Disease relevance of Tac1

• Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress [1].
• We examined whether neutral endopeptidase (NEP), a cell-surface enzyme that degrades SP in the extracellular fluid, terminates neurogenic inflammation in the colon [2].
• Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P [2].
• EKA/B displayed identical hemodynamic effects to SP in rats, causing short-lived falls in mean arterial blood pressure associated with tachycardia, mesenteric vasoconstriction, and marked hindquarter vasodilatation [3].
• Both schistosome granulomas and gut mucosa display an SP immune regulatory circuit [4].

Psychiatry related information on Tac1

• METHODS: Using a communication box system, foot shock stress (FS) and psychological stress (PS) were administered to mice and the degranulation rate of dermal mast cells, the number of SP-positive nerve fibers and changes in SP content were determined [5].
• We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse [6].
• Substance P is generally considered an excitatory neurotransmitter related to gut motor activity, although an inhibitory influence of neurokinin-1 (NK1) receptor activation on peristalsis has also been reported [7].
• The influence of substance P on nociception depended on the individual mouse's sensitivity to pain (control response latency) [8].
• However, in contrast to enkephalin immunoreactivity, immunolabeling for substance P was not significantly decreased at this time-point in the internal pallidum, a finding reminiscent of early grades of Huntington's disease [9].

High impact information on Tac1

• Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks [10].
• Furthermore, deletion of the preprotachykinin A gene reduced stimulus-induced surface insertion of DORs and abolished DOR-mediated spinal analgesia and morphine tolerance [11].
• The delta-opioid receptor and the precursor protein of a neuropeptide, substance P, are colocalized in the large dense-core vesicles of pain-sensing neurons [12].
• No gross abnormalities were seen in Pacinian corpuscles, cutaneous afferents containing substance P and calcitonin gene-related peptide, and deep nerve fibers in the joint capsule and tendon [13].
• In the periphery, Y1 receptor activation is sufficient and required for substance P release and the subsequent development of neurogenic inflammation and plasma leakage [14].

Chemical compound and disease context of Tac1

• Although it is well established that substance P (SP) interacts with the neurokinin 1 receptor (NK1R) to initiate neurogenic inflammation, the mechanisms that terminate inflammation are unknown [2].
• Concentrations of immunoreactive SP, NKA, and CGRP were measured in extracts of the eczema ears (n = 26), whereas extracts of the opposite ears were used as controls [15].
• Because METH augments striatal substance P (SP) levels, we hypothesized that this neuropeptide plays a role in methamphetamine-induced toxicity and neural damage in the striatum [16].
• Neurokinin-1 receptors are involved in behavioral responses to high-intensity heat stimuli and capsaicin-induced hyperalgesia in mice [17].
• Furthermore, pretreatment of mice with CP-96345 (2.5 mg/kg ip), an antagonist of the neurokinin-1 (NK(1)) receptor, protected mice against lung inflammation caused by H(2)S [18].

Biological context of Tac1

• Tachykinin 4 gene expression was detected primarily in adrenal gland and in the placenta, where, like neurokinin B, significant amounts of EKB-like immunoreactivity were detected [3].
• Because we have previously shown that intestinal inflammation results in down-regulation of NEP and diminished degradation of SP, our present results suggest that defects in NEP expression contribute to uncontrolled inflammation [2].
• In NEP knockout mice, the SP concentration in the colon was approximately 2.5-fold higher than in wild-type mice, suggesting increased bioavailability of SP [2].
• Also, experiments using irradiation lymphocytes showed that SP, SOM, or rIFN-gamma modulation of IgG2a release was not dependent on cell proliferation [19].
• Specific 125I-Bolton-Hunter substance P (125I-BHSP) binding sites are present on intact cortical astrocytes of the newborn mouse in primary culture [20].

Anatomical context of Tac1

• Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain [1].
• The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system [1].
• Thus, NEP maintains low levels of SP in the extracellular fluid under basal conditions and terminates its proinflammatory effects [2].
• Specific binding of substance P aminoterminal heptapeptide [SP(1-7)] to mouse brain and spinal cord membranes [21].
• Tachykinin peptides such as substance P (SP) function as neurotransmitters and neuromodulators in the mammalian central and peripheral nervous systems [22].

Associations of Tac1 with chemical compounds

• The present study examines mice with a targeted deletion of the Tac1 gene, which encodes the neuropeptides substance P and neurokinin A, in animal models relevant to depressive illness and anxiety [23].
• The excitatory neurotransmitter glutamate coexists with the peptide known as substance P in primary afferents that respond to painful stimulation [24].
• Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants [25].
• This elevated plasma leak was attenuated by recombinant NEP or the NK1R antagonist SR140333, and is thus caused by diminished degradation of SP [2].
• The highly specific SP receptor antagonist, CP-96,345, completely inhibited the effect of SP but not SOM on IgG2a release [19].

Physical interactions of Tac1

• SP binds the NK-1 receptor with highest affinity [26].
• Significant increases in SP, increased myeloperoxidase levels coupled with local morphological deterioration of the jejunum and impaired lymphocyte responses to exogenous SP in vitro have been associated with the model [27].
• OTR binding displayed an overlapping distribution with substance P mRNA and preproenkephalin mRNA, both markers for the shell and core of the nucleus accumbens [28].
• These results indicate that spermine-induced behaviour is mediated through the polyamine recognition site on NMDA receptor ion-channel complex without the involvement of substance P system in the mouse spinal cord [29].
• The utility of this approach was demonstrated in measuring the response mediated by the G-protein-coupled neurokinin NK1 receptor and the tyrosine kinase-linked platelet-derived growth factor (PDGF) receptor [30].

Enzymatic interactions of Tac1

• D. melanogaster NEP2 also differs from human NEP in the manner in which the peptidase cleaves the tachykinin, GPSGFYGVR-amide [31].

Co-localisations of Tac1

• In the cerebral perivascular nerve fibers and in trigeminal perikarya, CGRP is often colocalized with substance P and neurokinin A [32].

Regulatory relationships of Tac1

• Specific NK-1 receptor antagonists blocked all tachykinin-induced, IFN-gamma secretion [26].
• The activity of neuromedin K was blocked by the substance P antagonist [D-Pro2D-Trp7.9]substance P at doses of antagonist which effectively blocked the activity of the other tachykinins [33].
• Correspondingly, the addition of SP to these cells resulted in a rapid increase in intracellular Ca2+ levels that could be specifically blocked by an NK-2R antagonist [34].
• It was discovered that SP regulates SOM synthesis [35].
• PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors [36].

Other interactions of Tac1

• 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 [25].
• In contrast, toxin A administration in Crh(-/-) mice fails to result in an increased SP content [37].
• At birth, transgenic DRG showed increased neuron numbers, and displayed a normal proportion of neurons expressing substance P, calcitonin gene-related peptide and the NT3 receptor trkC [38].
• Also, SP and SOM may be components of a natural circuit within inflammation that regulates IFN-gamma production [26].
• There are three distinct tachykinin receptors, called NK-1, NK-2 and NK-3 [26].

Analytical, diagnostic and therapeutic context of Tac1

• Tac1 mutant mice were also less fearful in several animal models of anxiety [23].
• In depression-related paradigms, Tac1-deficient mice were more active in the Porsolt's forced-swimming test and the tail-suspension test, and they did not become hyperactive after bulbectomy [23].
• Altered nociception, analgesia and aggression in mice lacking the receptor for substance P [1].
• Yet, IFN-gamma secretion was unaffected when both SP and SOM were in the cell cultures [26].
• METHODS: Transgenic studies, immunohistochemistry, Western blotting, and reverse transcriptase-polymerase chain reaction were used to assess the expression of the preprotachykinin (PPT) gene, substance P, and NK1 in developing mice, in adult human articular cartilage, and in human chondrocytes in culture [39].

References