Rapid-Onset, Short-Duration Induction of Colorectal Contractions in Anesthetized, Adult, Male Rats.

Substantial clinical and preclinical evidence indicates that transient receptor potential vanilloid 1 (TRPV1) receptors are expressed on terminals of colorectal chemoreceptors and mechanoreceptors and are involved in various rectal hypersensitivity disorders with common features of colorectal overactivity. These stimulatory properties of TRPV1 receptors on colorectal function suggested that brief stimulation of TRPV1 might provide a means of pharmacologically activating the colorectum to induce defecation in patients with an "unresponsive" colorectum. The current studies explored the basic features of TRPV1 receptor-induced contractions of the colorectum in anesthetized rats with and without acute spinal cord injury (aSCI).

Recent Developments in On-Demand Voiding Therapies.

One cannot survive without regularly urinating and defecating. People with neurologic injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool.

Effect of GR205171 on autonomic dysreflexia induced by colorectal distension in spinal cord injured rats.

Study Design: Preclinical pharmacology.

Objectives: To determine whether blocking substance P signaling attenuates the hypertension and bradycardia evoked by colorectal distension (CRD) in spinal cord injured (SCI) rats.

Setting: University laboratory in Pennsylvania, U.

Colorectal and bladder prokinetic activity of [Lys, MeLeu, Nle]-NKA after intranasal or sublingual delivery in dogs.

The feasibility of eliciting defecation and urination after intranasal (IN) or sublingual (SL) delivery of a small peptide NK2 receptor agonist, [Lys, MeLeu, Nle]-NKA, was examined using prototype formulations in dogs. In anesthetized animals, administration of 100 or 300 µg/kg IN or 2.0-6.

Neurokinin 2 receptor-mediated bladder and colorectal responses in aged spinal cord injured rats.

Study Design: Animal proof of principle study.

Objectives: Bladder and bowel dysfunction are common after spinal cord injury (SCI) and in the elderly. Neurokinin 2 receptor agonists are known to produce on-demand urination and defecation in adult SCI rats.

Needs, priorities, and attitudes of individuals with spinal cord injury toward nerve stimulation devices for bladder and bowel function: a survey.

Study Design: Survey.

Objectives: To investigate the needs and priorities of people with spinal cord injury for managing neurogenic bladder and bowel function and to determine their willingness to adopt neuromodulation interventions for these functions.

Methods: Anonymous online survey.

Chronic, Twice-Daily Dosing of an NK2 Receptor Agonist [Lys,MeLeu,Nle]-NKA(4-10), Produces Consistent Drug-Induced Micturition and Defecation in Chronic Spinal Rats.

Acute administration of [Lys5,Me,Leu9,Nle10]-NKA(4-10) (LMN-NKA) produces contractions of the detrusor and rectum with voiding in intact and acutely spinal cord injured (SCI) rats. In the current study, the ability of LMN-NKA (10 μg/kg or 100 μg/kg, subcutaneous [SC], twice a day [bid]) or vehicle to induce voiding and defecation in chronic SCI rats was examined across 30 days. After the last day of administration, voiding response rates and bladder pressure (BP) responses to LMN-NKA (intravenous [IV] and SC) were evaluated under anesthesia.

Potency, efficacy, and selectivity of GR64349 at human recombinant neurokinin NK2 and NK1 receptors.

The affinity, potency, efficacy, and selectivity of the NK2 receptor agonist GR64349 ([Lys,Gly,-R-γ-lactam-Leu]NKA(3-10)) at human recombinant NK2 and NK1 receptors was examined. In radioligand binding studies, GR64349 displaced [I]-NKA binding to NK2 receptors with high affinity (pKi 7.77 + 0.

Prokinetic effects of the neurokinin NK2 receptor agonist [Lys,MeLeu,Nle]-NKA on bladder and colorectal activity in minipigs.

The effects of the neurokinin NK2 receptor agonist [Lys,MeLeu,Nle]-NKA (LMN-NKA) on bladder and colorectal function were examined in minipigs. In anesthetized animals, subcutaneous (SC) administration of 30-100 μg/kg increased peak bladder and colorectal pressures. Increases in bladder and colorectal pressure were inhibited by a 15 min pretreatment with the NK2 receptor antagonist GR 159897 (1 mg/kg intravenously (IV)).

Affinity, potency, efficacy, and selectivity of neurokinin A analogs at human recombinant NK2 and NK1 receptors.

A series of peptide NK2 receptor agonists was evaluated for affinity, potency, efficacy, and selectivity at human recombinant NK2 and NK1 receptors expressed in CHO cells to identify compounds with the greatest separation between NK2 and NK1 receptor agonist activity. Binding studies were performed using displacement of [125I]-NKA binding to NK2 receptors and displacement of [3H]-Septide binding to NK1 receptors expressed in CHO cells. Functional studies examining the increase in intracellular calcium levels and cyclic AMP stimulation were performed using the same cell lines.

New technology assessment and current and upcoming therapies for underactive bladder.

Background And Aims: Stakeholders from around the world came together to address the unmet needs of underactive bladder (UAB) at the 3rd International Congress for Underactive Bladder.

Methods: The main recommendation from the regulatory working group is a need for a meeting of UAB stakeholders and regulatory agencies including the FDA to discuss guidance for regulatory trial design for devices, drugs, and/or biologics for UAB.

Results: The following issues to be discussed and agreed upon for UAB trials: 1) Appropriate inclusion and exclusion criteria.

Colorectal and cardiovascular effects of [Lys,MeLeu,Nle]-NKA in anesthetized macaques.

The effects of the tachykinin NK2 receptor agonist LMN-NKA ([Lys,MeLeu,Nle]-NKA) on colorectal and arterial blood pressure were examined in anesthetized macaques. Intravenous (IV) administration of 1-100 μg/kg caused dose-related increases in colorectal pressure up to 120 mmHg above baseline, and area under the curve (AUC) up to 24,987 mmHg*s. This was accompanied at all doses by transient hypotension, with up to 26% reduction in mean arterial pressure (MAP) from baseline.

[Lys,MeLeu,Nle]-NKA Elicits NK2 Receptor-Mediated Micturition and Defecation, and NK1 Receptor-Mediated Emesis and Hypotension, in Conscious Dogs.

Tachykinin neurokinin 2 (NK2) receptor agonists may have potential to alleviate clinical conditions associated with bladder and gastrointestinal underactivity by stimulating contraction of visceral smooth muscle. The ability of [Lys,MeLeu,Nle]-neurokinin A (LMN-NKA) to elicit micturition and defecation was examined after repeated administration in groups of 2-10 conscious dogs. Administration of 10-100 g/kg, i.

NK2 and NK1 receptor-mediated effects of NKA and analogs on colon, bladder, and arterial pressure in anesthetized dogs.

Tachykinin NK2 receptor (NK2R) agonists have potential to alleviate clinical conditions associated with bladder and gastrointestinal under activity. The effects of agonists with differing selectivity for NK2R over NK1Rs on colorectal, bladder, and cardiovascular function were examined in anesthetized dogs. Intravenous (IV) administration of NKA, LMN-NKA ([Lys,MeLeu,Nle]-NKA), and [β-Ala]-NKA caused a dose-related increase in colorectal pressure (up to 98 mmHg) that was blocked by pretreatment with the NK2R antagonist GR 159897 (1 mg/kg), and hypotension (decrease in mean arterial pressure of ~40 mmHg) that was blocked by the NK1R antagonist CP-99,994 (1 mg/kg).

Prokinetic effects of neurokinin-2 receptor agonists on the bladder and rectum of rats with acute spinal cord transection.

The suitability of various neurokinin-2 (NK2) receptor agonists and routes of administration to elicit on-demand voiding of the bladder and bowel, as future therapy for individuals with spinal cord injury, was examined using a rat model. The current study examined the feasibility of alternative routes of administration, which are more practical for clinical use than intravenous (IV) administration. Voiding and isovolumetric cystometry were recorded in anesthetized, acutely spinalized, female rats after IV, subcutaneous (SC), intramuscular (IM), intranasal (IN), or sublingual (SL) administration of [Lys,MeLeu,Nle]-NKA (LMN-NKA).

Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo.

Aims: Bombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats and in a diabetic rat model of voiding dysfunction.

Material And Methods: In vivo cystometry experiments were performed in adult female Sprague-Dawley rats under urethane anesthesia.

Functional bombesin receptors in urinary tract of rats and human but not of pigs and mice, an in vitro study.

Aims: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the lower urinary tract, though their function and distribution in different species is largely unknown. This study examines whether BB receptor agonists can contract bladder smooth muscle in rats, mice, pigs and humans.

Methods: Bladder strips were placed in tissue baths for in vitro contractility.

Stability of the acetic acid-induced bladder irritation model in alpha chloralose-anesthetized female cats.

Time- and vehicle-related variability of bladder and urethral rhabdosphincter (URS) activity as well as cardiorespiratory and blood chemistry values were examined in the acetic acid-induced bladder irritation model in α-chloralose-anesthetized female cats. Additionally, bladder and urethra were evaluated histologically using Mason trichrome and toluidine blue staining. Urodynamic, cardiovascular and respiratory parameters were collected during intravesical saline infusion followed by acetic acid (0.

Effects of the 5-HT4 receptor agonist, cisapride, on neuronally evoked responses in human bladder, urethra, and ileum.

This study evaluated the effects of a 5-HT4 agonist, cisapride, on neuronally evoked smooth muscle responses in bladder, urethra and ileum and compared these effects with those of an acetylcholinesterase inhibitor, distigmine. Electrical field stimulation (EFS) was applied to human bladder and ileum smooth muscle strips from human organ transplant donors and to urethral strips from prostatectomy patients, to evoke neuronally mediated smooth muscle responses. EFS induced contractions in bladder and mixed responses, consisting of contractions and relaxations, in urethra and ileum.

Exogenous activation of muscarinic receptors decreases subsequent non-muscarinic bladder contractions in vivo in the female rat.

Aims: To determine if the muscarinic agonist, bethanechol, inhibits the non-cholinergic, atropine-resistant (i.e. putatively purinergic) component of naturally occurring (i.

Synaptic activation of bulbospongiosus motoneurons via dorsal gray commissural inputs.

Ejaculation is controlled by coordinated and rhythmic contractions of bulbospongiosus (BSM) and ischiocavernosus muscles. Motoneurons that innervate and control BSM contractions are located in the dorsomedial portion of the ventral horn in the L(5-6) spinal cord termed the dorsomedial (DM) nucleus. We characterized intrinsic properties of DM motoneurons as well as synaptic inputs from the dorsal gray commissure (DGC).

Characterization of bulbospongiosus muscle reflexes activated by urethral distension in male rats.

The urethrogenital reflex (UGR) is used as a surrogate model of the autonomic and somatic nerve and muscle activity that accompanies ejaculation. The UGR is evoked by distension of the urethra and activation of penile afferents. The current study compares two methods of elevating urethral intraluminal pressure in spinalized, anesthetized male Sprague-Dawley rats (n = 60).

Properties of urethral rhabdosphincter motoneurons and their regulation by noradrenaline.

The urethral rhabdosphincter (URS), commonly known as the external urethral sphincter, facilitates urinary continence by constricting the urethra. Striated muscle fibres in the urethral rhabdosphincter are innervated by Onuf's nuclei motoneurons in the spinal cord. Although noradrenaline (NA) reuptake inhibitors are shown to increase URS tone preventing urinary leakage in incontinent patients, whether or how NA affects URS motoneurons is unknown.

Neural control of the female urethral and anal rhabdosphincters and pelvic floor muscles.

The urethral rhabdosphincter and pelvic floor muscles are important in maintenance of urinary continence and in preventing descent of pelvic organs [i.e., pelvic organ prolapse (POP)].