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)

We previously found that quinolinic acid striatal excitotoxin lesions result in a relative sparing of somatostatin and neuropeptide Y neurons. In the present study we examined dose-response effects of excitotoxins acting at the three subtypes of glutamate receptors: N-methyl-D-aspartate (AA1), quisqualate (AA2), and kainic acid (AA3). Concentrations of both somatostatin-like immunoreactivity (SLI) and neuropeptide a Y-like immunoreactivity (NPYLI) were compared with those of substance P-like immunoreactivity (SPLI) and GABA. Kainic acid (AA3), quisqualic acid (AA2), and AMPA (AA2) resulted in dose-dependent reductions in all four neurochemical markers examined, while N-methyl-D,L-aspartate (AA1) and quinolinic acid (AA1) resulted in relative sparing of SLI and NPYLI. At doses of each excitotoxin which resulted in comparable 50% reductions in both GABA and SPLI only N-methyl-D,L-aspartate and quinolinic acid had no significant effect on concentrations of SLI and NPYLI. The relative sparing of somatostatin-neuropeptide Y neurons was confirmed histologically by using histochemical staining for NADPH-diaphorase neurons combined with either Nissl stains, or immunohistochemical staining for enkephalin. Lesions with N-methyl-D-aspartate agonists resulted in preferential sparing of NADPH-diaphorase neurons while these neurons were more vulnerable than other neurons to kainic acid or AMPA. Choline acetyltransferase neurons were relatively spared, as compared with other neurons, by agents acting at all three glutamate receptor subtypes. N-methyl-D,L-aspartate lesions were blocked with MK-801, while there was no effect on quisqualic acid or kainic acid lesions. The relative sparing of somatostatin-neuropeptide Y neurons following striatal excitotoxin lesions with N-methyl-D-aspartate (AA1) agonists probably reflects a paucity of AA1 receptors on these neurons. Since these neurons are also spared in Huntington's disease, excitotoxins acting at the N-methyl-D-aspartate (AA1) site provide an improved neurochemical model of this illness.
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PMID:Differential sparing of somatostatin-neuropeptide Y and cholinergic neurons following striatal excitotoxin lesions. 256 16

Rats given an intrathecal injection of substance P (0.3-10 nmol) or any of the excitatory amino acid agonists, N-methyl-D-aspartate (NMDA, 1-10 nmol), kainate (1 and 3 nmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA, 0.3-3 nmol), showed biting or licking the hind paws, scratching with the hind paws (only after substance P) and vocalization (only after excitatory amino acid agonists). The intrathecal co-administration of the NMDA antagonist, 2-amino-5-phosphonovaleric acid (APV, 10 nmol), inhibited behavioral responses to NMDA (10 nmol) and substance P (10 nmol) but not to kainate (3 nmol). Co-administration of the non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 nmol), suppressed responses to kainate (3 nmol), AMPA (3 nmol) and substance P (10 nmol) but not to NMDA (10 nmol). Co-administration of the substance P antagonist, CP-96,345 (3 nmol), inhibited the behavioral responses to substance P (10 nmol), but not to NMDA (10 nmol), kainate (3 nmol) and AMPA (3 nmol). The results suggest that the aversive behavior induced by intrathecal NMDA and non-NMDA agonists is mediated by activation of the corresponding glutamate receptors, but not by NK-1 receptors, and that the behavioral action of intrathecal substance P is mediated not only by direct activation of NK-1 receptors but also indirectly by NMDA and non-NMDA receptors for glutamate.
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PMID:Pharmacological evidence for involvement of excitatory amino acids in aversive responses induced by intrathecal substance P in rats. 750 86

The hypothesis tested was that inhibition of the L-arginine-nitric oxide (NO) pathway may represent a potential central mechanism of action for acetaminophen (paracetamol). Spinal administration of N-methyl-D-aspartate (NMDA, 0.5 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.1 nmol) or substance P (SP, 0.5 nmol) to the rat provoked a specific behaviour characterized by biting, scratching and licking (BSL). This behaviour was antagonized by pretreatment with acetaminophen for NMDA and SP but not for AMPA. Further, the antinociceptive effect of acetaminophen was readily reversed by administration of the natural substrate for nitric oxide synthase (NOS), L-arginine, but not by D-arginine. This suggests that the analgesic effect of acetaminophen is related to inhibition of NO generation. Potential mechanisms for this may involve NMDA and SP. Our data suggest that a significant portion of the analgesic effect of acetaminophen, when used clinically, may be related to an interaction with the central nervous system L-arginine-NO pathway.
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PMID:Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. 752 8

The frequency of spontaneous action potentials of locus coeruleus (LC) neurons was recorded extracellularly in pontine slices of the rat brain. Ethanol (1-100 mM) elevated the firing rate in most neurons; this effect was concentration-dependent. (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0.03-1 microM), kainate (0.1-3 microM), N-methyl-D-aspartate (NMDA; 1-30 microM), substance P (0.01-1 microM), nicotine (0.1-10 microM) and alpha,beta-methylene ATP (alpha,beta-meATP; 0.3-30 microM), all increased the firing. Application of ethanol (10-100 mM) to the superfusion medium for 10 min, reproducibly and concentration-dependently inhibited the facilitatory effect of NMDA (10 microM). However, the inhibitory effect of ethanol (100 mM) decreased during a 30-min superfusion period and after the wash-out of ethanol the sensitivity of LC neurons to NMDA (10 microM) tended to overshoot above their initial level. Although NMDA was more potent in the absence than in the presence of external Mg2+, ethanol (100 mM) continued to depress the facilitatory effect of a low concentration of NMDA (3 microM) in a Mg(2+)-free medium. By contrast, in a medium containing normal Mg2+, ethanol (100 mM) failed to significantly interfere with the increase in firing rate induced by a high concentration of NMDA (30 microM). The effects of kainate (0.5 microM), AMPA (0.3 microM) and nicotine (1 microM) were also depressed by ethanol (100 mM), while the effects of substance P (0.03 microM) and alpha,beta-meATP (30 microM) were not changed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by ethanol of excitatory amino acid receptors and nicotinic acetylcholine receptors at rat locus coeruleus neurons. 753 98

1. The effects of tachykinins and agonists selective for the three subtypes of neurokinin (NK) receptor have been tested on spinal neuronal responses both to the excitatory amino acids (EAAs) NMDA, AMPA and kainate, and to noxious heat stimuli. The agonists were applied by microiontophoresis in in vivo experiments in alpha-chloralose-anaesthetized, spinalized rats. 2. The NK1-selective agonist, GR 73632, enhanced responses to all three EAAs similarly, whilst the NK2-selective agonist, GR64349, reduced responses to AMPA and kainate without affecting those to NMDA, and the NK3 selective agonist, senktide, enhanced responses to AMPA and kainate. 3. The endogenous ligands substance P (SP) and neurokinin A (NKA) both enhanced responses to NMDA with little effect on responses to kainate, whereas neurokinin B (NKB) selectively enhanced responses to kainate without affecting those to NMDA. 4. The effects of GR73632 on EAA responses showed some differences between the dorsal and ventral horn, with more selectivity towards enhancement of NMDA responses in the ventral horn, but a smaller maximum effect. 5. Background activity was significantly enhanced by GR73632, GR64349, SP and NKA but not by senktide or NKB. GR73632 had the greatest effect on background firing, but this action was variable between cells and was related both to the location within the spinal cord and to the degree of spontaneous activity prior to GR73632 administration. 6. Responses to noxious heat were enhanced consistently only by NKA. 7. These data show that selective agonists for the tachykinin receptors are capable of modulating EAA responses differentially. SP, NKA and NKB appear to act via more than one receptor type when modulating EAA responses in vivo. This indicates that NK-EAA interactions can be more specific than suggested hitherto, with the combined actions at NKI and NK2 receptors biasing EAA responsiveness towards NMDA receptor mediated functions, whereas NK3 receptor activation would have the opposite effect. The physiological role of such interactions is likely to be complex.
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PMID:Modulation of excitatory amino acid responses by tachykinins and selective tachykinin receptor agonists in the rat spinal cord. 758 96

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

This study examined the effects of substance P (SP) and calcitonin gene-related peptide (CGRP) on synaptic transmission in a pontine slice containing the parabrachial nucleus (PBN). Stimulation of the ventral, external lateral portion of the PBN elicited glutamate-mediated EPSCs in cells recorded using the nystatin perforated-patch recording technique in the external lateral, external medial, and central lateral subnuclei of the PBN. Bath application of SP or CGRP dose-dependently and reversibly attenuated the evoked EPSC. The attenuation of the EPSC induced by both of these peptides was not accompanied by changes in input resistance of PBN cells over a wide voltage range, nor did these peptides alter the inward current induced by a brief bath application of AMPA. The combined application of subthreshold concentrations of these peptides revealed a synergistic interaction in reducing the evoked EPSC. The substance P neurokinin-1 receptor antagonist CGP49823 completely and reversibly blocked both the SP- and the CGRP-induced attenuation of the EPSC. However, the rat CGRP receptor antagonist human-CGRP8-37 did not block the actions of CGRP or SP on the EPSC. Using a metabolically stable analog of SP, SP (5-11), or an endopeptidase inhibitor, phosphoramidon, we were able to demonstrate that CGRP enhances the SP effect by inhibiting an SP endopeptidase. Application of phosphoramidon also revealed an endogenous SP "tone" apparently made effective by blockade of the endopeptidase. These results suggest that SP (and CGRP indirectly through an inhibition of the SP endopeptidase) acts on presynaptic NK-1 receptors to cause an inhibition of excitatory transmission in the PBN. These results indicate an important role of endopeptidases in regulating synaptic modulation by peptides.
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PMID:Peptidergic modulation of synaptic transmission in the parabrachial nucleus in vitro: importance of degradative enzymes in regulating synaptic efficacy. 881 87

The distribution of glutamate receptors in the developing striatum of the rat was studied using antibodies specific to AMPA and NMDA subtypes. Immunocytochemistry revealed a greater density of GluR1, GluR2/3, NMDAR1, and NMDAR2A/2B receptors in patches that matched the patches of substance P-immunoreactive neurons and dopaminergic terminals. GluR1-immunoreactive patches were the most distinctive and were present already at embryonic day 19.
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PMID:Glutamate receptor subtypes localize to patches in the developing striatum. 883 85

Studies in which glutamate (GLU) neurotransmission has been reduced at striatal synapses have shown that GLU influences the biosynthesis of certain peptide cotransmitters by striatal neurons. The present experiment was designed to test the effects of direct activation of the NMDA or AMPA types of GLU receptor on the levels of two mRNAs that encode the peptide cotransmitters met5-enkephalin (ME) and substance P (SP). In situ hybridization histochemistry of forebrain tissue sections from rats 8 h after a single intracerebroventricular infusion of NMDA or AMPA revealed a significant and dose-dependent elevation (to a maximum of almost 50%) of striatal ME mRNA when compared to vehicle-injected controls. SP mRNA was not significantly affected. NMDA was more effective than AMPA over the dose range used. Pretreatment with a potent and highly specific AMPA antagonist (NBQX) predictably blocked the AMPA-mediated elevation, and was only slightly effective against the NMDA-induced response. In striking contrast, pretreatment with a potent and highly selective NMDA antagonist (CGP37849) fully opposed both the NMDA- and the AMPA-mediated elevation of ME mRNA. These data further implicate the NMDA receptor in the regulation of peptide cotransmitter gene transcription. They suggest also that the AMPA receptor may play an indirect, synergistic role in the genetic responses of striatal neurons to GLU transmission.
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PMID:N-methyl-D-aspartate acutely increases proenkephalin mRNA in the rat striatum. 886 64

The intrathecal (i.t.) injection of capsaicin (0.1 nmol/mouse) through a lumbar puncture elicited scratching, biting and licking responses. Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (320 nmol), by i.t. injection, resulted in a significant inhibition of the behavioural response produced by i.t. capsaicin (0.1 nmol/mouse). Similar behavioural responses were induced by i.t. injections of NMDA (0.4 nmol), kainate (0.05 nmol) or AMPA (0.05 nmol), which were all inhibited by co-administration of L-NAME (20-80 nmol). L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the inhibitory effect of L-NAME on capsaicin-, NMDA-, kainate- and AMPA-induced behavioural response. Scratching, biting and licking responses induced by tachykinin receptor agonists, substance P, [Sar9,Met(O2)11]substance P, neurokinin A and neurokinin B were not affected by co-administration of L-NAME (40 and 80 nmol). These results suggest that spinal nitric oxide may play a significant role in mechanisms of the behavioural response to capsaicin, probably through the release of glutamate, but not tachykinins.
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PMID:Involvement of nitric oxide in spinally mediated capsaicin- and glutamate-induced behavioural responses in the mouse. 888 86


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