Disease relevance of Tacr1

• The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline [1].
• Using murine schistosomiasis, we evaluated whether SPr expression was subject to immunoregulation [2].
• Moreover, animals treated in vivo with the NK-1 receptor antagonist CP-96,345 produced smaller granulomas [3].
• Lack of NK1R signaling did, however, not impair the animals' ability to mount a protective immune response to HSV-2 following vaccination with an attenuated virus [4].
• However, NK-1R(-/-) mice are protected from inflammation, failing to present bladder inflammatory cell infiltrate or edema in response to antigen challenge [5].

Psychiatry related information on Tacr1

• More recently, the neuropeptide substance P (SP) and its receptor (the neurokinin-1 receptor [NK1R]) have been implicated in the pathophysiology of affective disorders, including depression [6].
• An increased tail flick latency following dydrogesterone injection supported the concept that decreased expression of the NK-1R on lymphocytes is associated with an increased pain threshold [7].

High impact information on Tacr1

• The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates [8].
• Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient KitW/KitW-v, and mast cell-reconstituted KitW/KitW-v mice [9].
• We speculate that mesenteric fat depots may participate in intestinal inflammatory responses via SP-NK-1R-related pathways, as well as other systemic responses to the presence of an ongoing inflammation of the colon [10].
• Intracolonic administration of trinitrobenzene sulfonic acid in mice causes inflammation in the colon that is accompanied by increased expression of proinflammatory cytokines and of the substance P (SP), neurokinin 1 receptor (NK-1R) in the proximal mesenteric fat depot [10].
• To study interneuron function in the basal ganglia, we tested and characterized an NK-1 receptor-based method for targeted ablation of specific classes of interneuron in the striatum [11].

Chemical compound and disease context of Tacr1

• We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation [1].
• NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects [12].
• Mice lacking NK-1Rs (C57BL/6J-NK-1R-/-) displayed a significantly reduced ACD inflammatory ear swelling response to dinitrofluorobenzene (DNFB) with histological less edema and 50% fewer infiltrating leukocytes compared with the ACD response in wild-type (+/+) animals [13].
• We tested the effects of the selective NK-1 receptor antagonists WIN-51,708 and L-733,060 on several markers of dopaminergic terminal toxicity in the mouse striatum [14].
• Capsazepine treatment significantly reduced the level of NK1R endocytosis, and this was associated with similar reductions in pancreatic MPO activity and histological severity of pancreatitis [15].

Biological context of Tacr1

• PMN chemotaxis was induced by SP and other neuropeptides in vitro, but was not affected by spantide I. mRNA for neurokinin-1-receptor-1 (NK-1R) was detected in the normal and infected corneas and on macrophages (Mphis), but not on PMNs (unstimulated or stimulated with endotoxin [LPS]) [16].
• NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis [12].
• Additionally, stress-induced upregulation of SP positive nerve fibers was absent in both NK-1R and W/W(v) mice [17].
• This supports the hypothesis that increased NK-1 receptor gene expression contributes to the development and maintenance of a hyperalgesic state [18].
• Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins [19].

Anatomical context of Tacr1

• Interleukin 12 (IL-12) also induced strong T-cell SPr expression [2].
• Antigen-sensitized NK-1R(-/-) mice also exhibit bladder mast cell degranulation in response to antigen challenge [5].
• The results provide evidence that kinin receptors participate in NK1 receptor-dependent neutrophil accumulation in inflamed mouse skin [20].
• The NK1 receptor localizes to the plasma membrane microdomains, and its activation is dependent on lipid raft integrity [21].
• The NK1 receptor was transiently expressed in HEK293 and HepG2 cell lines and its localization in membrane microdomains investigated using biochemical methods and immunofluorescent labeling [21].

Associations of Tacr1 with chemical compounds

• The results support the concept that NK1 agonists such as substance P cannot act on their own to mediate neutrophil accumulation in naive skin and provide direct evidence that in inflamed skin, under certain circumstances, the NK1 receptor can play a pivotal role in modulating neutrophil accumulation during the ongoing inflammatory process [20].
• The carrageenin (500 microg)-induced response was inhibited (p < 0.05) by a NK1 receptor antagonist, SR140333 (480 nmol/kg i.v. at -5 min), in the wild-type group [20].
• Here we have further examined this role by comparing the behavioural responses to intradermal capsaicin of mutant mice with a disruption of the NK1 receptor (NK1 KO) and wild-type (WT) mice [22].
• Neurokinin B induces oedema formation in mouse lung via tachykinin receptor-independent mechanisms [23].
• Furthermore, contractions induced by trypsin and SLIGRL were reduced by neurokinin receptor NK1 antagonist SR-140333 or NK2 antagonist SR-48968 alone or were further reduced by combined application of SR-140333 and SR-48968, indicating the involvement of neurokinin receptors [24].

Physical interactions of Tacr1

• SP binds the NK-1 receptor with highest affinity [3].

Co-localisations of Tacr1

• Expression of NK-1 R co-localized with expression of glucagon [25].

Regulatory relationships of Tacr1

• Specific NK-1 receptor antagonists blocked all tachykinin-induced, IFN-gamma secretion [3].
• By contrast, NK-2R inhibition significantly enhanced the ACD response in NK-1R null or in wild-type mice, whereas epicutaneous application of NK-2R agonists diminished the ACD inflammation [13].
• IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells [26].
• Substance P engages the T cell neurokinin 1 receptor (NK-1R) to enhance IFN-gamma production [26].
• Both IL-12 and IL-18 induced splenic T cells to express NK-1R transcripts [26].

Other interactions of Tacr1

• SR48968, NK2 receptor antagonist, but not SR140333, NK1 receptor antagonist, decreased the tone only in mdx gastric preparations [27].
• IL-12 induces SPr independently of TCR activation and IFN-gamma expression [2].
• We conclude that NKB is a potent stimulator of plasma extravasation through two distinct pathways: via activation of NK(1) receptors, and via a novel neurokinin receptor-independent pathway specific to NKB that operates in the mouse lung [23].
• However, T cells cultured with IL-12 and IL-10 did not express NK-1R [28].
• We determined whether genetic deletion of the NK1-R reduces mortality and, conversely, whether genetic deletion of NEP increases mortality in a lethal model of hemorrhagic pancreatitis [29].

Analytical, diagnostic and therapeutic context of Tacr1

• Splenocytes from schistosome-infected mice cultured for < or =18 h did not express SPr, as determined by quantitative polymerase chain reaction assay [2].
• The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry [12].
• By using RT-PCR, mRNA expression of NK1-R was confirmed in both the ovary and the uterus of wild-type mice [30].
• Immunohistochemistry demonstrated a consistent reduction of nNOS and NK2 receptor expression in mdx stomach smooth muscle cells and no change in nNOS and NK1 receptor expression in neurones [27].
• None of the tachykinin receptor agonists or antagonists modified motor performance and coordination on the rotarod apparatus or ambulation in an activity cage [31].

References