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)

Intrathecal (i.t.) administration of spermine (0.1-10000 fmol), an endogenous polyamine, produced the behavioural response mainly consisting of biting and/or licking of the hindpaw along with a slight hindlimb scratching directed toward the flank in mice, which peaked at 5-15 min and almost disappeared at 30 min after an injection. The behaviour induced by spermine (10 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-0.5 mg/kg). The characteristic behaviour was also inhibited dose-dependently by i.t. co-administration of ifenprodil (62.5-4000 pmol), a competitive antagonist of the polyamine recognition site on N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and D(-)-2-amino-5-phosphonovaleric acid (D-APV) (0.5-2 nmol) and 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (7. 8-500 pmol), the competitive NMDA receptor antagonists, and (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cycloheptene-5, 10-imine hydrogen maleate (MK-801) (0.5-4 nmol), an NMDA ion-channel blocker, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist. Both (2S, 3S)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicy clo [2.2.2]octane-3-amine] (CP-96,345), a non-peptidic neurokinin-1 (NK-1) receptor antagonist, and CP-96,344, its inactive 2R,3R enantiomer, inhibited spermine-induced behavioural response in a dose-dependent manner. However, [Tyr(6), D-Phe(7), D-His(9)]-substance P(6-11) (sendide) and [D-Phe(7), D-His(9)]-substance P(6-11), the selective antagonists for NK-1 receptors, were without affecting spermine-induced behaviour. These results indicate that spermine-induced behaviour is mediated through the polyamine recognition site on NMDA receptor ion-channel complex without the involvement of substance P system in the mouse spinal cord.
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PMID:Intrathecally administered spermine produces the scratching, biting and licking behaviour in mice. 1077 60

Nerve signals arising from sites of tissue or nerve injury lead to long-term changes in the central nervous system and contribute to hyperalgesia and the amplification and persistence of pain. These nociceptor activity-induced changes are referred to as central sensitization. Central sensitization involves an increase in the excitability of medullary and spinal dorsal horn neurons brought about by a cascade of events, including neuronal depolarization, removal of the voltage-dependent magnesium block of the N-methyl-D-aspartate (NMDA) receptor, calcium entry into neurons, phosphorylation of the NMDA receptor, a change in the cell's excitability, and an increase in synaptic strength. These changes also include activation of other ionotropic and metabotropic excitatory amino acid receptors, neuropeptides such as substance P, neurotrophins, and kinases involved in the phosphorylation process. Central sensitization occurs in trigeminal nociceptive pathways, and more robust neuronal hyperexcitability occurs following deep tissue stimulation than following cutaneous stimulation. By means of Fos protein immunocytochemistry, researchers have found that 2 distinct regions are activated: the subnucleus interpolaris/caudalis transition zone (Vi/Vc) and the caudal subnucleus caudalis. The latter exhibits changes very similar to those in the spinal dorsal horn, but the Vi/Vc zone likely is involved in autonomic nervous system processing and activation of the pituitary-adrenal axis. Descending systems are also an important component of the central sensitization process and provide the neural networks by which cognitive, attentional, and motivational aspects of the pain experience modulate pain transmission. These findings of nociceptor activity-induced neuronal plasticity have important clinical implications in the development of new approaches to the management of persistent pain.
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PMID:Central nervous system plasticity and persistent pain. 1082 30

We have assessed the role of activity in the adult frog visual system in modulating two aspects of neuronal plasticity: neurotransmitter expression and topographic map maintenance. Chronic treatment of one tectal lobe with the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione decreased the percentage of substance P-like immunoreactive (SP-IR) tectal cells in the untreated lobe while disrupting topographic map formation in the treated one. Treatment with the NMDA receptor antagonist d-(-)-2-amino-5-phosphonovaleric acid (d-AP-5) disrupted the topographic map but had no affect on SP-IR cells. These results indicate that maintenance of the topographic map is dependent on direct input from the glutamatergic retinal ganglion cells, whereas substance P (SP) expression is being regulated by a pathway that relays activity from one tectal lobe to the other. Such a pathway is provided by the cholinergic nucleus isthmi, which is reciprocally connected to the ipsilateral tectum and sends a projection to the contralateral one. Mecamylamine and atropine, antagonists of nicotinic and muscarinic receptors, respectively, were used together to block all cholinergic activity or alone to block receptor subclass activity. All three treatments decreased SP expression and disrupted the topographic map in the treated tectal lobe. We conclude that both SP expression and topographic map maintenance in the adult optic tectum are activity-dependent processes. Although our results are consistent with the maintenance of the topographic map through an NMDA receptor-based mechanism, they suggest that SP expression is regulated by a cholinergic interaction that depends on retinal ganglion cell input only for its activation.
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PMID:Activity-dependent regulation of substance P expression and topographic map maintenance by a cholinergic pathway. 1088 19

Alpha-actinin (alpha-actinin-2) is a protein which links the NR1 and NR2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptors to the actin cytoskeleton. Because of the importance of NMDA receptors in modulating the function of the striatum, we have examined the localization of alpha-actinin-2 protein and mRNA in striatal neurons, and its biochemical interaction with NMDA receptor subunits present in the rat striatum. Using an alpha-actinin-2-specific antibody, we found intense immunoreactivity in the striatal neuropil and within striatal neurons that also expressed parvalbumin, calretinin and calbindin. Conversely, alpha-actinin-2 immunoreactivity was not detected in neurons expressing choline acetyltransferase and neuronal nitric oxide synthase. Dual-label in situ hybridization revealed that the highest expression of alpha-actinin-2 mRNA is in substance P-containing striatal projection neurons. The alpha-actinin-2 mRNA is also present in enkephalinergic projection neurons and interneurons expressing parvalbumin, choline acetyl transferase and the 67-kDa isoform of glutamic acid decarboxylase, but was not detected in somatostatin-expressing interneurons. Immunoprecipitation of membrane protein extracts showed that alpha-actinin-2 is present in heteromeric complexes of NMDA subunits, but is not associated with AMPA receptors in the striatum. A subunit-specific anti-NR1 antibody co-precipitated major fractions of NR2A and NR2B subunits, but only a minor fraction of striatal alpha-actinin-2. Conversely, alpha-actinin-2 antibody immunoprecipitated only modest fractions of striatal NR1, NR2A and NR2B subunits. These data demonstrate that alpha-actinin-2 is a very abundant striatal protein, but exhibits cellular specificity in its expression, with very high levels in substance-P-containing projection neurons, and very low levels in somatostatin and neuronal nitric oxide synthase interneurons. Despite the high expression of this protein in the striatum, only a minority of NMDA receptors are linked to alpha-actinin-2. This interaction may identify a subset of receptors with distinct anatomical and functional properties.
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PMID:alpha-actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits. 1092 45

Studies have implicated substance P (SP) in the regulation of affective behaviour, memory function, pain influx, stress and opioid reward. All these dimensions are known to involve glutamate transmission mediated through the N-methyl-D-aspartate (NMDA) receptor. The SP N-terminal fragment SP(1-7) is shown to share some but oppose other effects of the parent compound. We have examined the effect of intracerebroventricular injections of SP(1-7) on the expression of the NMDA receptor subunits NR1, NR2A and NR2B mRNAs in the spinal cord and in discrete areas of the male rat brain. The results indicated that the heptapeptide induced a dose-dependent upregulation of the NR2A transcript in hippocampus, periaqueductal grey and ventral tegmental area, already within a few hours. The level of the NR2B mRNA was increased in hippocampus and nucleus accumbens. The expression of the transcript of the NR1 was enhanced in hippocampus and nucleus accumbens but attenuated in spinal cord. The observed effects of the SP(1-7) fragment are in agreement with what could be expected from the known effects of the heptapeptide on various behaviours involving glutamate transmission.
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PMID:Intracerebroventricular injection of the N-terminal substance P fragment SP(1-7) regulates the expression of the N-methyl-D-aspartate receptor NR1, NR2A and NR2B subunit mRNAs in the rat brain. 1097 86

NMDA and non-NMDA receptors exist extensively on the spinal dorsal horn neurons and are involved in mediating neurotransmission of spinal nociceptive information. NMDA receptor mainly mediates the neurotransmission of cutaneous nociceptive information, while non-NMDA receptor mainly contributes to the neurotransmission of muscular and visceral nociceptive information. One of the main reasons for this difference may be that the cutaneous and muscular nociceptive inputs induced more releases of aspartate and glutamate, respectively. There are co-operative interactions among the regulatory sites within NMDA receptor-channel complex in modulation of spinal nociception. The co-operative interaction between excitatory amino acids and substance P in modulation of spinal nociceptive information may occur on both the body and the dendrites of the nociceptive neuron.
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PMID:[Mediation of excitatory amino acids in synaptic transmission of spinal nociceptive information]. 1103 82

Transgenic mice expressing nerve growth factor (NGF) under the control of a myelin basic protein promoter display above normal NGF levels in the spinal white matter from birth to the age of 2 months. These transient high levels of NGF result in a lasting hyper-innervation of the spinal white matter by ectopic Substance P (SP)-immunoreactive (IR) sensory fibres. Ultrastructural studies in adult transgenic mice demonstrated that the SP-containing fibres establish synapses on neuronal dendrites in the white matter and that most such dendrites express SP receptors. The transgenic animals display a stimulus-induced hyperalgesia and allodynia in a test measuring the latency to tail withdrawal following a heat stimulus. The hyperalgesia and allodynia were reversed by systemic administration of SP receptor or NMDA receptor antagonists. Surprisingly, the application of morphine resulted in an increase in withdrawal latency which was greater than that observed in non-transgenic controls.
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PMID:NGF over-expression during development leads to permanent alterations in innervation in the spinal cord and in behavioural responses to sensory stimuli. 1104 32

Substance P, which modulates synaptic excitability, can be induced by a variety of stimuli. We studied the expression of hippocampal substance P in rats in using lithium-pilocarpine model of status epilepticus during development. Status epilepticus resulted in an age-specific manner of substance P expression that was anatomically distinctive in hippocampal subfields. Maximal induction of substance P immunoreactivity was seen in the CA1 region of the two-week-old rats, and progressively decreased in the three-, four-week-old rats and adults. Meanwhile, the number of substance P-immunoreactive neurons in the CA3 region and dentate granule cell layer was minimal in the two-week-old animals, but approximated the adult level in the three- and four-week-old rats. No substance P-immunoreactive axon terminals were seen in the strata pyramidale and lucidum in the CA3 region of the two-week-old rats, but they were found to progressively increase in the three-, four-week-old rats and adults. To confirm substance P expression after status epilepticus, we studied the expression of preprotachykinin-A mRNA in the hippocampus of the three-week-old rats by in situ hybridization. Two hours following injection of lithium-pilocarpine, preprotachykinin-A mRNA dramatically increased in the granule cells, as well as in the CA3 and CA1 pyramidal cell layers of the hippocampus. To evaluate the relationship between behavioral seizures and substance P induction, we used the NMDA receptor antagonist MK-801. Injection of MK-801 completely blocked lithium-pilocarpine-induced behavioral seizures and SP induction in the two-week-old rats. These results indicate that seizure activity selectively evokes age-dependent and region-selective expression of substance P.
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PMID:Patterns of status epilepticus-induced substance P expression during development. 1107 53

Noxious challenge of the rat gastric mucosa by hydrochloric acid (HCl) is signaled to the nucleus tractus solitarii (NTS) and area postrema (AP). This study examined the participation of glutamate and tachykinins in the medullary transmission process. Activation of neurons was visualized by in situ hybridization autoradiography of c-fos messenger RNA (mRNA) 45 min after intragastric (IG) administration of 0.5 M HCl or saline. IG HCl caused many neurons in the NTS and some neurons in the AP to express c-fos mRNA. The NMDA glutamate receptor antagonist MK-801 (2 mg/kg), the NK(1) tachykinin receptor antagonist GR-205,171 (3 mg/kg) and the NK(2) receptor antagonist SR-144,190 (0.1 mg/kg) failed to significantly reduce the NTS response to IG HCl, whereas the triple combination of MK-801, GR-205,171 and SR-144,190 inhibited it by 45--50%. Only in rats that had been preexposed IG to HCl 48 h before the experiment was MK-801 alone able to depress the NTS response to IG HCl. In contrast, the c-fos mRNA response in the AP was significantly augmented by MK-801, an action that was prevented by coadministration of GR-205,171 plus SR-144,190. Inhibition of neuronal nitric oxide synthase with 7-nitroindazole (45 mg/kg) was without effect on the IG HCl-evoked c-fos mRNA expression in the NTS and AP. Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK(1) and NK(2) receptors cooperate in the vagal afferent input from the acid-threatened stomach to the NTS and participate in the processing of afferent input to the AP in a different and complex manner. These opposing interactions in the AP and NTS and the increase in NMDA receptor function in the NTS after a gastric acid insult are likely to have a bearing on the neuropharmacology of dyspepsia.
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PMID:Cooperation of NMDA and tachykinin NK(1) and NK(2) receptors in the medullary transmission of vagal afferent input from the acid-threatened rat stomach. 1116 70

Brain-derived neurotrophic factor (BDNF) is synthesized by small neuron cell bodies in the dorsal root ganglia (DRG) and is anterogradely transported to primary afferent terminals in the dorsal horn where it is involved in the modulation of painful stimuli. Here we show that BDNF is released in the rat isolated dorsal horn after chemical stimulation by capsaicin or electrical stimulation of dorsal roots. Capsaicin superfusion (1-100 microm) induced a dose-dependent release of BDNF, measured using ELISA. The highest dose of capsaicin also induced a depletion of BDNF protein in the dorsal horn. BDNF release was also seen after electrical stimulation of the dorsal roots at C-fiber strength. This release was encoded by specific patterns of afferent fiber stimulation. Neither continuous low-frequency (480 pulses, 1 Hz) nor tetanic high-frequency (300 pulses in 3 trains, 100 Hz) stimulation evoked release of BDNF, although substance P (SP) release was observed under both of these conditions. However, BDNF was released after short bursts of high-frequency stimulation (300 pulses in 75 trains, 100 Hz) along with SP and glutamate. The NMDA antagonist d-AP-5 inhibited electrically evoked BDNF release. BDNF release was also measured after systemic or intrathecal NGF treatment. This upregulated BDNF content in the DRG and increased the capsaicin-evoked release of BDNF. Similarly, the amount of BDNF released by burst stimulation was increased after NGF treatment. This activity-dependent release continued to be encoded solely by this stimulation pattern. These experiments demonstrate that BDNF release in the dorsal horn is encoded by specific patterns of afferent fiber stimulation and is mediated by NMDA receptor activation.
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PMID:Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. 1140 34


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