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

Excitatory amino acids (EAAs) administered intrathecally (i.t.) in the mouse elicit a caudally directed biting and scratching behavior. N-methyl-D-aspartate (NMDA) is a potent agonist that produces this behavior, and its action is inhibited by the NMDA receptor antagonist, D-2-aminophosphonovaleric acid (D-APV). The behavioral response to the agonists resembles the response to i.t. substance P (SP) except that the response to the EAAs is more intense and, at higher doses, is accompanied by vocalization. The behavioral response to i.t. EAAs is not enhanced by i.t. SP. Whereas [D-Ala2-D-Leu5]enkephalin (DADL) and norepinephrine (NE) inhibit SP-induced biting and scratching, these compounds only partially inhibit EAA-induced behavior. Phencyclidine (PCP), on the other hand, inhibits completely NMDA-induced behavior but not behavior induced by SP or other EAAs. We conclude that the behavior induced by i.t. EAAs is mediated by spinal EAA receptors and that this response is pharmacologically distinct from responses to SP.
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PMID:Phencyclidine selectively blocks a spinal action of N-methyl-D-aspartate in mice. 242 2

Intrathecal (i.t.) pretreatment with 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, diminished scratching with the hindlimbs, vocalization, biting or licking, and myoclonic twitches produced by i.t. strychnine, kainic acid, or morphine in rats. APV did not diminish these behaviors when produced by i.t. substance P (SP). The SP analogue [D-Pro2,D-Trp7,9]-substance P (DPDT) failed to affect any behaviors produced by all of these compounds at non-paralytic doses. At these doses, neither APV nor DPDT changed the thermal and mechanical pain thresholds. These results indicate that SP does not produce scratching at the primary afferent synapse in the spinal cord, that hindlimb scratching in rats is neither necessary nor sufficient to infer the presence of pain in rats, and that SP may not be involved uniquely, if at all, in the transmission of nociceptive information at the primary afferent synapse.
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PMID:Is substance P a primary afferent neurotransmitter for nociceptive input? IV. 2-Amino-5-phosphonovalerate (APV) and [D-Pro2,D-Trp7,9]-substance P exert different effects on behaviors induced by intrathecal substance P, strychnine and kainic acid. 245 42

Quinolinic acid (QA) is an endogenous excitotoxin present in mammalian brain that reproduces many of the histologic and neurochemical features of Huntington's disease (HD). In the present study we have examined the ability of a variety of systemically administered compounds to modify striatal QA neurotoxicity. Lesions were assessed by measurements of the intrinsic striatal neurotransmitters substance P, somatostatin, neuropeptide Y, and GABA. Histologic examination was performed with Nissl stains. The antioxidants ascorbic acid, beta-carotene, and alpha-tocopherol administered s.c. for 3 d prior to striatal QA lesions had no significant effect. Other drugs were administered i.p. 1/2 hr prior to QA striatal lesions. The following were ineffective in blocking QA excitotoxicity: allopurinol, 50 and 100 mg/kg; ketamine, 75 mg/kg; nimodipine, 2.4, and 10 mg/kg; baclofen, 10 mg/kg; 2-amino-5-phosphonovalerate, 50 mg/kg; and 2-amino-7-phosphonoheptanoate, 50 mg/kg. Oral taurine administration for 4 weeks resulted in significantly increased levels of brain taurine but had no significant effect in blocking QA neurotoxicity. Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 resulted in a dose-responsive protection against QA toxicity, with complete block at a dose of 4 mg/kg. If the pathogenesis of HD involves QA or another excitotoxin acting at the NMDA receptor, it is possible that MK-801 could retard the degenerative process.
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PMID:Systemic approaches to modifying quinolinic acid striatal lesions in rats. 246 37

These experiments examined the effects of intrathecally administered gamma-aminobutyric acid (GABA) agonists on the effects of intrathecally administered excitatory amino acid (EAA) agonists: N-methyl-D-aspartic acid (NMDA), quisqualic acid and kainic acid. We have found that muscimol, a GABAA receptor agonist, but not baclofen, a GABAB receptor agonist, dose-dependently inhibited caudally directed biting and scratching behavior induced by all three EAA agonists. This nonselective blockade of the expression of effects mediated by all three types of EAA receptor is in marked contrast to the selective blockade of NMDA effects seen previously in the case of mu opioids and phencyclidine receptor agonists. Inhibition by muscimol was blocked with the GABAA receptor antagonist, bicuculline. Decreased latency or hyperalgesia in the tail-flick test, found previously to be induced selectively by NMDA and blocked by an NMDA receptor antagonist, was similarly affected by muscimol but not baclofen, each given intrathecally. However, muscimol prolonged the tail-flick latency only after presentation of NMDA suggesting a possible antinociceptive effect of GABAA agonists in the presence of agonists at NMDA receptors. This study together with the preceding paper resolves GABA-mediated spinal antinociception into two components: a GABAA agonist selectively blocks nociception involving EAA receptors whereas a GABAB agonist selectively blocks substance P spinal activity (the preceding paper).
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PMID:Muscimol, gamma-aminobutyric acidA receptors and excitatory amino acids in the mouse spinal cord. 246 78

Microinjections of N-methyl-D-aspartate (NMDA) into the medial area of the nucleus tractus solitarii (NTS) of the rat led to a decrease in arterial pressure and heart rate. The NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP5) reduced the cardiovascular responses to NMDA. Depressor and bradycardic responses to aortic nerve stimulation were reduced by AP5 but not by a substance P antagonist, injected into the NTS. High K+ stimulation caused a calcium-dependent release of glutamate and aspartate from tissues in the area of the NTS. These results provide evidence of NMDA receptor-mediated modulation of the aortic baroreceptor reflex in the rat NTS.
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PMID:Evidence of N-methyl-D-aspartate receptor-mediated modulation of the aortic baroreceptor reflex in the rat nucleus tractus solitarii. 289 14

The effects of beta-amyloid protein 1-40 (beta AP 1-40), substance P (SP), and the amidated and carboxylic acid C-terminated forms of the SP homologous beta AP fragment 25-35 (beta AP 25-35-NH2 and beta AP 25-35-COOH) were studied on [3H]MK-801 binding to the rat brain NMDA receptor cation channel. All peptides gave dose-dependent enhancements of [3H]MK-801 binding stimulated by low glycine. beta AP 25-35-COOH, but not beta AP 25-35-NH2 produced an inhibition of [3H]MK-801 binding stimulated by high glycine in the presence of either low or high glutamate. Low glutamate-stimulated [3H]MK-801 binding was also inhibited by SP but not by beta AP 1-40. It is concluded that beta AP related peptides exert differential effects on the NMDA receptor complex at the glycine and possibly also the glutamate recognition sites.
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PMID:beta-Amyloid related peptides exert differential effects on [3H]MK-801 binding to rat cortical membranes. 751 97

The mammalian suprachiasmatic nucleus (SCN) has been identified as a circadian pacemaker. N-methyl-D-aspartate (NMDA), non-NMDA and substance P receptors have been suggested to be involved in handling of photic information in the SCN. In the Aplysia eyes, in which the circadian clocks are involved, serotonin- or cAMP-induced phase changes of the circadian rhythm were reported to be blocked by protein-synthesis inhibitors. Therefore, we investigated whether protein-synthesis inhibitor can block the non- NMDA receptor agonist (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA)- or substance P (SP)-induced phase changes of SCN activity rhythm. Although application of 10 microM cycloheximide alone during the early part of the subjective night did not cause phase change, it blocked both 10 microM AMPA- and 1 microM SP-induced phase delay. The present result suggests that protein synthesis may be required in the manifestation of AMPA- and SP-induced phase change of circadian clock.
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PMID:Protein-synthesis inhibitor blocks (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-or substance P-induced phase shift of the circadian rhythm of neuronal activity in the rat suprachiasmatic nucleus in vitro. 751 59

Neuronal plasticity associated with altered sensations arising from tissue damage involves both established (e.g. substance P and excitatory amino acids) and novel (e.g. nitric oxide and metabolites of arachidonic acid) mediators released from terminals of primary afferent neurons or synthesised in the spinal cord. These and other mediators lead to activity-dependent synaptic plasticity and enhanced sensitivity to noxious stimuli (hyperalgesia). Activation of the N-methyl-D-aspartate (NMDA) receptor results in a calcium-dependent production of nitric oxide, while activation of alpha-amino-3-hydroxy-5-methylisoxazole-5-propionate (AMPA)-and 1,3- trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD)-sensitive glutamate receptors results in a phospholipase A2 (PLA2)-mediated production of different intracellular mediators, including arachidonic acid. Thermal hyperalgesia requires NMDA receptor activation and is primarily mediated by production of nitric oxide. Mechanical hyperalgesia requires AMPA and metabotropic glutamate receptor coactivation, and is primarily mediated by cyclo-oxygenase products of arachidonic acid metabolism.
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PMID:Spinal mediators of hyperalgesia. 752 81

To determine the role of NK-1 substance P receptors and N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the spinal dorsal horn in the hyperalgesia induced by repeated cold stress (RCS), we examined the effects of intrathecal injections of antagonists to NK-1, NMDA and non-NMDA receptors on the nociceptive threshold of RCS rats for paw-pressure stimulation. Intrathecal injections of the NK-1 antagonist (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine (CP-96,345, 0.3-3 nmol/rat), the NMDA antagonist 2-amino-5-phosphonovaleric acid (APV, 1-10nmol/rat), and the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1-10 nmol/rat) suppressed RCS-induced hyperalgesia in a dose-dependent manner, without affecting the nociceptive threshold of normal rats. Combinations of any two of CP-96,345 (3 nmol/rat), APV (10 nmol/rat), and CNQX (10 nmol/rat) did not produce a larger inhibition than that produced by their single doses. The present results suggest that the enhancement of the substance P-NK-1 receptor system and glutamate-NMDA and non-NMDA receptor systems in the spinal dorsal horn is at least partly involved in the RCS-induced hyperalgesia.
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PMID:Effects of intrathecally injected glutamate and substance P antagonists on repeated cold stress-induced hyperalgesia in rats. 753 76

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


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