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)

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 aim of the present in vivo microdialysis study was to determine the possible contribution of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors to capsaicin-induced release of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat. Perfusion of a microdialysis probe with capsaicin (50 or 100 microM) induced a significant eight-fold increase of the extracellular SP-LI level. The capsaicin (50 microM)-evoked release of SP-LI was blocked by spinal administration of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (D-APV; 5 mM), but not by the AMPA/KA antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione disodium (NBQX; 0.5 mM). In contrast, the SP-LI release induced by 100 microM capsaicin could not be prevented by D-APV (10 mM) or NBQX (0.5 mM). The data suggest that the spinal SP-LI release induced by a moderate concentration of capsaicin is in part dependent on the release of glutamate acting on NMDA receptors.
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PMID:Involvement of spinal N-methyl-D-aspartate receptors in capsaicin-induced in vivo release of substance P in the rat dorsal horn. 1174 21

We evaluated the role of spinal glutamate and substance P receptors in noxious stimulus-induced antinociception (NSIA). NSIA was produced by subdermal capsaicin administration in the hind paw of the rat and measured as attenuation of the jaw-opening reflex. NSIA was completely blocked by spinal intrathecal administration of the selective NMDA receptor antagonist LY235959 as well as the mGluR5 antagonists MPEP and SIB-1757 and partially attenuated by the selective AMPA/kainate receptor antagonist NBQX; however, neither the mGluR1 receptor antagonist LY367385 nor the NK1 antagonist L-703,606 affected NSIA. These results suggest that NSIA depends on glutamate, released from the central terminals of the primary afferent nociceptors, acting primarily on NMDA and mGluR5 receptors. Although substance P is also known to be released by similar stimuli, NK1 receptors do not appear to play a role in NSIA. The implications of these findings in the context of a proposed spinal circuit that mediates NSIA are discussed.
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PMID:Contribution of spinal glutamatergic mechanisms in heterosegmental antinociception induced by noxious stimulation. 1458 Nov 25

Substance P (SP) is a well-established pain messenger in the spinal cord, although its role in substantia gelatinosa (lamina II) still remains elusive. We carried out patch-clamp recordings on lamina II neurons from transverse mouse spinal cord slices (P8-12), using the selective NK1 receptor agonist [Sar9,Met(O2)11]-SP (SM-SP, 3-5 microM) in the presence of NBQX. Activation of NK1 receptors was confirmed after pre-incubation with selective NK1 antagonist L732,138 (4 microM) that consistently blocked the effects of SM-SP (nine neurons). After SM-SP challenge and spontaneous inhibitory post-synaptic current (sIPSC) analysis, 50% of recorded neurons (15 out of 30) were found to display a transient increase in frequency; in five neurons this was also associated with increase of peak amplitude. Five out of eight neurons displayed pure GABAA microM) receptor-mediated sIPSCs, whereas the remaining ones showed mixed GABAergic/glycinergic events. After miniature IPSC analysis, a significant increase in frequency was observed in three out of 14 SM-SP responsive neurons. At least four different morphological types were apparent among NK1-responsive neurons after filling with Lucifer Yellow/biocytin: fusiform with dorso-ventral dendritic arbors (i); round-to-oval with dendritic arborization mainly directed to lamina I (ii) or III (iii), and round-to-oval with dendrites sparsely distributed all around the cell body (iv). Thus, there was no correlation between morphology and electrophysiological properties of responsive neurons. Our observations provide new insights on the processing of sensory neurotransmission in spinal cord, and indicate that activation of NK1 receptors is involved in the maintenance of the inhibitory tone of substantia gelatinosa interneurons.
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PMID:NK1 receptor activation leads to enhancement of inhibitory neurotransmission in spinal substantia gelatinosa neurons of mouse. 1549 83

Allodynia or hyperalgesia induced by peripheral nerve injury may be involved in changes in the sensitivity of neurotransmitters at the spinal cord level. In order to clarify the functional role of neurotransmitters in peripheral nerve injury, we used rats with nerve injury induced by chronic constriction of the sciatic nerve (CCI rat model) and estimated the effects of the intrathecal injection of drugs known to affect glutamate and tachykinin receptors. In sham-operated rats, the NMDA receptor agonist NMDA and AMPA-kinate receptor agonist RS-(5)-bromowillardin reduced withdrawal latency. The non-competitive NMDA receptor antagonist MK-801, competitive NMDA receptor antagonist AP-5 and AMPA-kinate receptor antagonist NBQX increased withdrawal latency. Substance P (SP) increased the withdrawal latency but only transitorily. The NK1 receptor antagonist RP67580 increased withdrawal latency, but the NK2 receptor antagonist SR48968 did not show an effect. In CCI rats, RS-(5)-bromowillardin reduced withdrawal latency, but NMDA did not show an effect. NBQX increased withdrawal latency, while MK-801 and AP-5 showed little or no effect. SP reduced withdrawal latency, and both RP67580 and SR48968 increased it. These results indicate that the alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in the spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.
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PMID:Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain. 1690 66

Inhibitory neurotransmission in spinal cord dorsal horn is mainly mediated by gamma-amino butyric acid (GABA) and glycine. By patch clamp recordings and correlative immunocytochemistry, we studied here the effect of 2 microM capsaicin-induced vanilloid receptor-1 (TRPV1) activation on IPSCs in spinal lamina II neurons from post-natal mice. Specificity was confirmed after pre-incubation with the competitive antagonist SB366791 (10 microM). After a single capsaicin pulse, an intense increase of spontaneous IPSC (sIPSC) frequency was observed in the presence of NBQX 10 microM (62/81 neurons; approximately 76%) or NBQX 10 microM + AP-5 20-100 microM (27/42 neurons; approximately 64%). Only a subpopulation (approximately 40%) of responsive neurons showed a significant amplitude increase. Seventy-two percent of the neurons displayed pure GABA(A) receptor-mediated sIPSCs, whereas the remaining ones showed mixed GABAergic/glycinergic events. After two consecutive capsaicin pulses, frequency rises were very similar, and both significantly higher than controls. When the second pulse was given in the presence of 4 microM L732,138, a selective antagonist of the substance P (SP) preferred receptor NK1, we observed a significant loss in frequency increase (63.90% with NBQX and 52.35% with NBQX + AP-5). TTX (1 microM) largely (approximately 81.5%) blocked the effect of capsaicin. These results show that TRPV1 activation on primary afferent fibers releases SP. The peptide then excites inhibitory neurons in laminae I, III and IV, leading to an increased release of GABA/glycine in lamina II via a parallel alternative pathway to glutamate.
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PMID:Vanilloid receptor-1 (TRPV1)-dependent activation of inhibitory neurotransmission in spinal substantia gelatinosa neurons of mouse. 1731 9

We hypothesized that cough evoked by mechanical stimulation of the tracheobronchial tree in the rabbit is primarily mediated by glutamatergic neurotransmission at the level of the caudal portions of the medial subnucleus of the nucleus tractus solitarii (NTS) and the lateral commissural NTS where cough-related afferents terminate, and that this reflex is potentiated by local release of substance P. To test our hypothesis, we performed bilateral microinjections (30-50 nl) of ionotropic glutamate receptor antagonists or substance P into these locations in pentobarbitone anaesthetized, spontaneously breathing rabbits. Blockade of NMDA and non-NMDA receptors by 50mM kynurenic acid abolished the cough reflex without affecting the Breuer-Hering inflation reflex or the pulmonary chemoreflex. Blockade of non-NMDA receptors using 10mM CNQX or 5mM NBQX caused identical effects. Blockade of NMDA receptors by 10mM D-AP5 strongly reduced, but did not abolish cough responses. Microinjections of 1mM substance P increased peak and rate of rise of abdominal muscle activity as well as cough number. These results are the first to provide evidence that ionotropic glutamate receptors, especially non-NMDA receptors, located within specific regions of NTS are primarily involved in the mediation of cough evoked by mechanical stimulation of the tracheobronchial tree in the rabbit. Present findings on substance P cough-enhancing effects extend previous observations and are relevant to the tachykinin-mediated central sensitization of the cough reflex. They also may provide hints for further studies on centrally acting antitussive drugs.
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PMID:The role of excitatory amino acids and substance P in the mediation of the cough reflex within the nucleus tractus solitarii of the rabbit. 1772 May 51

The neural pathways through which substance P (SP) influences fear and anxiety are poorly understood. However, the amygdala, a brain area repeatedly implicated in fear and anxiety processes, is known to contain large numbers of SP-containing neurons and SP receptors. Several studies have implicated SP neurotransmission within the amygdala in anxiety processes. In the present study, we evaluated the effects of site-specific infusions of an SP receptor antagonist, GR 82334, on conditioned fear responses using the fear-potentiated startle paradigm. GR 82334 infusion into the basolateral (BLA) or the medial (MeA) nuclei of the amygdala, but not into the central nucleus of the amygdala (CeA), dose dependently reduced fear-potentiated startle. Similar effects were obtained with GR 82334 infusion into the ventromedial nucleus of the hypothalamus (VMH), to which the MeA projects, and into the rostral dorsolateral periaqueductal gray (PAG), to which the VMH projects, but not into the deep layers of the superior colliculus/deep mesencephalic nucleus (dSC/DpMe), an output of the CeA previously shown to be important for fear-potentiated startle. Consistent with previous findings, infusion of the AMPA receptor antagonist, NBQX, into the dSC/DpMe, but not into the PAG, did disrupt fear-potentiated startle. These findings suggest that multiple outputs from the amygdala play a critical role in fear-potentiated startle and that SP plays a critical, probably modulatory role, in the MeA to VMH to PAG to the startle pathway based on these and data from others.
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PMID:Effects of substance P in the amygdala, ventromedial hypothalamus, and periaqueductal gray on fear-potentiated startle. 1841 59