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- Title
[Lys<sup>5</sup>,MeLeu<sup>9</sup>,Nle<sup>10</sup>]-NKA<sub>(4–10)</sub> induces neurokinin 2 receptor mediated urination and defecation and neurokinin 1 receptor mediated flushing in rats: measured using the rapid detection voiding assay.
- Authors
Cook, Jason B.; Piatt, Raymond; Marson, Lesley
- Abstract
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. 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. 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. 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.
- Subjects
HIGH throughput screening (Drug development); KRUSKAL-Wallis Test; INJECTIONS; URINATION; ANIMAL experimentation; TIME; CELL receptors; DEFECATION; HEALTH outcome assessment; RATS; DESCRIPTIVE statistics; RESEARCH funding; DATA analysis software; PHYSIOLOGIC salines
- Publication
Journal of Basic & Clinical Physiology & Pharmacology, 2023, Vol 34, Issue 2, p227
- ISSN
0792-6855
- Publication type
Article
- DOI
10.1515/jbcpp-2022-0119