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Changes in somato-vesical reflexes during postnatal development in the kitten☆

The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinate the activity of smooth and striated muscles of the bladder and urethral outlet. Although the neural units that can induce contraction and relaxation of the bladder and urethra are located in the lumbosacral spinal cord and peripheral nervous pathways, the coordination between different components of the lower urinary tract necessary for efficient micturition requires a hierarchical neural system, in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brainstem that initiates reflex voiding. Then, voluntary micturition depends on suprapontine inputs from the forebrain that modulate the brainstem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the reflex micturition is a spinobulbospinal pathway that has essential connections between the lumbosacral spinal cord and brainstem structures such as the periaqueductal gray matter and Pontine micturition center, which can induce bladder contractions and reciprocal urethral relaxation during voiding. However, these suprapontine and spinobulbospinal pathways, which are responsible for voluntary and reflex voiding, respectively, are still immature in infants and young children, resulting in involuntary voiding, and are often impaired in adults due to diseases or injuries of the nervous system, leading to reemergence of involuntary micturition and urinary incontinence. This chapter summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling voluntary and reflex micturition.

The present study examined whether early life maternal separation (MS), a model of childhood separation anxiety, predisposes to panic at adulthood. For this purpose, male pups were submitted to 3-h daily maternal separations along postnatal (PN) days of either the ‘stress hyporesponsive period’ (SHRP) from PN4 to PN14 (MS11) or throughout lactation from PN2 to PN21 (MS20). Pups were further reunited to conscious (CM) or anesthetized (AM) mothers to assess the effect of mother-pup interaction upon reunion. Controls were subjected to brief handling (15 s) once a day throughout lactation (BH20). As adults (PN60), rats were tested for the thresholds to evoke panic-like behaviors upon electrical stimulation of dorsal periaqueductal gray matter and exposed to an elevated plus-maze, an open-field, a forced swim and a sucrose preference test. A factor analysis was also performed to gain insight into the meaning of behavioral tests. MS11-CM rather than MS20-CM rats showed enhanced panic responses and reductions in both swimming and sucrose preference. Panic facilitations were less intense in mother-neglected rats. Although MS did not affect anxiety, MS11-AM showed robust reductions of defecation in an open-field. Factor analysis singled out anxiety, hedonia, exploration, coping and gut activity. Although sucrose preference and coping loaded on separate factors, appetite (adult weight) correlated with active coping in both forced swim and open-field (central area exploration). Concluding, whereas 3h-daily maternal separations during SHRP increased rat’s susceptibility to experimental panic attacks, separations throughout lactation had no effects on panic and enhanced active coping.

Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. Lower urinary tract symptoms in children include overactive bladder, voiding postponement, stress incontinence, giggle incontinence, and dysfunctional voiding. Gastrointestinal co-morbidities, including constipation or fecal incontinence, are commonly associated with lower urinary tract (LUT) symptoms in children, often reaching 22–34%. This review summarized the potential mechanisms underlying functional lower urinary and gastrointestinal co-morbidities in children. It also covered the current understanding of clinical pathophysiology in the pediatric population, anatomy and embryological development of the pelvic organs, role of developing neural circuits in regulation of functional co-morbidities, and relevant translational animal models.

This was a non-systematic review of the published literature, which summarized the available clinical and translational studies on functional urologic and gastrointestinal co-morbidities in children, as well as neural mechanisms underlying pelvic organ ‘cross-talk’ and ‘cross-sensitization’.

Co-morbidity of pediatric lower urinary and gastrointestinal dysfunctions could be explained by multiple factors, including a shared developmental origin, close anatomical proximity, and pelvic organ ‘cross-talk’. Daily physiological activity and viscero-visceral reflexes between the lower gastrointestinal and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant modulatory role of the neural pathways. Recent studies have provided evidence that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs due to a phenomenon known as pelvic organ ‘cross-sensitization’. Cross-sensitization between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs. Investigation of functional changes in nerve fibers and neurons sets certain limits in conducting appropriate research in humans, making the use of animal models necessary to uncover the underlying mechanisms and for the development of novel therapeutic approaches for long-term symptomatic treatment of LUTD in the pediatric population.

Pediatric LUTD is often complicated by gastrointestinal co-morbidities; however, the mechanisms linking bladder and bowel dysfunctions are not well understood. Clinical studies have suggested that therapeutic modulation of one system may improve the other system's function. To better manage children with LUTD, the interplay between the two systems, and how co-morbid GI and voiding dysfunctions can be more specifically targeted in pediatric clinics need to be understood.

The effects of intravesical administration of a muscarinic receptor agonist (oxotremorine-M, OXO-M) and antagonist (atropine methyl nitrate, AMN) and of a nicotinic receptor agonist (nicotine) and antagonist (hexamethonium, C₆) on reflex bladder activity were investigated in conscious female chronic spinal cord injured (SCI) cats using cystometry. OXO-M (50 μM) decreased bladder capacity (BC) for triggering micturition contractions, increased maximal micturition pressure (MMP), increased frequency and area under the curve of pre-micturition contractions (PMC-AUC). Nicotine (250 μM) decreased BC, increased MMP, but did not alter PMC-AUC. The effects of OXO-M on BC and PMC-AUC were suppressed by intravesical administration of AMN (50–100 μM), and the effects of nicotine were blocked by hexamethonium (1 mM). Antagonists infused intravesically alone did not alter reflex bladder activity. However, AMN (0.2 mg/kg, subcutaneously) decreased PMC-AUC. 8-OH-DPAT (0.5 mg/kg, s.c.), a 5-HT_1A receptor agonist, suppressed the OXO-M-induced decrease in BC but not the enhancement of PMC-AUC. These results indicate that activation of cholinergic receptors located near the lumenal surface of the bladder modulates two types of reflex bladder activity (i.e., micturition and pre-micturition contractions). The effects may be mediated by activation of receptors on suburothelial afferent nerves or receptors on urothelial cells which release transmitters that can in turn alter afferent excitability. The selective action of nicotine on BC, while OXO-M affects both BC and PMC-AUC, suggests that micturition reflexes and PMCs are activated by different populations of afferent nerves. The selective suppression of the OXO-M effect on BC by 8-OH-DPAT without altering the effect on PMCs supports this hypothesis. The failure of intravesical administration of either AMN or hexamethonium alone to alter bladder activity indicates that cholinergic receptors located near the lumenal surface do not tonically regulate bladder reflex mechanisms in the SCI cat.

Bladder reflexes evoked by stimulation of pudendal afferent nerves (PudA-to-Bladder reflex) were studied in normal and chronic spinal cord injured (SCI) adult cats to examine the reflex plasticity. Physiological activation of pudendal afferent nerves by tactile stimulation of the perigenital skin elicits an inhibitory PudA-to-Bladder reflex in normal cats, but activates an excitatory reflex in chronic SCI cats. However, in both normal and chronic SCI cats electrical stimulation applied to the perigenital skin or directly to the pudendal nerve induces either inhibitory or excitatory PudA-to-Bladder reflexes depending on stimulation frequency. An inhibitory response occurs at 3–10 Hz stimulation, but becomes excitatory at 20–30 Hz. The inhibitory reflex activated by electrical stimulation significantly (P < 0.05) increases the bladder capacity to about 180% of control capacity in normal and chronic SCI cats. The excitatory reflex significantly (P < 0.05) reduces bladder capacity to about 40% of control capacity in chronic SCI cats, but does not change bladder capacity in normal cats. Electrical stimulation of pudendal afferent nerves during slow bladder filling elicits a large amplitude bladder contraction comparable to the contraction induced by distension alone. A bladder volume about 60% of bladder capacity was required to elicit this excitatory reflex in normal cats; however, in chronic SCI cats a volume less than 20% of bladder capacity was sufficient to unmask an excitatory response. This study revealed the co-existence of both inhibitory and excitatory PudA-to-Bladder reflex pathways in cats before and after chronic SCI. However our data combined with published electrophysiological data strongly indicates that the spinal circuitry for both the excitatory and inhibitory PudA-to-Bladder reflexes undergoes a marked reorganization after SCI.

Bladder contractions evoked by pudendal nerve stimulation in both spinal intact and spinal transected cats support the possibility of restoring urinary function in persons with chronic spinal cord injury (SCI). However, electrically evoked bladder responses in persons with SCI were limited to transient contractions at relatively low pressures. This prompted the present study, which presents a detailed quantification of the responses evoked by selective stimulation of individual branches of the pudendal nerve at different stimulation frequencies. In spinal intact cats anesthetized with α-chloralose, selective frequency-dependent electrical activation of the sensory (2 Hz ≤ f ≤ 50 Hz), cranial sensory (f ≤ 5 Hz), dorsal genital (f ≥ 20 Hz) and rectal perineal (f ≤ 10 Hz) branches of the pudendal nerve evoked sustained bladder contractions dependent on the stimulation frequency. Contractions evoked by selective electrical stimulation resulted in significant increases in voiding efficiency compared to bladder emptying by distension-evoked contractions (p_ANOVA < 0.05). Acute spinal transection abolished reflex bladder contractions evoked by low frequency stimulation of the cranial sensory or rectal perineal branches, whereas contractions evoked by high frequency stimulation of the dorsal genital branch remained intact. This study presents evidence for two distinct micturition pathways (spino-bulbo-spinal vs. spinal reflexes) activated by selective afferent pudendal nerve stimulation, the latter of which may be applied to restore bladder function in persons with SCI.