UNIPROT:P20366 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of selective tachykinin (neurokinin, NK) NK1 and NK2 receptor antagonists have been examined on spinal neurones in alpha-chloralose anaesthetized, spinalized rats. They were tested for effects on responses both to excitatory amino acids (EAA) and to noxious heat stimuli. They were also tested for their ability to reverse the actions of selective NK agonists. 2. The NK1-selective antagonists GR82334 (peptide) and CP-99,994 (non-peptide), when applied by microiontophoresis, both reduced responses to kainate > AMPA > NMDA. Intravenous CP-99,994 (3 mg kg-1) also reduced responses to kainate but had inconsistent effects on nociceptive responses. 3. GR82334, applied microiontophoretically, reduced the enhancement by the selective NK1 agonist, GR73632 of both responses to EAAs and background activity. Systemic CP-99,994 (< or = 10 mg kg-1) failed to reverse the effects of GR73632. 4. The selective peptide NK2 antagonist, GR103537, had no consistent effects on responses to EAAs when applied by iontophoresis. In contrast, the non-peptide NK2 antagonist, GR159897, administered systemically (0.5-2 mg kg-1, i.v.) enhanced responses to kainate (but not NMDA); responses to noxious heat were enhanced only weakly. 5. Iontophoretically-administered GR103537 attenuated the effects of the NK2 agonist GR64349, which selectively reduced responses to kainate compared to those to NMDA. Systemically administered GR159897 (< or = 2 mg kg-1, i.v.) caused little antagonism of the effects of GR64349. 6. The data indicate that under these conditions the non-peptide antagonists are not reliable at reversing the actions of selective NK agonists. 7. These results suggest that there is a tonic release of endogenous tachykinins that can modulate glutamatergic neurotransmission in the spinal cord. They provide further support for the hypothesis that release of endogenous NKs acting on NK1 and NK2 receptors can promote NMDA receptor mediated glutamatergic transmission.
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PMID:Endogenous modulation of excitatory amino acid responsiveness by tachykinin NK1 and NK2 receptors in the rat spinal cord. 758 97

The present investigation assessed the effect of chronic blockade of kainate/quisqualate binding sites with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on preproenkephalin (PPE) and preprotachykinin (PPT) mRNA abundance in the neostriatum of the rat brain. Daily injection of CNQX for seven consecutive days decreased PPE mRNA abundance approximately 25% below vehicle-injected controls in dorsolateral, dorsomedial, anterior caudate-putamen (dlCPu, dmCPu and aCPu, respectively) and nucleus accumbens (NAc). Similarly, PPT mRNA abundance was significantly decreased in dlCPu, dmCPu and aCPu but not in the accumbens. The data demonstrate that non-NMDA receptor activity modulates basal levels of expression of PPE and PPT mRNAs in the neostriatum of the rat brain.
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PMID:Attenuation of neostriatal preproenkephalin and preprotachykinin mRNA abundance by chronic treatment with the kainate/quisqualate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione in the rat brain. 765 90

Whole-cell patch-clamp technique of freshly isolated rat spinal dorsal horn (DH) neurons, intracellular recording from DH neurons in a slice preparation, and high performance liquid chromatography with fluorimetric detection of release of endogenous glutamate and aspartate from spinal cord slice following activation of primary afferent fibers were employed to investigate interactions between excitatory amino acids (EAA) and tachykinins [substance P (SP) and neurokinin A (NKA)]. Potentiation of N-methyl-D-aspartate (NMDA)-, quisqualate (QA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, but not kainate-induced currents by SP and NKA was found. Spantide II, a claimed novel nonselective tachykinin antagonist, effectively blocked the SP (2 nM)-induced potentiation of the responses of DH neurons to NMDA. In the presence of glycine (0.1 microM), the SP-evoked increase of the NMDA-induced current was prevented. However, 7-chlorokynurenic acid (2 microM), a competitive antagonist at the glycine allosteric site of the NMDA receptor, led to the reestablishment of the SP effect. Brief high frequency electrical stimulation of primary afferent fibers produced a long-lasting potentiation of presumed monosynaptic and polysynaptic excitatory postsynaptic potentials and sustained enhanced release of endogenous glutamate (218.3 +/- 66.1%) and aspartate (286.3 +/- 58.0%). Possible functional implications of the observed phenomena are discussed in relation to transmission and integration of sensory information, including pain.
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PMID:Interactions between excitatory amino acids and tachykinins in the rat spinal dorsal horn. 768 51

Intrastriatal injection of malonate, a reversible inhibitor of succinate dehydrogenase (SDH), produced age-dependent striatal lesions, which were significantly greater in 4- and 12-month-old animals than in 1-month-old animals. Both histologic and neurochemical studies showed that the lesions were significantly attenuated by administration of the noncompetitive NMDA receptor antagonist MK-801. Water-suppressed chemical shift magnetic resonance imaging showed that malonate produces increased striatal lactate concentrations and striatal lesions on T2-weighted scans that were attenuated by MK-801. Neurochemical characterization of the lesions showed significant decreases in markers of medium-sized spiny neurons (GABA and substance P), whereas a marker of medium-sized aspiny neurons (somatostatin) was not different from control values, consistent with an NMDA receptor-mediated mechanism. The effects of intrastriatal injections of malonate on ATP concentrations were compared with those of the irreversible SDH inhibitor 3-nitropropionic acid (3-NP). The ATP depletions following an equimolar injection of malonate were less marked and more transient than those of 3-NP. These results show that the competitive SDH inhibitor malonate produces more transient and milder bioenergetic defects than 3-NP, which are associated with selective activation of NMDA receptors. The results strengthen the possibility that a subtle impairment of energy metabolism may play a role in the pathogenesis of Huntington's disease.
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PMID:Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. 768 41

The effect of N-methyl-D-aspartate (NMDA) receptor blockade on the expression of preproenkephalin (PPE), preprotachykinin (PPT) and preprodynorphin (PPD) mRNAs in the caudate-putamen and nucleus accumbens was assessed with the non-competitive NMDA receptor antagonist MK-801. Administration of MK-801 once daily for 7 consecutive days increased the abundance of all three neuropeptide mRNAs in the caudate-putamen (CPU) and nucleus accumbens (NAc). (1) PPE mRNA abundance was increased in the anterior CPU (26%) as well as dorsal and ventral CPU (46% and 39%, respectively) but was unaffected in the NAc. (2) PPT mRNA was increased in the NAc (33%), anterior CPU (27%), dorsal CPU (43%) and ventral CPU (67%). In the ventral CPU, PPT mRNA abundance doubled when the dose of MK-801 increased two-fold (from 67% to 119% above control). (3) PPD mRNA was elevated in dorsal and ventral regions of the CPU (49% and 24%, respectively) and in anterior CPU (50%). In the NAc PPD mRNA was increased only at the higher dose (0.1 mg/kg) of MK-801. Cellular analysis of the distribution of grains per cell shows that increases are due to increased accumulation of mRNA by previously expressing cells of the CPU and NAc. These observations demonstrate that NMDA receptor activity plays a significant role in the regulation of neuropeptide expression in the caudate-putamen and accumbens of the rat brain.
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PMID:Elevation of striatal and accumbal preproenkephalin, preprotachykinin and preprodynorphin mRNA abundance subsequent to N-methyl-D-aspartate receptor blockade with MK-801. 776 91

An experimental arthritis, induced by injection of the knee joint with kaolin and carrageenan, results in guarding of and decreased weight bearing on the limb. At the time of injection, a transient increased release of all amino acids examined is measurable in samples collected by microdialysis. A second and prolonged increase of aspartate (ASP), glutamate (GLU), and glutamine (GLN) concentrations follows after 3 h. The increased release at time of injection is blocked by microdialysis application of a non-N-methyl-D-aspartate (non-NMDA) or an NMDA receptor antagonist, and the release of ASP, GLU, and GLN in the late phase is blocked by pretreatment with a non-NMDA (CNQX), an NMDA (AP7) or a neurokinin 1 (NK1; CP-96,345) antagonist. Dorsal horn immunoreactive staining of GLU, substance P (SP), and calcitonin gene-related peptide (CGRP) is reflective of the events occurring in the late phase of amino acid release since GLU release is positively correlated with GLU staining density. Increased immunoreactivity for GLU, SP, and CGRP at 8 hr in the arthritic animals is differentially altered by pretreatment of the spinal cord dorsal horn with non-NMDA, NMDA, or NK1 receptor antagonists. The differential staining pattern for GLU, SP, and CGRP, the differential release of ASP and GLU, and the differential activation of the EAA and NK1 receptors implies that ASP, GLU, SP, and CGRP are each involved in the processing of sensory information and that their roles in the central sensitization occurring with the inflammatory process, are unique.
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PMID:Spinal cord amino acid release and content in an arthritis model: the effects of pretreatment with non-NMDA, NMDA, and NK1 receptor antagonists. 790 87

Considerable evidence suggests that both substance P and glutamate play a role in the spinal transmission of the exercise pressor reflex. We tested two hypotheses. First, after a lumbosacral intrathecal injection of a glutamatergic receptor antagonist, the reflex cardiovascular and ventilatory responses to static contraction are attenuated. Second, after a lumbosacral intrathecal injection of a substance P receptor antagonist and a glutamatergic receptor antagonist, the reflex cardiovascular and ventilatory responses to static contraction are abolished. We found that 1) the reflex cardiovascular responses to static contraction were unaffected (P > 0.05) after the intrathecal injection of the N-methyl-D-aspartate (NMDA) receptor antagonists, dl-2-amino-5-phosphonopentanoate (+/- AP-5) or 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (+/- CPP); 2) the reflex pressor response to static muscular contraction was attenuated by > 50% after the intrathecal injection of the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); and 3) the reflex pressor response to static contraction was almost abolished after the intrathecal injection of the substance P receptor antagonist, CP-96,345, and CNQX. Our results suggest that substance P and glutamate are two neurotransmitters involved in the spinal transmission of the exercise pressor reflex and that substance P and glutamate exert their effects via neurokinin-1 (NK-1) and non-NMDA receptors, respectively.
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PMID:Blockade of non-NMDA receptors attenuates reflex pressor response to static contraction. 791 Dec 79

In this article, first, the different stages of acquisition and processing of nociceptive information from peripheral receptor to brain are reviewed and the plastic changes that accompany tissue injury are underlined. For instance, the subclassification of peripheral receptors in nociceptors and non-nociceptors (e.g., mechanoreceptors, thermoreceptors) must be understood in the light of peripheral sensitization. This phenomenon is the probable explanation for primary hyperalgesia, the decrease in pain threshold at the site of injury. The observation that substance P enhances N-methyl-D-aspartate (NMDA)-elicited responses suggests that these two receptors may operate in concert to prolong and amplify the afferent input generated by peripheral tissue injury. Such afferent barrage induces a state of central sensitization. Second, the major problems in the management of cancer pain, i.e. the development of tolerance to opioids and opioid-insensitive pain, are discussed. The loss of drug effect observed after chronic exposure of the opioid receptor (tolerance) may be the consequence of the down-regulation or desensitization phenomenon (where the total number of receptors coupled to the second messenger is reduced). The agonist dose-response begins to shift to the right. The dramatic analgesic improvement obtained with subanaesthetic doses of ketamine, an NMDA receptor antagonist, in those of our cancer patients who have become resistant to morphine is intriguing. As shown for tolerance, insensitivity to opioids may represent a rightward shift in the opioid dose-response curve and the analgesic effect of ketamine the reversal of that shift.
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PMID:Pain management: physiopathology, future research and endpoints. 814 5

The binding characteristics of histogranin (HN), an endogenous peptide first recognized for its antagonism of N-methyl-D-aspartate (NMDA) responses, were determined in membrane preparations of rat brain. [125I][Ser1]HN, a stable bioactive analog of HN, bound specifically and reversibly to a homogenous population of high-affinity sites with a Kd of 25 nM and a Bmax of 410 fmol/mg protein. The binding of [125I][Ser1]HN increased linearly with membrane protein concentration and was destroyed upon membrane pretreatment with trypsin. The binding displayed rapid association and dissociation kinetics and was blocked by peptides possessing close homology with HN in the following order: [Ser1]HN-(1-15) > HN > [Ser1]HN-(1-14) > HN-(2-15) > [Ser1]-HN-(1-10) > HN-(6-10). Unrelated peptides such as substance P, beta-endorphin, neuropeptide Y, [Met5]enkephalin, [Leu5]enkephalin, dynorphin A(1-13) and neuromedin C were inactive in competition binding assays against [125I]Ser1]HN. Ligands of the binding domains of the NMDA receptor, such as (+)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, (+) 5-methyl-10,11-dihydro 5H-dibenzo[a, d]cyclohepten-5,10-imine hydrogen maleate, 1-N-(2-thienyl)cyclohexylpiperidine, glycine and glutamate were also ineffective in competing for [125I][Ser1]HN binding sites. Interestingly, specific ligands for the polyamine site on the NMDA receptor, as well as the cations Mg++ and Zn++ inhibited [125I][Ser1]HN binding. The polyamine antagonist diethylenetriamine produced a noncompetitive inhibition with an IC50 (175 nM) comparable to that of HN (75 nM). The cations Zn++ and Mg++ displaced [125I][Ser1]HN binding with IC50 values of 18 and 240 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of [125I][Ser1]histogranin binding sites in rat brain. 822 61

1. The goal of the present study was to identify potential neurotransmitter candidates in the Breuer-Hering (BH) reflex pathway, specifically at synapses between the primary afferents and probable second-order neurones (pump cells) within the nucleus tractus solitarii (NTS). We hypothesized that if activation of specific receptors in the NTS is required for production of the BH reflex, then (1) injection of the receptor agonist(s) would mimic the reflex response (apnoea), (2) injection of appropriate antagonists would impair the apnoea produced by either lung inflation or agonist injection, and (3) second-order neurones in the pathway would be excited by either lung inflation or agonists while antagonists would prevent the response to either. 2. Studies were carried out either in spontaneously breathing or in paralysed, thoracotomized and ventilated rats in which either diaphragm EMG or phrenic nerve activity, expired CO2 concentration and arterial pressure were continuously monitored. The BH reflex was physiologically activated by inflating the lungs. 3. Pressure injections (0.03-15 pmol) of selective excitatory amino acid (EAA) receptor agonists, quisqualic acid (Quis) and N-methyl-D-aspartic acid (NMDA) into an area of the NTS shown previously to contain neurones required for production of the BH reflex produced dose-dependent apnoeas that mimicked the response to lung inflation. Injection of substance P (0.03-4 pmol) did not alter baseline respiratory pattern. 4. Injections of the EAA antagonists, kynurenic acid (Kyn; 0.6-240 pmol), 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the BH region of the NTS reversibly impaired the apnoea produced by lung inflation. All three antagonists reduced or abolished the apnoeas resulting from injection of Quis or NMDA, and slowed baseline respiratory frequency. In contrast, injections of the highly selective NMDA receptor antagonist, D-2-amino-5-phosphonovaleric acids (AP5), in doses sufficient to block the apnoeic response to NMDA, neither altered the reflex apnoea evoked by lung inflation nor the baseline respiratory pattern. 5. Pump cells located within the BH region were excited by pressure injections of the broad spectrum EAA agonist, DL-homocysteic acid (DLH). Kyn reversibly blocked the excitation of pump cells in response to either lung inflation or DLH injection. 6. These findings suggest that EAAs mediate primary afferent excitation of second-order neurones in the Breuer-Hering reflex pathway, primarily through the activation of non-NMDA EAA receptor subtypes.
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PMID:Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats. 822 27

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