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Otilonium bromide ( OB) is a spasmolytic drug successfully used for the treatment of irritable bowel syndrome ( IBS). Its efficacy has been attributed to the block of L- and T-type Ca2+ channels and muscarinic and tachykinin receptors in the smooth muscle. Furthermore, in healthy rats, repeated OB administration modified neurotransmitter expression and function suggesting other mechanisms of action. On this basis, we investigated whether repeated OB treatment prevented the functional and neurochemical changes observed in the colon of rats underwent to wrap restrain stress ( WRS) a psychosocial stressor considered suitable to reproduce the main IBS signs and symptoms. In control, WRS and OB/ WRS rats functional parameters were measured in vivo and morphological investigations were done ex vivo in the colon. The results showed that OB counteracts most of the neurotransmitters changes caused by WRS. In particular, the drug prevents the decrease in SP-, NK1r-, nNOS-, VIP-, and S100β-immunoreactivity ( IR) and the increase in CGRP-, and CRF1r- IR. On the contrary, OB does not affect the increase in CRF2r- IR neurons observed in WRS rats and does not interfere with the mild mucosal inflammation due to WRS. Finally, OB per se increases the Mr2 expression in the muscle wall and decreases the number of the myenteric Ch AT- IR neurons. Functional findings show a significantly reduction in the number of spontaneous abdominal contraction in OB treated rats. The ability of OB to block L-type Ca2+ channels, also expressed by enteric neurons, might represent a possible mechanism through which OB exerts its actions. [ABSTRACT FROM AUTHOR]

Background: Rolapitant, a novel neurokinin-1 receptor antagonist, provided effective protection against chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase 3 trial of patients receiving moderately emetogenic chemotherapy or an anthracycline and cyclophosphamide regimen. The current analysis explored the efficacy and safety of rolapitant in preventing CINV in a subgroup of patients receiving carboplatin.Methods: Patients were randomized 1:1 to receive oral rolapitant (180 mg) or a placebo 1 to 2 hours before chemotherapy administration; all patients received oral granisetron (2 mg) on days 1 to 3 and oral dexamethasone (20 mg) on day 1. A post hoc analysis examined the subgroup of patients receiving carboplatin in cycle 1. The efficacy endpoints were as follows: complete response (CR), no emesis, no nausea, no significant nausea, complete protection, time to first emesis or use of rescue medication, and no impact on daily life.Results: In the subgroup administered carboplatin-based chemotherapy (n = 401), a significantly higher proportion of patients in the rolapitant group versus the control group achieved a CR in the overall phase (0-120 hours; 80.2% vs 64.6%; P < .001) and in the delayed phase (>24-120 hours; 82.3% vs 65.6%; P < .001) after chemotherapy administration. Superior responses were also observed by the measures of no emesis, no nausea, and complete protection in the overall and delayed phases and by the time to first emesis or use of rescue medication. The incidence of treatment-emergent adverse events was similar for the rolapitant and control groups.Conclusions: Rolapitant provided superior CINV protection to patients receiving carboplatin-based chemotherapy in comparison with the control. These results support rolapitant use as part of the antiemetic regimen in carboplatin-treated patients. Cancer 2016;122:2418-2425. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background and Purpose: The tachykinin NK2 receptor antagonist ibodutant is under Phase III clinical investigation to treat female patients with irritable bowel syndrome. The aim of this study was to investigate the NK2 receptor-related gender specificity in a model of colitis.Experimental Approach: Colitis was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.5 mL, 30 mg·mL(-1) in 30% ethanol) in female and male guinea pigs. Electromyographic recording of the responses to colorectal distension (CRD) was made 3 days later. Ibodutant (0.33 , 0.65, 1.9 and 6.5 mg·kg(-1) ) was given s.c., 30 min before CRD. Release of neurokinin A and substance P from isolated mucosal and smooth muscle tissues following treatment with KCl (80 mM) or capsaicin (10 μM) was measured by EIA. Plasma pharmacokinetics of ibodutant following a single s.c. administration (0.73 or 2.1 mg·kg(-1) ) were measured over 24 h.Key Results: Ibodutant did not affect abdominal contractions in control animals. After TNBS-induced colitis, ibodutant prevented the increased visceral hypersensitivity to CRD in females, at lower doses than in males. Ibodutant pharmacokinetics did not differ between females and males. Tachykinins release was greater in smooth muscle than in mucosal samples. Capsaicin-stimulated release of tachykinins from inflamed mucosal samples from females was significantly lower than in males.Conclusions and Implications: Ibodutant prevented abdominal nociception in a model of visceral hypersensitivity in guinea pigs with a greater efficacy in females than in males. Our results highlight a gender-related difference in colonic visceral hypersensitivity and mucosal nerve activation. [ABSTRACT FROM AUTHOR]

Background Colonic samples from asymptomatic diverticulosis ( DS) patients presented enhanced electrical field stimulation ( EFS)-contractions, in an earlier study of ours, suggesting increased endogenous responses. The aim of this study was to explore changes in excitatory neuromuscular transmission and to assess the pharmacodynamics of spasmolytic agents in DS. Methods Circular muscle strips from sigmoid colon of DS patients ( n = 30; 69.5 ± 14.8 years) and controls ( n = 32; 64.7 ± 16.2 years) were studied using organ baths to evaluate the direct effect of excitatory agonists (carbachol, neurokinin A [ NKA] and substance P [ SP]), and the effect of antagonists (atropine and NK2 antagonist GR94800) and spasmolytic drugs (otilonium bromide [ OB] and N-butyl-hyoscine) on the contractions induced by EFS-stimulation of excitatory motorneurons. qRT- PCR was also performed to compare mRNA expression of M2, M3, NK2 receptors and L-type calcium channels. Key Results Contractions to carbachol (Emax: 663.7 ± 305.6% control vs 2698.0 ± 439.5% DS; p < 0.0005) and NKA (Emax: 387.8 ± 35.6% vs 1102.0 ± 190.1%; p < 0.0005) were higher in DS group, without differences for SP. Higher potency for DS patients was observed in the concentration-response curves for atropine ( pIC50 = 8.56 ± 0.15 control vs pIC50 = 9.95 ± 0.18 DS group; p < 0.005) and slightly higher for GR94800 ( pIC50 = 7.21 ± 0.18 control vs pIC50 = 7.97 ± 0.32 group; p < 0.0001). Lower efficacy (Emax) and potency ( pIC50) was observed for spasmolytic drugs in DS, whereas no differences were found regarding the relative expression of the receptors evaluated between groups. Conclusions & Inferences The greater response to cholinergic and tachykinergic agonists and greater potency for muscarinic and NK2 antagonists observed in DS might play a role in the spasticity found in diverticular disease. [ABSTRACT FROM AUTHOR]

Neurokinin ? (NKB) and its G-proteincoupled receptor, NK3R, have been implicated in the neuroendocrine control of GnRH release; however, litde is known about the structure-function relationship of this ligand-receptor pair. Moreover, loss-of-function NK3R mutations cause GnRH deficiency in humans. Using missense mutations in NK3R we previously identified in patients with GnRH deficiency, we demonstrate that Y256H and Y315C NK3R mutations in the fifth and sixth transmembrane domains (TM5 and TM6), resulted in reduced whole-cell (79.3±7.2%) or plasma membrane (67.3±7.3%) levels, respectively, compared with wild-type (WT) NK3R, with near complete loss of inositol phosphate (IP) signaling, implicating these domains in receptor trafficking, processing, and/or stability. We further demonstrate in a FRETbased assay that R295S NK3R, in the third intracellular loop (IL3), bound NKB but impaired dissociation of Gq-protein subunits from the receptor compared with WT NK3R, which showed a 10.0 ± 1.3% reduction in FRET ratios following ligand binding, indicating activation of Gq-protein signaling. Interestingly, R295S NK3R, identified in the heterozygous state in a GnRHdeficient patient, also interfered with dissociation of G proteins and IP signaling from wild-type NK3R, indicative of dominant-negative effects. Collectively, our data illustrate roles for TM5 and TM6 in NK3R trafficking and ligand binding and for IL3 in NK3R signaling.-- Noel, S. D., Abreu, A. P., Xu, S., Muyide, T., Gianetti, E., Tusset, C., Carroll, J., Latronico, A. C., Seminara, S. B., Carroll, R. S., Kaiser, U. B. TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The colon-derived peptide hormone, peptide YY (PYY), regulates colonic motility, secretion and postprandial satiety; but little is known about the influence of endogenous PYY on 5-HT release from colonic mucosa. Tachykinin NK2 receptor-selective agonist, βAla-NKA-(4-10) induces 5-HT release from guinea pig colonic mucosa via NK2 receptors on the mucosal layer. The present study was designed to determine the influence of endogenous PYY on 5-HT release from guinea pig colonic mucosa, evoked by the NK2 receptor agonist, βAla-NKA-(4-10). EXPERIMENTAL APPROACH Muscle layer-free mucosal preparations of guinea pig colon were incubated in vitro and the outflow of PYY or 5-HT and its metabolite, 5-HIAA, from these preparations were determined by enzyme immunoassays or HPLC with electrochemical detection respectively. KEY RESULTS βAla-NKA-(4-10) produced a tetrodotoxin-resistant sustained increase in the outflow of PYY and 5-HT from the mucosal preparations. The βAla-NKA-(4-10)-evoked 5-HT outflow was partially inhibited by Y1 receptor antagonist, BIBO3304, and Y2 receptor antagonist, BIIE0246, but with less potency. Exogenously-applied PYY also produced a sustained increase in the outflow of 5-HT that was inhibited by Y1 blockade but not Y2 blockade. CONCLUSION AND IMPLICATIONS Our findings support the view that the NK2 receptor-selective agonist, βAla-NKA-(4-10) produces a long-lasting PYY release from guinea pig colonic mucosa via NK2 receptors on L cells and βAla-NKA-(4-10)-evoked 5-HT release is in part mediated by endogenously released PYY, acting mainly on Y1 receptors on EC cells. The PYY-containing L cells appear to play a role in controlling the release of 5-HT from colonic EC cells. [ABSTRACT FROM AUTHOR]

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [18F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (Tmax; ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (Tmax ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25-30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10−6M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R. [ABSTRACT FROM AUTHOR]

NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP. J. Cell. Physiol. 227: 1358-1366, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In the rat isolated urinary bladder, NaHS (30?µM-3?mM) and capsaicin (10?nM-3?µM) produced concentration-dependent contractile responses (pEC50=3.5±0.02 and 7.1±0.02, respectively) undergoing dramatic tachyphylaxis. In preparations in which sensory nerves were rendered desensitized (defunctionalized) by high-capsaicin (10?µM for 15?min) pretreatment, neither capsaicin itself nor NaHS produced any motor effect. NaHS-induced contractile effects were totally prevented by the simultaneous incubation with tachykinin NK1 (GR 82334; 10?µM) and NK2 (nepadutant; 0.3?µM) receptor-selective antagonists. Tetrodotoxin (1?µM) only partially reduced the response to NaHS. These results provide pharmacological evidence that H2S stimulates capsaicin-sensitive primary afferent nerve terminals, from which tachykinins are released to produce the observed contraction by activating NK1 and NK2 receptors. While the molecular site of action of H2S remains to be investigated, our discovery may have important physiological significance since H2S concentrations capable of stimulating sensory nerves overlap those occurring in mammalian tissues under normal conditions.British Journal of Pharmacology (2004) 142, 31-34. doi:10.1038/sj.bjp.0705764 [ABSTRACT FROM AUTHOR]

Exposure of the gastric mucosa to backdiffusing acid is signalled to the brainstem via vagal afferents. This study examined whether exposure of the Sprague–Dawley rat stomach to hydrochloric acid (HCl) or ammonium hydroxide (NH4OH), a noxious chemical produced by Helicobacter pylori, activates different vagal afferent pathways as reflected by different circuitries in the medullary brainstem. Two hours after intragastric treatment with HCl or NH4OH the activation of neurons in the nucleus tractus solitarii at the rostrocaudal extension of the area postrema (NTSAP) was visualized by c-Fos immunohistochemistry and their chemical coding characterized by double-labelling immunohistochemistry. Exposure of the rat gastric mucosa to HCl (0.15–0.5 m) or NH4OH (0.1–0.3 m) led to a concentration-dependent expression of c-Fos in the NTSAP. The number and distribution of NTSAP neurons activated by 0.35 m HCl and 0.3 m NH4OH were similar; the highest number of activated neurons occurring in the medial part of the NTSAP. Some 60% of the NTSAP neurons activated by intragastric HCl and NH4OH stained for the high affinity glutamate transporter EAAC1, while some 30% contained calbindin or neuropeptide Y. Glutamate receptors of the N-methyl- d-aspartate type were found on approximately 50% of the c-Fos-positive cells in the NTSAP, whereas tachykinin NK1, NK2 and NK3 receptors were present on 5–10% of the activated neurons. The similar number and distribution of c-Fos-expressing neurons within the NTSAP and their identical chemical coding indicate that exposure of the rat stomach to backdiffusing concentrations of HCl and NH4OH activates the same vagal afferent – NTSAP pathway. [ABSTRACT FROM AUTHOR]

Summary 1. The main aim of the present study was to establish the functional in vivo effects of tachykinins on net fluid transport by the jejunum and ileum of anaesthetized rats. Tachykinins were administered by retrograde infusion in saline into the left common carotid artery. The possible involvement of 5-hydroxytryptamine (5-HT) in tachykinin-induced intestinal secretion was also investigated. 2. Some tachykinins were potent at reversing net absorption to secretion, particularly in the jejunum, where the rank order of potency was neurokinin (NK) A > substance P (SP) > NKB. The potency of the NK[sub 1] receptor-selective agonist [Sar[sup 9] ,Met(O[sub 2] )[sup 11] ]-SP was the same as SP. Neurokinin A reduced net fluid absorption from the lumen of the jejunum at an intra-arterial infusion rate of 0.64 µg/kg per min. Infusions of NKA at 1.6 and 4 µg/kg per min induced net secretion into the lumen of the jejunum. These two higher infusion rates also affected fluid transport by the ileum, although not to the same extent as seen in the jejunum. The relative potency of SP was not affected by captopril (10 mg/kg, i.v.). 3. The secretory response of the jejunum to infusion of 4 µg/kg per min SP was blocked in animals administered the NK[sub 1] receptor antagonist SR 140 333 (1 mg/kg, i.v.). In addition, SR 140 333 blocked the secretory response to 4 µg/kg per min NKA. However, NKA still induced secretion in animals that had received the NK[sub 2] receptor antagonist SR 48 968 (0.3 mg/kg, i.v.). 4. A role for an endogenous tachykinin in the intestinal secretory action of 5-HT was not clearly established using the present model. Although SR 140 333 increased the absorption rate from the jejunum in animals infused intra-arterially with 5-HT, 5-HT itself did not cause a significant reduction in absorption. There were no significant differences in the absorption rates from the ileum between the control group and groups infused with 5-HT with and without SR 140 333. 5. The present study provides functional evidence for the existence of NK[sub 1] receptors in the rat small intestine, particularly in the proximal region, where their activation influences fluid transport. It is suggested that the presently used rat model is suitable for screening tachykinin antagonists for potential antidiarrhoeal activity. [ABSTRACT FROM AUTHOR]

Abstract We demonstrate the expression of functional tachykinin receptors in rat spiral ganglion neurons (SGNs) using calcium signal measurement and whole-cell patch clamp recording. Substance P (SP; 10 µm, 1 s application) induced a transient increase in intracellular calcium. The SP dose–response study showed an EC50 of 18.8 µm and a Hill slope of 0.77. Comparison between specific agonists for the three tachykinin receptor (NKR) types showed the potency NKR3 > NKR1 > NKR2 at 10 µm. The Ca2+ response could be evoked in Ca2+ -free medium and was blocked by N-ethylmaleimide and U-73122, indicating that Ca2+ was released from intracellular stores via a G-protein and phospholipase C pathway. Under whole-cell voltage clamp recording at a holding potential of -50 mV, SP (10 µm, 1 s) evoked a slowly developing transient inward current. The current reversed near to 0 mV and ionic permeability experiments revealed a cation nonselective conductance also permeable to large organic cations such as N-methyl-d-glucamine and tetraethylammonium. Neither removing extracellular calcium nor chelating intracellular calcium with 10 mm BAPTA could block the SP-evoked current. This conductance appeared coupled to G-protein activation as intracellular GDP-βS blocked the SP-evoked current. Mutual desensitization and occlusion studies with acetylcholine and ATP showed that the SP-evoked conductance share effector channels and/or intracellular processes with the purinergic/cholinergic conductance. In SGNs, SP could have both a trophic action, via a calcium response, and a neuromodulatory role, by a depolarizing action through the activation of nonselective cation channels. [ABSTRACT FROM AUTHOR]

Motor effects produced by tachykinins were studied in human isolated corpus spongiosum and cavernosum. In quiescent preparations neurokinin A caused potent contractions (pD[sub2] = 8.3 -7.9 respectively) prevented by the NK[sub2] receptor-selective antagonist nepadutant. whereas [Sar[sub9]]SP sulfone and senktide (NK[sub1] and NK[sub3] receptor-selective agonists) produced no effect or spare contractions. In KCI-precontracted carpus spongiosum septide (pD[sub2] = 7.1) and [Sar[sup9]]SP sulfonc (pD[sub2] = 7.7) produced tetrodotoxin-resistant relaxations. abolished by the tachykinin NK[sub1] receptor-seleclive antagonist SR 140333. [Sar[sup9]]SP sulfone (1μM) produced similar relaxations in precontracted corpus cavernosum. Electrical field stimulation (EFS) elicited tetrodotoxin-sensitive relaxations. which were additive to those produced by [Sar[sup9]]SP sulfone. N[supω]-nitro-L-arginine (L-NOARG) totally prevented both [Sar[sup9]SP sulfone- and EFS-induced relaxation. These results show that tachykinin NK[sub1] and NK[sub2] receptors mediate opposite motor effects in human penile tissues, suggesting a possible modulatory role of tachykinins on smooth muscle tone in these organs. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine (5-HT)4 receptor agonists stimulate gut motility through cholinergic pathways, although there are data suggesting that noncholinergic (tachykininergic) excitatory pathways may also be involved. Differences may exist between the small bowel and colon. Our aims were: (i) to compare the prokinetic effect exerted by the 5-HT4 receptor agonist ML10302 in the canine small bowel and colon in vivo; and (ii) to investigate the role of tachykininergic pathways in mediating this response. In fasting, conscious dogs, chronically fitted with electrodes and strain-gauge force transducers along the small bowel and colon, intravenous injection of ML10302 (35 μg kg–1) immediately stimulated spike activity and significantly increased propagated myoelectrical events at both intestinal levels. In the small bowel, the effects of ML10302 were unchanged by previous administration of the selective NK1 tachykinin receptor antagonist SR140333, the NK2 tachykinin receptor antagonist SR48968, or the NK3 tachykinin receptor antagonist SR142801. In the colon, all tachykinin receptor antagonists significantly inhibited stimulation of spike and mechanical activity by ML10302, without affecting ML10302-induced propagated myoelectrical events. Atropine (100 μg kg–1 i.v.) suppressed the stimulatory effect of ML10302 at both intestinal levels. In conclusion, the 5-HT4 receptor agonist ML10302 induced significant prokinesia both in the small bowel and colon through activation of cholinergic pathways. Tachykininergic pathways are not involved in the ML10302-induced prokinesia in the small bowel, but they play an important role in mediating the colonic motor response to ML10302. [ABSTRACT FROM AUTHOR]

Attempts were made to label tachykinin NK[sub 2] binding sites in the adult rat brain using [[sup 125]I]neurokinin A (NKA) as ligand in the presence of NK[sub 1] and NK[sub 3] agonist or antagonist to avoid labelling of NK[sub 1] and NK[sub 3] binding sites, respectively. A high-affinity, specifically NK[sub 2]-sensitive, [[sup 125]I]NKA-binding, temperature-dependent, reversible, sensitive to GTPγS and correspondence to a single population of binding sites (K[sub D] and B[sub max] values: 2.2 nm and 7.3 fmol/mg protein) was demonstrated on hippocampal membranes. Competition studies performed with tachykinins and tachykinin-related compounds indicated that the pharmacological properties of these NK[sub 2]-sensitive [[sup 125]I]NKA binding sites were identical to those identified in the rat urinary bladder and duodenum. NKA, neuropeptide K, and neuropeptide γ, as well as the potent and selective NK[sub 2] antagonists SR 144190, SR 48968 and MEN 10627, presented a nanomolar affinity for these sites. The regional distribution of these NK[sub 2]-sensitive [[sup 125]I]NKA binding sites differs markedly from those of NK[sub 1] and NK[sub 3] binding sites, with the largest labeling being found in the hippocampus, the thalamus and the septum. Binding in other brain structures was low or negligible. A preliminary autoradiographic analysis confirmed [[sup 125]I]NKA selective binding in hippocampal CA1 and CA3 areas, particularly, and in several thalamic nuclei. [ABSTRACT FROM AUTHOR]

SUMMARY1. The aim of the present study was to characterize the tachykinin receptors mediating contractions of the uterus from the oestrogen-primed rat. Apparent pKB values versus mammalian tachykinins and some subtype-selective agonists were determined for the non-peptide NK1, NK2 and NK3 receptor antagonists SR 140333, SR 48968 and SR 142801, respectively. 2. Apparent pKB values for SR 48968 tested at concen- trations of 3, 10 and 30 nmol/L versus neurokinin (NKA, [Lys5MeLeu9Nle10] NKA(4–10) and [Nle10] NKA(4–10) were 8.79, 9.44 and 9.33, respectively, indicating activation of an NK2 receptor and, in the case of NKA, the possible activation of an additional receptor subtype. SR 48968 (30 nmol/L) did not affect responses to NKB (1 μmol/L), senktide (30 nmol/L), substance P (SP; 100 nmol/L) or [Sar9Met(O2)11] SP (100 nmol/L), indicating its selectivity at this concentration. 3. SR 140333 (1–100 nmol/L) reduced the effects of the NK1-preferring agonists SP and [Sar9Met(O2)11] SP, indicating the presence of NK1 receptors. The pKB estimate versus [Sar9Met(O2)11] was 9.01. SR 140333 (100 nmol/L) did not affect responses to NK2 and NK3 receptor-preferring agonists. 4. SR 142801 (100 nmol/L to 1 μmol/L) produced small rightward shifts in the log concentration–response curves to NKB, yielding an apparent pKB value of 7.0. At 1 μmol/L, SR 142801 reduced responses to the NK2 agonists, suggesting some non-selectivity at this concentration. 5. Taken together, these data provide strong evidence that tachykinin-induced contractions of the uterus of the oestrogen-primed rat are mediated by NK2 receptors, with some contribution from... [ABSTRACT FROM AUTHOR]

The author discusses the study conducted by N. Wada and colleagues regarding the roles of E-series prostaglandin (EP) 1 receptor antagonist in cyclophosphamide (CYP)-induced cystitis rats. The author mentions the mechanisms of prostaglandin E2 (PGE2) for micturition control such as one mediated by tachykinin receptors. He adds that tachykinin receptor antagonists are not applied in the clinical field for urinary disorders treatment.