Micturition Reflex Research Articles

Genitourinary dysfunction in Parkinson's disease

Bladder dysfunction (urinary urgency/frequency) and sexual dysfunction (erectile dysfunction) are common nonmotor disorders in Parkinson's disease (PD). In contrast to motor disorders, genitourinary autonomic dysfunctions are often nonresponsive to levodopa treatment. The brain pathology causing the bladder dysfunction (appearance of overactivity) involves an altered dopamine-basal ganglia circuit, which normally suppresses the micturition reflex. By contrast, hypothalamic dysfunction is mostly responsible for the sexual dysfunction (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection. The pathophysiology of the genitourinary dysfunction in PD differs from that in multiple system atrophy; therefore, it might aid in differential diagnosis. Anticholinergic agents are used to treat bladder dysfunction in PD, although these drugs should be used with caution particularly in elderly patients who have cognitive decline. Phosphodiesterase inhibitors are used to treat sexual dysfunction in PD. These treatments might be beneficial in maximizing the patients' quality of life.

Is the periaqueductal gray an essential relay center for the micturition reflex pathway in the cat?

The periaqueductal gray (PAG), especially in a region between the levels the oculomotor nucleus and the trochlear nucleus, was suggested to be the essential relay center that conveys information of bladder fullness to the pontine micturition center (Barrington's nucleus). The present study examined this hypothesis by transecting the brainstem in anesthetized cats. In eight cases of the midbrain transection, all ( n = 3) or most ( n = 5) of the PAG between the levels the oculomotor nucleus and the trochlear nucleus was separated from the intact side of the brain. Furthermore, in the former three cases, the PAG at the level caudal to the trochlear nucleus was separated from the intact brain by more than half ( n = 2) or completely ( n = 1). In all these cases, there were no remarkable differences in the amplitude of the micturition contraction (80–98% of that before transection), irrespective of the levels of the transection. In the cases of the pontine transection, micturition contraction disappeared after transecting through the caudal part of Barrington's nucleus ( n = 1) or through regions caudal to this nucleus ( n = 5). In the one case that received a transection through the rostral part of Barrington's nucleus, the amplitude of the micturition contraction was 43% of that before transection. This study demonstrates that Barrington's nucleus is essential, but the PAG is not essential, for evoking micturition. Our results suggest that the information of bladder fullness in the cat is conveyed to Barrington's nucleus either directly from the lumbosacral neurons or indirectly via relay neurons located below the midbrain.

New insights into molecular targets for urinary incontinence.

Urinary incontinence (UI) is a disease affecting quality of life of 200 million patients worldwide. It is characterized by involuntary loss of urine. The factors involved are cystitis, detrusor hyperreflexia, spinal injury, benign prostatic hyperplasia, etc. The surge in the number of reviews on this subject indicates the amount of research devoted to this field. The prevalence is increasing at an alarming rate but unfortunately, only a few medications are currently available for this condition. There are peripheral as well as central targets including cholinergic, vanilloid, prostaglandin, kinin, calcium channel, cannabinoid, serotonin, and GABA-receptors, which act by different mechanisms to treat different types of incontinence. Drugs acting on the central nervous system (CNS) increase urinary bladder capacity, volume, or pressure threshold for micturition reflex activation while peripherally acting drugs decrease the amplitude of micturition contraction and residual volume. Anticholinergic drugs specifically M3 receptor antagonists are the first choice but have frequent side effects such as dry mouth, CNS disturbances, etc. Therefore, there is a need to understand the biochemical pathways that control urinary dysfunction to determine the potential to which they can be exploited in the treatment of this condition. This article reviews the central and peripheral molecular targets and the potential therapeutic approaches to the treatment of UI.

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology of Voiding Dysfunction and Pharmacological Therapy

Normal lower urinary tract function consists of voiding and storage. During voiding, the pontine micturition reflex center orders the sacral parasympathetic nucleus to increase parasympathetic activity, resulting in urinary bladder detrusor contraction via activation of post-synaptic muscarinic receptors (M2/3) and in the relaxation of both urethral and prostatic smooth muscle by nitric oxide (NO). In addition, the rhabdosphincter relaxes by inhibition of the pudendal nucleus at the sacral portion. During the storage phase, increase in sympathetic activity relaxes the urinary bladder via activation of post-synaptic β3-receptors and in the contraction of both urethral and prostatic smooth muscles via α1-adrenoceptor. Many factors influence voiding function, including lower urinary tract disorders (benign prostatic hyperplasia in males, urethral stricture) and neurological disorders (central and peripheral). Theories of pharmacotherapy for voiding dysfunction are 1) increase detrusor contractility and 2) decrease urethral resistance. The former includes agonists for muscarinic receptors and cholinesterase inhibitor; and the latter includes α1-adrenoceptor antagonists, NO donors, benzodiazepines, baclofen, dantrolene, and boturinum toxin.

Changes in afferent activity after spinal cord injury.

To summarize the changes that occur in the properties of bladder afferent neurons following spinal cord injury. Literature review of anatomical, immunohistochemical, and pharmacologic studies of normal and dysfunctional bladder afferent pathways. Studies in animals indicate that the micturition reflex is mediated by a spinobulbospinal pathway passing through coordination centers (periaqueductal gray and pontine micturition center) located in the rostral brain stem. This reflex pathway, which is activated by small myelinated (Adelta) bladder afferent nerves, is in turn modulated by higher centers in the cerebral cortex involved in the voluntary control of micturition. Spinal cord injury at cervical or thoracic levels disrupts voluntary voiding, as well as the normal reflex pathways that coordinate bladder and sphincter function. Following spinal cord injury, the bladder is initially areflexic but then becomes hyperreflexic due to the emergence of a spinal micturition reflex pathway. The recovery of bladder function after spinal cord injury is dependent in part on the plasticity of bladder afferent pathways and the unmasking of reflexes triggered by unmyelinated, capsaicin-sensitive, C-fiber bladder afferent neurons. Plasticity is associated with morphologic, chemical, and electrical changes in bladder afferent neurons and appears to be mediated in part by neurotrophic factors released in the spinal cord and the peripheral target organs. Spinal cord injury at sites remote from the lumbosacral spinal cord can indirectly influence properties of bladder afferent neurons by altering the function and chemical environment in the bladder or the spinal cord.

Anatomical tracer injections into the lower urinary tract may compromise cystometry and external urethral sphincter electromyography in female rats

Physiological and anatomical investigations are commonly combined in experimental models. When studying the lower urinary tract (LUT), it is often of interest to perform both urodynamic studies and retrogradely labeled neurons innervating the peripheral target organs. However, it is not known whether the use of anatomical tracers for the labeling of, e.g. spinal cord neurons may interfere with the interpretation of the physiological studies on micturition reflexes. We performed cystometry and external urethral sphincter (EUS) electromyography (EMG) under urethane anesthesia in adult female rats at 5–7 days after injection of a 5% fluorogold (FG) solution or vehicle into the major pelvic ganglia (MPG) or the EUS. FG and vehicle injections into the MPG and EUS resulted in decreased voiding efficiency. MPG injections increased the duration of both bladder contractions and the inter-contractile intervals. EUS injections decreased EUS EMG bursting activity during voiding as well as increased both the duration of bladder contractions and the maximum intravesical pressure. In addition, the bladder weight and size were increased after either MPG or EUS injections in both the FG and vehicle groups. We conclude that the injection of anatomical tracers into the MPG and EUS may compromise the interpretation of subsequent urodynamic studies and suggest investigators to consider experimental designs, which allow for physiological assessments to precede the administration of anatomical tracers into the LUT.

Role of the bladder urothelium in voiding dysfunction

The urothelium is a highly effective constant permeability barrier that protects the blood from toxic urinary substances. However, a large and growing body of evidence supports additional roles for the urothelium, including sensory and transduction/signaling roles that enable responses to chemical or mechanical stimuli. Reciprocal communication between urothelial cells with closely located bladder nerves and other cell types, including detrusor smooth muscle and interstitial cells, is likely. Diseases affecting the urinary bladder may affect urothelial receptor channel expression and release of chemical mediators. Urothelial neuropeptide receptor, chemokine receptor, and neurotrophin receptor expression, transduction/signaling, and modulation in animal models of urinary bladder inflammation and human studies of bladder dysfunction are presented. Substrates underlying micturition reflex plasticity induced by urinary bladder disease/dysfunction are likely to include bladder primary afferent cells, lumbosacral spinal cord, and the urothelium.

Ameliorating effects of cloperastine on dysfunction of the urinary bladder caused by cerebral infarction in conscious rats

We investigated the effects of the centrally acting antitussives dextromethorphan and cloperastine on urinary bladder dysfunction 24 h after cerebral infarction in rats using the cystometry technique. First, cystometrography was performed in conscious male Sprague-Dawley rats. Cerebral infarction was then induced by occlusion of the left middle cerebral artery. Twenty-four hours after cerebral infarction, the effect of each drug on micturition disorder was estimated for 5 parameters: bladder capacity, maximum voiding pressure, micturition latency, flow rate, and urethral resistance. Cerebral infarction markedly reduced bladder capacity, micturition latency, and flow rate and increased urethral resistance. After cerebral infarction, intravenous dosing of saline had no effect on these parameters. Dextromethorphan (20 mg/kg) and cloperastine (2.5 and 5.0 mg/kg) at antitussive effective doses significantly increased bladder capacity and micturition latency. Unlike dextromethorphan, cloperastine ameliorated decreases in flow rate and increases in urethral resistance caused by cerebral infarction. These results suggest that cloperastine may have therapeutic value for the treatment of disorders of the micturition reflex associated with cerebral infarction, and that the drug may become a base compound from which to develop more active drugs for such disorders.

Functional Transient Receptor Potential Vanilloid 1 is Expressed in Human Urothelial Cells

We investigated the expression and functional status of TRPV1 receptor in human urothelial cells. Human urothelium was cultured and TRPV1 receptor expression was studied by immunocytochemistry and reverse transcriptase-polymerase chain reaction. The influence of inflammatory mediators on TRPV1 mRNA levels was also studied. Functional assays (cobalt uptake measurements and whole cell voltage clamp records) were used to study the response of urothelial cells to capsaicin, temperature, low pH and inflammatory mediators. Capsaicin induced adenosine triphosphate release from urothelial cells was assessed by bioluminescence. TRPV1 protein and mRNA were detected in human urothelial cells and mRNA more than tripled in the presence of inflammatory mediators. Nerve growth factor treatment alone did not affect TRPV1 mRNA expression. Capsaicin (100 nM and 1 microM) and heat (41C and 45C) evoked cobalt uptake and inflammatory mediators lowered the temperature threshold for TRPV1 activation to 37C. Capsaicin (1 microM) induced TRPV1 desensitization to further applications of the agonist. In whole cell patch clamp experiments 1 microM capsaicin and a heat ramp from 37C to 50C caused inward currents. The same concentration of capsaicin induced the release of about 7 fmol adenosine triphosphate per mg. TRPV1 receptors expressed by human urothelial cells respond to capsaicin and thermal stimuli. Capsaicin evoked release of adenosine triphosphate suggests that human urothelial TRPV1 is involved in the afferent branch of the micturition reflex. Inflammatory mediators decrease the TRPV1 thermal threshold of activation to body temperature and increase its expression. This finding may be relevant for symptoms associated with cystitis.

Selective α1A-blocker improves bladder storage function in rats via suppression of C-fiber afferent activity

In the present study, we used animal models to investigate whether the selective α(1A)-blocker silodosin exerts inhibitory effects on detrusor overactivity by modulating C-fiber afferent activity. To desensitize C-fiber afferents, 0.3 mg/kg of resiniferatoxin (RTX) was subcutaneously injected into some female Sprague-Dawley rats 2 days before creation of each model. (1) Left middle cerebral artery occlusion was performed to create a cerebral infarction (CI) model (CI rats). The effects of intravenous (i.v.) and intrathecal (i.t.) administrations of silodosin on cystometrography parameters were evaluated in conscious rats. (2) Rhythmic bladder pressure was recorded in rats under urethane anesthesia. Prostaglandin (PG) E(2) (0.4 mg/mL) was continuously administered intraurethrally, and the effects of intra-arterial (i.a.) silodosin on the micturition reflex (MR) were investigated. (1) Silodosin (i.v.) dose-dependently increased bladder capacity (BC) in CI rats without decreasing bladder contraction pressure, but had no effects on BC in RTX-CI rats. Silodosin (i.t.) markedly increased BC in CI rats, but not in RTX-CI rats. (2) After intraurethral administration of PGE(2), the bladder contraction interval (BCI) was markedly reduced in non-RTX rats, but unchanged in RTX rats. Silodosin (i.a.) significantly prolonged BCI in non-RTX rats receiving intraurethral PGE(2). These results suggest that the α(1A)-AR subtype activates C-fiber afferents, and that consequently α(1A)-blockade can improve bladder storage function.

Influence of glutamatergic projections to the rostral pontine reticular formation on micturition in rats

Aims We examined the effect of injecting glutamate or a glutamate receptor antagonist into the rostral pontine reticular formation (RPRF) on the micturition reflex in anesthetized rats and conscious rats. Main method Forty-eight female rats were divided into an isovolumetric cystometry group and a continuous cystometry group. Under urethane anesthesia or while conscious, physiological saline, glutamate, or MK-801 (a glutamate receptor antagonist) was injected into the RPRF, and then the changes of bladder activity were examined. Key findings There was no significant change of bladder activity after injection of physiological saline. In anesthetized rats, the injection of either glutamate or MK-801 into the RPRF transiently inhibited bladder contractions. There was a complete recovery of bladder activity 10–20 min after glutamate or MK-801 injection and there were no significant changes of cystometry parameters after the recovery of bladder contractions. In conscious rats, injection of glutamate into the RPRF prolonged the interval between bladder contractions and decreased the baseline bladder pressure. On the other hand, injection of MK-801 into the RPRF caused numerous small bladder contractions, some of which were accompanied by a leakage of a small amount of fluid from around the urethral catheter. Significance RPRF neurons receive glutamatergic projections, possibly from the forebrain, and the RPRF inhibits the micturition reflex pathway. RPRF neurons are also regulated by inhibitory interneurons, which receive glutamatergic projections as well. Therefore, the RPRF plays an important role in the regulation of urine storage.

Mechanosensitive Primary Bladder Afferent Activity in Rats With and Without Spinal Cord Transection

Spinal cord injury induces functional and morphological changes in bladder afferent pathways. However, direct evidence for changes in the excitability of afferent nerve activity primarily originating from the bladder has not been clearly demonstrated. Thus, we determined the characteristics of peripheral mechanosensitive bladder afferents in the pelvic nerve and possible afferent changes in Adelta and C fibers after spinal cord injury. Adult female rats were divided into 2 groups, including spinal cord injured and neurologically intact animals. In the spinal cord injury group the spinal cord was transected at Th9 at 4 weeks before functional experiments. For single unit afferent activity monitoring fine filaments were dissected from the L6 dorsal root and bladder afferent fibers were identified. Single unit afferent activity was studied during constant filling with saline. Two afferent patterns were linked to small phasic increases in intravesical pressure during bladder filling, including accelerated and nonaccelerated types. The incidence of the accelerated type was significantly higher in the spinal cord injury group than in the neurologically intact group regarding Adelta and C fibers. However, we found no relationship between conduction velocity and the functional properties of bladder mechanosensitive afferent fibers in neurologically intact or spinal cord injured rats. Results indicate that mechanosensitive bladder afferent activity has several patterns and is facilitated after spinal cord injury, especially in concert with small bladder contractions (micromotions). The functional properties of these individual afferent fibers are not related in an obvious manner to their conduction velocity and, thus, probably the afferent fiber type.

Effects of cholinesterase inhibition in supraspinal and spinal neural pathways on the micturition reflex in rats

To investigate whether activation of brain and spinal cholinergic pathways affects the micturition reflex in rats. The effects of intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration of neostigmine as a cholinesterase inhibitor and oxotremorine-M (OXO-M) as a muscarinic acetylcholine receptor (mAChRs) agonist, on the micturition reflex were evaluated by infusion cystometrography (CMG) in urethane-anaesthetized untreated rats or rats pretreated with capsaicin. Neostigmine injected i.c.v. increased bladder capacity (BC) and pressure threshold (PT) dose-dependently, with an increase in maximum voiding pressure (MVP) and a decrease in voiding efficiency (VE) at higher doses. Also, neostigmine injected i.t. increased the BC and PT dose-dependently without changing MVP or VE, and these effects were not apparent in capsaicin-pretreated rats. In both routes, atropine as an antagonist of mAChRs, but not mecamylamine as a nicotinic-AChR antagonist, almost completely antagonized the effects of neostigmine. The rank order of potencies of the antagonists for increasing effects of BC induced by 1 nmol of neostigmine was: pirenzepine (an M(1) mAChR antagonist) = atropine > 4-DAMP (an M(3) mAChR antagonist) " methoctramine (an M(2) mAChR antagonist) and tropicamide (an M(4) mAChR antagonist) via the i.c.v. route; and atropine > methoctramine > pirenzepine > tropicamide and 4-DAMP via the i.t. route, respectively. OXO-M injected via i.c.v. and i.t. had the same effects on BC, PT, MVP and VE as neostigmine by i.c.v. and i.t., respectively. These results indicate that activation of muscarinic cholinergic mechanisms by the cholinesterase inhibitor in the brain and spinal cord can inhibit the micturition reflex, mainly by affecting afferent pathways. These mAChR-induced inhibitory effects seem to be mediated through M(1)/M(3) receptor subtypes in the brain, while in the spinal cord, the M(1)/M(2) receptor subtypes might be involved in inhibitory effects, which are mediated via inhibition of mechanoceptive C-fibre afferent pathways.

Brain Switch for Reflex Micturition Control Detected by fMRI in Rats

The functions of the lower urinary tract are controlled by complex pathways in the brain that act like switching circuits to voluntarily or reflexly shift the activity of various pelvic organs (bladder, urethra, urethral sphincter, and pelvic floor muscles) from urine storage to micturition. In this study, functional magnetic resonance imaging (fMRI) was used to visualize the brain switching circuits controlling reflex micturition in anesthetized rats. The fMRI images confirmed the hypothesis based on previous neuroanatomical and neurophysiological studies that the brain stem switch for reflex micturition control involves both the periaqueductal gray (PAG) and the pontine micturition center (PMC). During storage, the PAG was activated by afferent input from the urinary bladder while the PMC was inactive. When bladder volume increased to the micturition threshold, the switch from storage to micturition was associated with PMC activation and enhanced PAG activity. A complex brain network that may regulate the brain stem micturition switch and control storage and voiding was also identified. Storage was accompanied by activation of the motor cortex, somatosensory cortex, cingulate cortex, retrosplenial cortex, thalamus, putamen, insula, and septal nucleus. On the other hand, micturition was associated with: 1) increased activity of the motor cortex, thalamus, and putamen; 2) a shift in the locus of activity in the cingulate and insula; and 3) the emergence of activity in the hypothalamus, substantia nigra, globus pallidus, hippocampus, and inferior colliculus. Understanding brain control of reflex micturition is important for elucidating the mechanisms underlying neurogenic bladder dysfunctions including frequency, urgency, and incontinence.

Mechanisms by which the serotonergic system inhibits micturition in rats

Aims Serotonergic neurons and amino acid neurons are involved in the central nervous control of lower urinary tract function. We investigated the role of the serotonergic system in the central regulation of micturition, as well as the relationship between serotonergic neurons and amino acid neurons in the lumbosacral cord of rats. Main methods Under urethane anesthesia, bladder and urethral activity were recorded before and after intrathecal injection of serotonin (5-hydroxytryptamine: 5-HT), a 5-HT 2A receptor antagonist (ketanserin: KET), or KET + 5-HT by isovolumetric cystometry and measurement of the urethral pressure in intact rats and rats with hypogastric nerve transection (HGNT). Amino acid levels in the lumbosacral cord were also measured after intrathecal injection of 5-HT in intact rats. Key findings In intact rats, intrathecal injection of 5-HT transiently abolished rhythmic bladder contractions, decreased the maximal bladder contraction pressure, and increased the intravesical baseline pressure and the urethral baseline pressure. Intrathecal injection of KET + 5-HT also transiently abolished rhythmic bladder contractions. In HGNT rats, intrathecal injection of 5-HT transiently abolished rhythmic bladder contractions and increased the urethral baseline pressure. Intrathecal injection of 5-HT decreased the level of glycine in the lumbosacral cord. Significance The serotonergic system may be involved in blocking the afferent pathway of the micturition reflex, increasing sympathetic activity, and secondary promotion of urethral contraction through inhibition of glycinergic neurons in the lumbosacral cord. 5-HT 2A receptors may be involved in these effects on the bladder and urethra. Therefore, the serotonergic system may play a role of the maintenance of urine storage.

Roles of Glycinergic and Gamma‐aminobutyric‐ergic Mechanisms in the Micturition Reflex in Rats

The micturition reflex is one of the autonomic reflexes mediated by the spinobulbospinal reflex pathway that passes through the pontine micturition center. In the central nervous system, glutamate is a major excitatory amino acid, while glycine and gamma-aminobutyric acid (GABA) are major inhibitory neurotransmitters and act to inhibit the micturition reflex at supraspinal and/or spinal sites. Glycine and GABA have additive or synergistic inhibitory effects on bladder activity. Hypofunction of glycinergic/GABAergic mechanisms in the lumbosacral spinal cord induces voiding dysfunctions, such as detrusor overactivity (DO) or detrusor-sphincter dyssynergia (DSD) after spinal cord injury (SCI) or bladder outlet obstruction in rats. Intrathecal, intravenous, or dietary glycine inhibits both bladder and urethral activity in normal and spinal cord injury (SCI) rats. Therefore, glycine might be a useful agent for the treatment of DO. Intrathecal muscimol and baclofen (GABA(A) and GABA(B) agonists, respectively) also inhibit non-voiding bladder contractions by suppressing C-fiber bladder afferents in SCI rats. They also improve DSD by suppressing Onuf's nucleus and C-fiber bladder afferents. Baclofen is approved for the treatment of DO in SCI patients, but this agent has not been widely used because the therapeutic window of the drug is modest and the dose is limited by side-effects. Glutamic acid decraboxylase (GAD), the GABA synthesis enzyme, gene delivery by using non-replicating herpes simplex virus (HSV) vectors inhibits DO by suppressing C-fiber bladder afferents without affecting voiding contraction in SCI rats. Therefore, GAD gene therapy can restore urine storage function without affecting voiding function; it would be more beneficial than drug therapy for the treatment of urinary problems in SCI patients.

Urothelial α1D Receptor is Predominantly Involved in the Adrenergic Facilitation of Micturition Reflex

Previous studies using specific antagonists have shown that α1‐adrenergic receptors (AR) in the urinary bladder epithelium (urothelium) serve as a regulator of micturition reflex. To confirm the urothelial adrenergic effect on the micturition reflex, we investigated the functional role of the α1D‐AR subtype in the urothelium on micturition reflex using α1D‐AR knockout (α1D‐KO) mice. An immunohistochemical analysis showed that the α1D‐AR was localized to the umbrella cells in the mouse urothelium. Cystometry using wild‐type mice demonstrated that the intravesical infusion of noradrenaline (NA) into the urinary bladder shortened the intercontraction interval (ICI) in a dose‐dependent manner, without changing the maximum voiding pressure (MVP). In contrast, α1D‐KO mice exhibited no change in the ICI in response to the intravesical infusion of NA. These results indicate a predominant involvement of the α1D‐AR in facilitation of micturition reflex by NA. Interestingly, the intravenous injection of NA did not alter the ICI and the MVP in wild‐type mice. Thus, locally releasing NA might play an important role in the facilitation of micturition reflex via the urothelial α1D−AR subtype.

Significance of Nitric Oxide and its Modulation Mechanisms in Micturition Disorders

Nitric oxide (NO) pathway is of critical importance in the physiological regulation of micturition reflex. NO released from urothelium and suburothelium depresses afferent micturition pathway, while in the central nervous system NO has dual effects on afferent pathway; i.e, excitatory effect in the spinal cord and brain stem and inhibitory effect in the forebrain. Elevated endogenous NO synthase (NOS) inhibitors and increased arginase activity in the lower urinary tracts contribute to NO deficiency, leading to impairement of NO‐mediated relaxations and excitation of different pathway. Therefore, manipulation of endogenous NOS inhibitors and arginase may be new targets of micturition disorders.

Spinal Cord Injury‐Induced Neurogenic Bladder

Spinal cord injury (SCI) is one of the most debilitating and devastating injuries to humans. Lower urinary tract dysfunction is of most concern in the management of SCI patients. Proper management depends on understanding the mechanisms underlying the development of neurogenic bladder. Suprasacral SCI induces detrusor areflexia and urine retention initially. The recovery of lower urinary tract function occurs several weeks later, but the voiding function deteriorates and manifests by hyperreflexia and incomplete voiding secondary to the simultaneous contraction of the detrusor and external urethral sphincter (detrusor–sphincter dyssynergia) during voiding. Electrophysiological and pharmacological studies of animals reveal that the recovery of lower urinary tract function relies on the plasticity of bladder afferent pathways. The Aδ afferents convey proprioception and initiate micturition reflex in intact cats and rats. Chronic SCI animals exhibit hyperreflexia during storage and incomplete expulsion during voiding. The Aδ afferent pathway is replaced by capsaicin‐sensitive C‐fiber afferents in chronic SCI cats. In chronic SCI rats, voiding is still mediated thru Aδ afferents. However, C‐fiber afferents modify bladder function and induce bladder hyperreflexia and detrusor–sphincter dyssynergia in chronic SCI rats. Thus, multiple factors have been implicated in the development of neurogenic bladder induced by SCI.

Involvement of orexin-A on micturition reflex in normal and cyclophosphamide-induced cystitis bladder in rat

The purpose of the present study was to investigate the effect of orexin-A in the spinal cord on bladder function in normal rats and cyclophosphamide (CYP)-induced cystitis rat models. The effects of intrathecal (i.t.) injection of orexin-A (0.01, 0.1 and 1.0 nmol) on bladder function were examined during continuous infusion cystometrogram (CMG) in urethane anesthetized normal and CYP-induced cystitis rats. The effects of i.t. injection of selective orexin-1 receptor (OXR1) antagonist SB334867 (10 nmol) on orexin-A-induced bladder overactivity in normal rats and SB334867 (10 and 30 nmol) on changes in bladder function in normal and CYP-induced cystitis rats were investigated. The effects of intravenous (i.v.) injection of orexin-A (0.3 and 1.0 nmol) on micturition reflex were also investigated in normal rats. I.t. injection of orexin-A (0.1 and 1.0 nmol) significantly decreased the intercontraction intervals (ICI) in normal and CYP-induced cystitis rats. I.t. injection of SB334867 (10 nmol) significantly increased the ICI of orexin-A induced overactive bladder in normal rats and i.t. injection of SB334867 (30 nmol) also increased the ICI in normal rat bladder. However, in CYP-injected cystitis rat models, i.t. injection of SB334867 did not change the bladder function. I.v. injection of orexin-A failed to affect the bladder function in normal rats. Orexin mRNA levels in the lateral hypothalamus were significantly decreased in CYP-induced cystitis rats. These results indicate that orexin-A in the spinal cord activates micturition reflex via OXR1 in normal rats. In addition, OXR1 antagonist did not have any effect on micturition reflex in CYP-induced cystitis rats.