excitability of the nerve circuits in this region was controlled by the action of an inhibitory neurotransmitter chemical called GABA. However, if GABA's effect was removed, bladder emptying became abnormally frequent. These results advance our understanding of the normal control of bladder function, and have implications for the development of new treatments for some forms of incontinence.Abstract In urethane-anaesthetised rats continuous infusion of saline into the bladder (6 ml h −1 ) evoked periodic sharp rises in intravesicular pressure accompanied by rhythmic bursting of external urethral sphincter (EUS) EMG and expulsion of urine from the urethral meatus. Microinjection of the GABA agonist muscimol (250 pmol) into the caudal ventrolateral periaqueductal grey (PAG), but not at other sites in the PAG, either depressed reflex voiding frequency (−60%, n = 7) and tonic EUS EMG activity (−38%, n = 6) or completely inhibited voiding (four sites). Microinjection of the GABA antagonist bicuculline (BIC; 1 nmol) into the same region, to reduce ongoing GABA tone, increased reflex voiding frequency (+467%, n = 16) and tonic activity in the EUS (+56%, n = 7) whilst bursting activity in the EUS became desynchronised. Although muscimol failed to change reflex micturition when microinjected into the dorsal caudal PAG, microinjection of BIC at these sites evoked pronounced autonomic arousal and increased reflex voiding frequency (+237%, n = 34). The results demonstrate that the functional integrity of synapses in the caudal ventrolateral PAG is essential to permit micturition. Transmission through the region is normally regulated by a tonic GABAergic inhibitory influence. In contrast, the functional integrity of the dorsal caudal PAG is not essential for reflex micturition. However, micturition may be initiated from this region via projections to the caudal ventrolateral PAG, as part of the behavioural response to psychological threat or other stressful stimuli.

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation

“…Any central GABAergic pathways that are involved would have also been antagonized after administration of intravenous picrotoxin. Intrathecal blockade of GABA was important because central GABAergic mechanisms are known to exist in the PAG (42), and these results demonstrated that the GABAergic neurons participating in pudendal afferent stimulation-evoked inhibition are located in the lumbosacral spinal cord.…”

Neural Control of the Lower Urinary Tract

“…The authors concluded that the PAG does not have an essential role in reflex micturition but rather is involved in transmitting bladder filling information to higher brain centers. Subsequently, the techniques used in transection experiments were questioned by other investigators (593) who noted that the PAG lesions in the experiments of Tasaki et al (619) were often incomplete and a part of the caudal ventrolateral PAG was preserved in some experiments.…”

“…Conversely excitatory neurons in the PAG that relay bladder afferent information to PMC direct neurons are likely to be "phasic micturition neurons" identified by Sakakibara et al (536). It is known that a GABAergic inhibitory mechanism in the PAG tonically controls the bladder volume set-point for initiating micturition (593). In the hypothetical circuit in Figure 22, this mechanism is represented by an independent inhibitory neuron synapsing with the PAG relay neuron.…”

“…On the other hand microinjections of low doses of inhibitory agents such as GABA A de Groat et al Page 32 receptor agonists (muscimol), or opioid peptides at these sites increases the bladder volume threshold for inducing micturition without altering the magnitude of the micturition reflex measured as the amplitude of voiding contractions (398,413,480,593). Conversely, injections of GABA A receptor (bicuculline) or opioid receptor antagonists (naloxone) reduce the bladder volume threshold indicating that tonic activation of inhibitory receptors in these centers can alter the set point of the micturition switch (398,480,593). Because pharmacologic modulation of the PAG circuitry clearly alters the bladder volume threshold it seems reasonable to conclude that PAG input to the PMC switching circuit also regulates the set-point for the micturition switch.…”

“…The large percentage of micturition storage neurons is consistent with other observations indicating that the dopaminergic neurons in the SN/VTA have a predominate inhibitory influence on micturition. For example, electrical stimulation in the SN terminates ongoing micturition (711) and destruction of dopaminergic neurons using the toxin MPTP or 6-hydroxydopamine facilitates the micturition reflex (705,707 the control of GABAergic neurons in the PAG (332); where GABAergic inhibition also plays an important role in the control of micturition (593).…”