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

Marson, Lesley; Piatt, Raymond; Cook, Jason B.; Thor, Karl B.

doi:10.1038/s41393-021-00684-8

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…Figure4shows LMN-NKA also induced efficient defecation and urination in awake, behaving rats. Comparable results were obtained in all species and rat models(Cook et al 2023, Kullmann et al 2017, Marson et al 2021, Marson et al 2020, Marson et al 2018, Rupniak et al 2018a, Rupniak et al 2018b, Rupniak et al 2018c, Rupniak et al 2023, Rupniak et al 2019 of acute and chronic spinal cord injury(Marson et al 2021, Marson et al 2020, Marson et al 2018, diabetes, aging, and in aged diabetic and aged SCI rats(Marson et al 2021). No indication of tachyphylaxis (minutes after administration) or tolerance (weeks of administration) were found(Figures 4…”

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confidence: 63%

Recent Developments in On-Demand Voiding Therapies

Thor,

Marson,

Katofiasc

et al. 2024

J Pharmacol Exp Ther

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One cannot survive without regularly urinating and defecating. People with neurological 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. Catheterassociated urinary tract infections frequently require hospitalization, while manual bowel programs are time-consuming (1-2 hours), stigmatizing, and cause rectal pain and discomfort.Laxatives and enemas produce defecation, but onset and duration are unpredictable, prolonged, and difficult to control, which can produce involuntary defecation and fecal incontinence. Patients with spinal cord injury (SCI) consider recovery of bladder and bowel function a higher priority than recovery of walking. Bladder and bowel dysfunction are a top reason for institutionalization of elderly. Surveys indicate that convenience, rapid onset and short duration, reliability and predictability, and efficient voiding are priorities of SCI individuals.Despite the severe, unmet, medical need; there is no literature regarding on-demand, rapidonset, short-duration, drug-induced, voiding therapies. This article provides in depth discussion of recent discovery and development of two candidates for on-demand voiding therapies. The first, DTI-117, a neurokinin 2 receptor agonist, induces both urination and defecation after systemic administration. The second, DTI-301, is a TRPV1 receptor agonist that induces defecation after intrarectal administration. The review also presents clinical studies of a combination drug therapy administered via iontophoresis and preclinical studies of neuromodulation devices that induce urination and defecation.

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confidence: 63%

Recent Developments in On-Demand Voiding Therapies

Thor,

Marson,

Katofiasc

et al. 2024

J Pharmacol Exp Ther

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“…In 51 rats, the spinal cord was transected at T3/4 as previously described (Rupniak et al, 2023) under full anesthesia using aseptic procedures. A complete spinal transection at T3 was chosen because individuals with high thoracic lesions (above T6) have a high incidence of autonomic dysreflexia (AD), and bowel stimulation can induce AD (Inskip et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

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

Cook,

Piatt,

Burgard

et al. 2024

J Pharmacol Exp Ther

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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). Cumulative concentrationresponse curves to intrarectal (IR) capsaicin (CAP) solutions (0.003% to 3.0%) were performed in anesthetized aSCI and spinal intact rats. CAP produced an "inverted U", cumulative concentration-response curve with a threshold for inducing colorectal contractions at 0.01% and a peak response at 0.1% and slight decreases in responses up to 3%. Decreases in responses with concentrations > 0.1% are due to a rapid desensitization (i.e. < 30 min) of TRPV1 receptors to each successive dose. Desensitization appeared fully recovered within 24 hours in spinal intact rats. Colorectal contractions were completely blocked by atropine, indicating a reflexogenic activation of parasympathetic neurons, and responses were completely unaffected by a neurokinin 2 receptor antagonist, indicating that release of neurokinin A (NKA) from afferent terminals and subsequent direct contractions of the smooth muscle was not involved. IR administration of 3 other TRPV1 receptor agonists produced similar results as CAP. Significance statementIndividuals with spinal cord injury often lose control of defecation. Time consuming and inconvenient bowel programs using digital stimulation of the rectum and manual extraction of stool are used to empty the bowel.We show that intrarectal administration of the TRPV1 receptor agonist, capsaicin, can induce rapid-onset, shortduration colorectal contractions capable of inducing defecation in spinal cord injured and intact rats. Therefore, TRPV1 agonists show promise as potential therapeutics to induce defecation in individuals with neurogenic bowel.

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“…3 NK2R and its ligands are widely expressed in different tissues, including the central and peripheral nervous systems, cardiovascular system, muscles, immune system, and digestive system. [3][4][5] Evidence has indicated an association between NK2R activation and diverse biological activities. 6,7 For example, NK2R is essential in hypersensitivity pneumonitis, 8 and it was involved in IL-5-induced hyperairway responsiveness in guinea pig models.…”

Section: Introductionmentioning

confidence: 99%

“…NK2R and its ligands are widely expressed in different tissues, including the central and peripheral nervous systems, cardiovascular system, muscles, immune system, and digestive system 3–5 . Evidence has indicated an association between NK2R activation and diverse biological activities 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Homology modeling, virtual screening, molecular docking, and ADME approaches to identify a potent agent targeting NK2R protein

Soltani,

Hashemy

2023

Biotech and App Biochem

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Neurokinin/tachykinin receptors are classified as the G‐protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues. NK2R is associated with a range of biological events, such as inflammation, smooth muscle contraction, intestinal motor functions, and asthma. Despite these diverse activities, no approved drugs targeting NK2R have been developed yet. Our study focuses on finding potential inhibitors for NK2R using virtual screening, molecular docking, and ADME (absorption, distribution, metabolism, and excretion) approaches. We used a homology modeling approach and AlphaFold DB to obtain the three‐dimensional structure of mouse and human NK2R proteins, respectively. The homology model of NK2R was predicted using MODELLER v10.3 and further refined and validated using the 3Drefine tool and RAMPAGE server, respectively. Molecular docking was performed using a library of 910 structurally similar molecules to four NK1R antagonists: aprepitant, casopitant, fosaprepitant, and rolapitant. Molecular docking revealed six small molecules that displayed high Chemscore fitness scores, and binding energies with desirable ligand–NK2R interactions. The evaluation of the in silico ADME profile, solubility, and permeability of the ligand molecules has revealed that the small molecules are potentially nontoxic and have the chance of exhibiting biological activity after oral administration. Further experimental studies (in vitro and in vivo assays) are required to evaluate the effectiveness of these inhibitors as therapeutic targets.

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

Cited by 4 publications

References 23 publications

Recent Developments in On-Demand Voiding Therapies

Recent Developments in On-Demand Voiding Therapies

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

Homology modeling, virtual screening, molecular docking, and ADME approaches to identify a potent agent targeting NK2R protein

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