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)

The phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor, the kainic acid (KA) receptor and the quisqualate (QA) receptor were visualised, using autoradiography in the human spinal cord and the distributions compared with that of benzodiazepine (BDZ) receptors and substance P (SP). All of the receptor types, and SP, were concentrated in lamina II of the dorsal horn, consistent with physiological data indicating that glutamate is a neurotransmitter of primary afferent terminals in the spinal cord.
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PMID:Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord. 168 76

Modulation of spinal systems activated by N-methyl-D-aspartate (NMDA) and substance P administered IT have been an area of interest in several laboratories. In the present investigations, behavior induced by the excitatory amino acid kainic acid, but not quisqualate, is demonstrated to be modulated in a manner similar to that previously observed for NMDA. Biting, scratching and licking behavior was induced by IT injections of excitatory amino acids or substance P in mice. Behavior induced by kainic acid (IT) injection was inhibited in a dose-dependent manner by coadministration of morphine (ICV), norepinephrine (IT), N-ethyl carboxamidoadenosine (NECA) (IT) and agonists interacting at PCP receptors (IT). Kainic acid and NMDA differed, however, in that a dopaminergic agonist, apomorphine, inhibited kainic acid-, but not NMDA-induced behavior and a selective NMDA receptor antagonist inhibits NMDA-, but not kainic acid-induced behavior. Behavior induced by quisqualate (IT) was not inhibited by any treatment and may have nonspecific actions in this type of assay. Our observations support independent spinal sites of action for behavior induced by kainic acid and NMDA, but several similarities were observed in the modulation of spinal systems activated by these agents.
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PMID:Descending systems activated by morphine (ICV) inhibit kainic acid (IT)-induced behavior. 171 10

Compounds that produce depolarization of nociceptive neurons in the dorsal horn of the spinal cord also elicit a rather specific kind of caudally directed biting, licking, and/or scratching behavior when they are injected intrathecally in mice. We sought to use this elicited grooming behavior as a test for compounds that might inhibit the neurons excited by the excitatory agents. All three neurokinins--substance P, neurokinin A (substance K), neurokinin B (neuromedin K)--and excitatory amino acids active at N-methyl-D-aspartate (NMDA) or quisqualate receptors produce similar behaviors, which last for 1 minute after i.t. injection. Our data indicate that mu opioid agonists or alpha adrenergic agonists block both neurokinin-elicited behavior and EAA-elicited behavior; delta opioid agonists block only neurokinin-elicited behavior; and PCP/sigma "opioid" agonists block only EAA-elicited behavior. Somatostatin and serotonin produce qualitatively different behaviors by themselves and, when administered with neurokinins, partially block neurokinin-elicited behavior.
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PMID:Pharmacological studies of grooming and scratching behavior elicited by spinal substance P and excitatory amino acids. 245 61

Substance P and excitatory amino acids have been implicated as potential nociceptive neurotransmitters in several investigations. Excitatory amino acids acting at N-methyl-D-aspartate (NMDA) receptors are of particular interest because of the description of NMDA/phencyclidine (PCP) receptor complexes. PCP receptors are one of two populations of receptors resolved from a population previously referred to as 'sigma opioid' receptors. Agonists, including sigma opioid agonists, interacting with PCP receptors non-competitively inhibit NMDA-induced effects. Therefore, it has been suggested that NMDA/PCP receptor complexes in nociceptive systems may explain the antinociceptive effects of sigma opioid agonists. In the present studies, highly selective ligands for PCP and sigma receptors were coadministered with NMDA or substance P i.t. The rank order potency for inhibition of NMDA-induced behavior was (+/-)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) greater than PCP greater than (+/-)N-allyl-normetazocine ((+/-)-SKF10,047). 1,3-Di-ortho-tolyl-guanidine (DTG) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+/-)-3PPP) were inactive. Inhibition of NMDA-induced behavior by PCP receptor agonists was not reversed by haloperidol, a putative sigma receptor antagonist. These data support PCP, but not sigma, receptor-mediated inhibition of behavior induced by NMDA. Behavior induced by i.t. administration of substance P was similarly inhibited by PCP receptor agonists, but inhibition could be reversed by coadministration of haloperidol or (+)-butaclamol. These data suggest a dopaminergic mechanism for PCP inhibition of substance P-induced behavior. Our results confirm the existence of NMDA/PCP receptor complexes in spinal systems mediating nociception and suggest agonists may induce antinociception by interacting with spinal PCP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo characterization of phencyclidine/sigma agonist-mediated inhibition of nociception. 246 11

Adenosine 5'-triphosphate (ATP), substance P (SP) and non-cholinergic nerve stimulation contracted the guinea-pig urinary bladder. SP and two poorly-degradable analogues of ATP, the enantiomers of adenylyl 5'-(beta, gamma-methylene)-diphosphonate (AMP-PCP and L-AMP-PCP), were used to desensitize the guinea-pig bladder. Desensitization of the bladder by AMP-PCP (50 microM) or by L-AMP-PCP (50 microM) abolished the responses to ATP, and inhibited the responses to non-cholinergic nerve stimulation and to SP. The responses to histamine were unaffected. Desensitization by SP (1 microM) inhibited the responses to SP itself, but not the responses to ATP, L-AMP-PCP or non-cholinergic nerve stimulation. These results suggest that SP may act partly by releasing ATP, and support the suggestion that ATP rather than SP is the non-cholinergic stimulatory transmitter.
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PMID:Desensitization of the guinea-pig urinary bladder by the enantiomers of adenylyl 5'-(beta, gamma-methylene)-diphosphonate and by substance P. 620 88

Capsaicin in the adult animal causes antinociception due to the massive release of neurotransmitters, including substance P (SP), from primary afferent C-fibers. The results of the present study indicate that capsaicin-induced antinociception in the adult is sensitive to inhibition by dizocilpine (MK-801). The failure of a high dose (10 nmoles) of (+-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) to mimic the effect of MK-801 (1 nmole) on antinociception induced by 0.8 micrograms of capsaicin suggests that the inhibition by MK-801 is mediated by a phencyclidine (PCP) site but is not associated with NMDA activity. The inability of haloperidol (1 nmole) to affect the actions of capsaicin argues against an interaction with sigma sites. Behavioral sensitization to intrathecally administered kainic acid (KA) has been proposed to reflect similar neuronal activity to that underlying pain transmission. KA sensitization is inhibited by pretreatment with capsaicin (0.8 microgram) or SP(1-7) (10 nmoles) and the influence of MK-801, CPP and haloperidol on these inhibitory effects of capsaicin and SP(1-7) were identical to those on capsaicin-induced antinociception. These data are consistent with the hypothesis that the antinociceptive effect of capsaicin in the adult is similar to that of the N-terminus of SP, both of which involve a pathway sensitive to MK-801 but not mediated by NMDA-type activity.
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PMID:MK-801 inhibits the effects of capsaicin in the adult mouse by an action involving phencyclidine (PCP) sites not linked to NMDA activity. 769 10

Behavioral responses to kainic acid (KA) injected intrathecally in mice are enhanced by N-but not C-terminal fragments of substance P (SP). Repeated injections of KA result in sensitization to KA-induced activity, an effect that appears to be mediated by SP N-terminal activity and inhibited by PCP ligands. The present study was initiated to determine whether the ability of SP N-terminal fragments to enhance KA activity is also sensitive to PCP ligands. We compared the effect of a PCP ligand, dizocilpine (MK-801), to that of haloperidol, a sigma ligand and dopamine antagonist. MK-801 (1 nmol) failed to alter the enhancement of behavioral responses to KA (25 pmol) produced by SP(1-7) (22.5 pmol, 30 min). However, pretreatment with 1 nmol of either haloperidol or the N-terminal SP antagonist, [D-Pro2-D-Phe7]SP(1-7) [D-SP(1-7)], prevented potentiation of KA by SP(1-7). Like SP(1-7), 5 nmol of the sigma ligand 1,3-di(2-tolyl)guanidine (DTG) also enhanced behaviors elicited by KA, and this effect was also blocked by haloperidol or D-SP(1-7), but not spiperone (2.5 nmol), a dopamine antagonist. Together these data suggest that sigma receptors are involved in the potentiation of KA. A large dose of SP(1-7) (10 nmol) or DTG (20 nmol) did not alter the response to KA 24 hr later, yet further potentiated responses to KA 30 min after SP(1-7) (22.5 pmol) or DTG (5 nmol), suggesting sensitization to the effects of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of sigma activity by the amino-terminus of substance P in the mouse spinal cord: involvement of phencyclidine (PCP) sites not linked to N-methyl-D-aspartate (NMDA) activity. 769 72

The nicotinic acetylcholine receptor (AChR) is the paradigm of the neurotransmitter-gated ion channel superfamily. The pharmacological behavior of the AChR can be described as three basic processes that progress sequentially. First, the neurotransmitter acetylcholine (ACh) binds the receptor. Next, the intrinsically coupled ion channel opens upon ACh binding with subsequent ion flux activity. Finally, the AChR becomes desensitized, a process where the ion channel becomes closed in the prolonged presence of ACh. The existing equilibrium among these physiologically relevant processes can be perturbed by the pharmacological action of different drugs. In particular, non-competitive inhibitors (NCIs) inhibit the ion flux and enhance the desensitization rate of the AChR. The action of NCIs was studied using several drugs of exogenous origin. These include compounds such as chlorpromazine (CPZ), triphenylmethylphosphonium (TPMP+), the local anesthetics QX-222 and meproadifen, trifluoromethyl-iodophenyldiazirine (TID), phencyclidine (PCP), histrionicotoxin (HTX), quinacrine, and ethidium. In order to understand the mechanism by which NCIs exert their pharmacological properties several laboratories have studied the structural characteristics of their binding sites, including their respective locations on the receptor. One of the main objectives of this review is to discuss all available experimental evidence regarding the specific localization of the binding sites for exogenous NCIs. For example, it is known that the so-called luminal NCIs bind to a series of ring-forming amino acids in the ion channel. Particularly CPZ, TPMP+, QX-222, cembranoids, and PCP bind to the serine, the threonine, and the leucine ring, whereas TID and meproadifen bind to the valine and extracellular rings, respectively. On the other hand, quinacrine and ethidium, termed non-luminal NCIs, bind to sites outside the channel lumen. Specifically, quinacrine binds to a non-annular lipid domain located approximately 7 A from the lipid-water interface and ethidium binds to the vestibule of the AChR in a site located approximately 46 A away from the membrane surface and equidistant from both ACh binding sites. The non-annular lipid domain has been suggested to be located at the intermolecular interfaces of the five AChR subunits and/or at the interstices of the four (M1-M4) transmembrane domains. One of the most important concepts in neurochemistry is that receptor proteins can be modulated by endogenous substances other than their specific agonists. Among membrane-embedded receptors, the AChR is one of the best examples of this behavior. In this regard, the AChR is non-competitively modulated by diverse molecules such as lipids (fatty acids and steroids), the neuropeptide substance P, and the neurotransmitter 5-hydroxytryptamine (5-HT). It is important to take into account that the above mentioned modulation is produced through a direct binding of these endogenous molecules to the AChR. Since this is a physiologically relevant issue, it is useful to elucidate the structural components of the binding site for each endogenous NCI. In this regard, another important aim of this work is to review all available information related to the specific localization of the binding sites for endogenous NCIs. For example, it is known that both neurotransmitters substance P and 5-HT bind to the lumen of the ion channel. Particularly, the locus for substance P is found in the deltaM2 domain, whereas the binding site for 5-HT and related compounds is putatively located on both the serine and the threonine ring. Instead, fatty acid and steroid molecules bind to non-luminal sites. More specifically, fatty acids may bind to the belt surrounding the intramembranous perimeter of the AChR, namely the annular lipid domain, and/or to the high-affinity quinacrine site which is located at a non-annular lipid domain. Additionally, steroids may bind to a site located on the extracellular hydrophi
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PMID:Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor. 974 59

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.
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PMID:Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions. 1065 39

This study aimed to assess the molecular mechanism of the histone deacetylase inhibitor (HDACI) valproate acid (VPA) alone or in combination with the antipsychotic drug chlorpromazine in the epigenetic regulation of schizophrenia. A total of 60 perinatal CD-SD rats were divided in a control group (16 animals) and a schizophrenia model group (44 animals). For the schizophrenia model group the rats received phencyclidine (PCP) 10 mg/kg/day by intradermal injection on days 7, 9, and 11 after birth. The model was confirmed by the Morris water test in 40 rats. The control and model rats were divided into 7 groups. The Real Time PCR assay was used to detect the mRNA expression changes of GABA system gene [GABBR1 (GABA B receptor 1)], GAD1 (glutamic acid decarboxylase1), GAD2 (glutamic acid decarboxylase2), Lipase metabolic key enzyme LPL (lipoprotein lipase) gene, glutamate neurotransmitter gene GRIA2 (AMPA subtype glutamate receptors 2), inward rectifier potassium channel members KCNJ4 (potassium voltage-gated channel subfamily J member 4) and neuropeptide signal gene TAC1 (tachykinin precursor 1,TAC1) in four brain regions: the prefrontal cortex (PC), the amygdala (AM), the caudate-putamen (CPU) and the hippocampus (HIP). The platform arrival time of PMV and PMVC groups was significantly reduced compared to the PM group, the reduction being more significant in the PMV group. In the four brain regions of the epigenetic animal model of schizophrenia, the expression of GABBR1, GAD1, and GAD2 genes increased significantly. Following administration of HDACI VPA, the mRNA expression of this gene in the four brain regions decreased or approached normal levels. GABBR1 GAD1 and GAD2 are likely to be the target genes affected by the HDACI VPA.
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PMID:Molecular mechanism of action of valproate acid alone or in combination with chlorpromazine in the epigenetic regulation of schizophrenia. 3057 48


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