[Lys5,MeLeu9,Nle10]-NKA(4-10)诱导大鼠神经激肽2受体介导的排便和神经激肽1受体介导的潮红:采用快速检测排尿法测定。

Q3 Pharmacology, Toxicology and Pharmaceutics Journal of Basic and Clinical Physiology and Pharmacology Pub Date : 2023-03-01 DOI:10.1515/jbcpp-2022-0119

Jason B Cook, Raymond Piatt, Lesley Marson

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摘要

目的:神经激肽2受体(NK2R)激动剂可通过直接收缩逼尿肌和胃肠道平滑肌治疗膀胱和肠功能障碍。NK2R激动剂[Lys5, MeLeu9, Nle10]-NKA(4-10) (LMN-NKA)可诱导大鼠排尿和排便，但也会产生皮肤潮红的潜在副作用。虽然LMN-NKA是一种NK2R激动剂，但它也对神经激肽1受体(NK1R)有亲和力。因此，本研究的目的是在给药前通过阻断NK2Rs或NK1Rs来确定与LMN-NKA诱导的排尿、排便和脸红有关的神经激肽受体(NKR)亚型。方法:为了实现这一目标，我们开发了一种简单的高通量“快速检测排尿法”来检测大鼠快速发生的药物性排尿。在LMN-NKA剂量-反应实验中，注射LMN-NKA (10-100 μg/kg，皮下)，监测尿、便和冲洗30 min。在NKR拮抗剂实验中，在驯化期前注射对照物、NK2R拮抗剂GR159897或NK1R拮抗剂CP-99,994。驯化后，注射生理盐水或100 μg/kg LMN-NKA，观察30分钟行为。结果:LMN-NKA使排尿、排便和脸红呈剂量相关增加。阻断NK2Rs可减少排尿和阻塞排便，但不影响冲洗。阻断NK1Rs不会改变lmn - nka诱导的排尿或排便，但会减少lmn - nka诱导的潮红。结论:通过快速检测排尿实验，我们发现lmn - nka诱导的排尿是由NK2Rs介导的，而冲洗是由NK1Rs介导的。因此，对NK2和NK1Rs选择性更强的药物应该产生快速的排尿和排便，而不会产生潮红的潜在副作用。

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[Lys⁵,MeLeu⁹,Nle¹⁰]-NKA_(4-10) induces neurokinin 2 receptor mediated urination and defecation and neurokinin 1 receptor mediated flushing in rats: measured using the rapid detection voiding assay.

Objectives: Neurokinin 2 receptor (NK2R) agonists may be useful for treating bladder and bowel dysfunction via direct contraction of detrusor and gastrointestinal smooth muscle. The NK2R agonist [Lys5, MeLeu9, Nle10]-NKA(4-10) (LMN-NKA) induces urination and defecation, but also produces the potential side effect of dermal flushing in rats. Although LMN-NKA is a NK2R agonist, it also has affinity for neurokinin 1 receptors (NK1R). Therefore, the goal of this study was to determine the neurokinin receptor (NKR) subtypes responsible for LMN-NKA-induced urination, defecation, and flushing by blocking either NK2Rs or NK1Rs before LMN-NKA administration.

Methods: To accomplish this goal, we developed a simple high-throughput 'rapid detection voiding assay' to detect rapid-onset drug-induced urination and defecation in rats. In LMN-NKA dose-response experiments, LMN-NKA (10-100 μg/kg, subcutaneous) was injected and urination, defecation, and flushing were monitored for 30 min. For NKR antagonist experiments, vehicle, the NK2R antagonist GR159897, or the NK1R antagonist CP-99,994 were injected before an acclimation period. Following acclimation, saline or 100 μg/kg LMN-NKA were injected, and behavior was observed for 30 min.

Results: LMN-NKA produced dose-related increases in urination, defecation, and flushing. Blocking NK2Rs reduced urination and blocked defecation, without affecting flushing. Blocking NK1Rs did not change LMN-NKA-induced urination or defecation but reduced LMN-NKA-induced flushing.

Conclusions: Using the rapid detection voiding assay we show that LMN-NKA-induced urination and defecation are mediated by NK2Rs, while flushing is mediated by NK1Rs. Therefore, drugs that are more selective for NK2 vs. NK1Rs should produce rapid-onset urination and defecation without producing the potential side effect of flushing.

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来源期刊

Journal of Basic and Clinical Physiology and Pharmacology Pharmacology, Toxicology and Pharmaceutics-Pharmacology

CiteScore

3.90

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0.00%

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期刊介绍： The Journal of Basic and Clinical Physiology and Pharmacology (JBCPP) is a peer-reviewed bi-monthly published journal in experimental medicine. JBCPP publishes novel research in the physiological and pharmacological sciences, including brain research; cardiovascular-pulmonary interactions; exercise; thermal control; haematology; immune response; inflammation; metabolism; oxidative stress; and phytotherapy. As the borders between physiology, pharmacology and biochemistry become increasingly blurred, we also welcome papers using cutting-edge techniques in cellular and/or molecular biology to link descriptive or behavioral studies with cellular and molecular mechanisms underlying the integrative processes. Topics: Behavior and Neuroprotection, Reproduction, Genotoxicity and Cytotoxicity, Vascular Conditions, Cardiovascular Function, Cardiovascular-Pulmonary Interactions, Oxidative Stress, Metabolism, Immune Response, Hematological Profile, Inflammation, Infection, Phytotherapy.