UNIPROT:P20366 - FACTA Search

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)

Increases in neuronal activity in response to tissue injury lead to changes in gene expression and prolonged changes in the nervous system. These functional changes appear to contribute to the hyperalgesia and spontaneous pain associated with tissue injury. This activity-dependent plasticity involves neuropeptides, such as dynorphin, substance P and calcitonin gene-related peptide, and excitatory amino acids, such as NMDA, which are chemical mediators involved in nociceptive processing. Unilateral inflammation in the hindpaw of the rat results in an increase in the expression of preprodynorphin and preproenkephalin mRNA in the spinal cord, which parallels the behavioral hyperalgesia associated with the inflammation. Cellular intermediate-early genes, such as c-fos, are also expressed in spinal cord neurons following inflammation and activation of nociceptors. Peripheral inflammation results in an enlargement of the receptive fields of many of these neurons. Dynorphin applied to the spinal cord also induces an enlargement of receptive fields. NMDA antagonists block the hyperexcitability produced by inflammation. A model has been proposed in which dynorphin, substance P and calcitonin gene-related peptide enhance excitability at NMDA receptor sites, leading first to dorsal horn hyperexcitability and then to excessive depolarization and excitotoxicity.
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PMID:Activity-dependent neuronal plasticity following tissue injury and inflammation. 137 25

A striatal dopaminergic denervation leads to changes in the expression of messenger RNA encoding prepropeptides contained in striatal efferent neurons. Such a dopaminergic lesion also abolishes a functional equilibrium between dopaminergic and cholinergic transmissions, generally believed to operate within the neostriatum, which constitutes the theoretical basis for the clinical use of antimuscarinic drugs in extrapyramidal diseases. It is possible, therefore, that changes in prepropeptide messenger RNA expression are mediated by an alteration in cholinergic transmission. To test this hypothesis, we have examined in rats whether trihexyphenidyl, an antimuscarinic drug of wide clinical use, can counteract the changes in preproenkephalin, preprotachykinin and preprodynorphin messenger RNA expression produced by a unilateral 6-hydroxydopamine lesion of substantia nigra dopaminergic neurons. Two weeks after the lesion, trihexyphenidyl was continuously administered through an osmotic minipump (5 mg/day for 15 days) to half of the lesioned and sham-operated rats, the other half receiving the vehicle. Using quantitative in situ hybridization histochemistry, messenger RNAs were analysed at two rostrocaudal levels (anterior and central) of the neostriatum. In parallel, M1 muscarinic receptors were measured by autoradiography of [3H]pirenzepine binding sites. In sham-operated rats, trihexyphenidyl administration produced a significant increase (17-27%) in M1 binding sites. In addition, preproenkephalin messenger RNA levels were decreased (-38%) in the central part, while preprodynorphin messenger RNA levels were significantly increased (+22%) at both striatal levels. In 6-hydroxydopamine-lesioned rats, the expected changes in messenger RNAs were observed when ipsi- versus contralateral side values were compared, but changes were not always detected when comparison was established between values from the dopamine-denervated neostriatum and those from sham-operated rats. The trihexyphenidyl administration in 6-hydroxydopamine-lesioned animals was unable to reproduce the up-regulation of M1 receptors, even in the intact neostriatum. This antimuscarinic treatment further increased preproenkephalin messenger RNA levels in the denervated anterior neostriatum, amplifying the ipsi- versus contralateral difference. It also potentiated the imbalance in preprotachykinin messenger RNA expression, mainly as a result of an increase of preprotachykinin messenger RNA levels in the intact neostriatum. In contrast, trihexyphenidyl treatment by increasing preprodynorphin messenger RNA in both neostriata abolished the ipsi- versus contralateral difference observed in lesioned rats. In conclusion, with the exception of preprodynorphin messenger RNA, trihexyphenidyl treatment was unable to counteract the imbalance in prepropeptide messenger RNA expression produced by a unilateral striatal dopaminergic denervation and even amplified this effect. These results question the neostriatum as the site of action of antimuscarinic drugs in producing their therapeutic effect in extrapyramidal syndromes.
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PMID:Chronic blockade of muscarinic cholinergic receptors by systemic trihexyphenidyl (Artane) administration modulates but does not mediate the dopaminergic regulation of striatal prepropeptide messenger RNA expression. 763 73

The effect of N-methyl-D-aspartate (NMDA) receptor blockade on the expression of preproenkephalin (PPE), preprotachykinin (PPT) and preprodynorphin (PPD) mRNAs in the caudate-putamen and nucleus accumbens was assessed with the non-competitive NMDA receptor antagonist MK-801. Administration of MK-801 once daily for 7 consecutive days increased the abundance of all three neuropeptide mRNAs in the caudate-putamen (CPU) and nucleus accumbens (NAc). (1) PPE mRNA abundance was increased in the anterior CPU (26%) as well as dorsal and ventral CPU (46% and 39%, respectively) but was unaffected in the NAc. (2) PPT mRNA was increased in the NAc (33%), anterior CPU (27%), dorsal CPU (43%) and ventral CPU (67%). In the ventral CPU, PPT mRNA abundance doubled when the dose of MK-801 increased two-fold (from 67% to 119% above control). (3) PPD mRNA was elevated in dorsal and ventral regions of the CPU (49% and 24%, respectively) and in anterior CPU (50%). In the NAc PPD mRNA was increased only at the higher dose (0.1 mg/kg) of MK-801. Cellular analysis of the distribution of grains per cell shows that increases are due to increased accumulation of mRNA by previously expressing cells of the CPU and NAc. These observations demonstrate that NMDA receptor activity plays a significant role in the regulation of neuropeptide expression in the caudate-putamen and accumbens of the rat brain.
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PMID:Elevation of striatal and accumbal preproenkephalin, preprotachykinin and preprodynorphin mRNA abundance subsequent to N-methyl-D-aspartate receptor blockade with MK-801. 776 91

The effects of a repeated treatment with nicotine on the expression of mRNAs encoding preproenkephalin (PPE), preprotachykinin-A (PPT-A), and preprodynorphin (PPDYN) were examined by in situ hybridization histochemistry in various subregions of the nucleus accumbens (Acb). In saline-treated rats, optical density measurements on autoradiographic films showed marked anteroposterior decreasing gradients for PPE and PPT-A mRNAs in the rostral pole and the core, in the cone, and in the ventral shell of the Acb, whereas a lower anteroposterior gradient was observed for PPDYN mRNA signals. The intensity of the three mRNA signals also varied according to Acb subregion. However, analysis of percentages of prepropeptide mRNA-containing neurons as compared to total neurons showed, in the rostral pole, the core, and the cone, a similar percentage of PPE mRNA (around 45%)- and PPT-A mRNA (around 40%)-expressing neurons. The ventral shell can be distinguished from the other subregions by a lower percentage of PPE mRNA (35.8%)- and PPT-A mRNA (30.6%)-expressing neurons. The percentage of PPDYN mRNA-containing neurons, by contrast, was similar (around 37%) in the core, the cone, and the ventral shell. Repeated nicotine administration increases the PPE mRNA level in the rostral pole and the anterior third of the core without any change in PPT-A and PPDYN mRNA levels in the various Acb subregions examined. The PPE mRNA increase does not support an effect mediated through an interaction of nicotine with DA neurons. The effect could be linked to a nicotine activation of other afferents to the anterior Acb and/or to a direct nicotine stimulation of PPE mRNA neurons.
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PMID:Distribution of preproenkephalin, preprotachykinin A, and preprodynorphin mRNAs in the rat nucleus accumbens: effect of repeated administration of nicotine. 872 14

This study investigated the effects of pharmacological blockade or stimulation of muscarinic receptors on constitutive and amphetamine-stimulated preprodynorphin, substance P and pre-proenkephalin gene expression in rat striatum. Acute administration of the non-selective muscarinic antagonist, scopolamine (2.5, 5 and 10 mg/kg, s.c.), caused a dose-dependent increase in preprodynorphin and substance P, but not preproenkephalin, messenger RNA expression in the dorsal and ventral striatum as revealed by quantitative in situ hybridization. In contrast, acute injection of the non-selective muscarinic receptor agonist, oxotremorine (0.125, 0.25 and 0.5 mg/kg, s.c.), caused a dose-dependent increase in basal levels of preproenkephalin messenger RNA in the dorsal striatum, without causing a significant effect on constitutive striatal preprodynorphin and substance P expression. Pretreatment with scopolamine (2.5 mg/kg, s.c.) significantly augmented striatal induction of preprodynorphin and substance P messenger RNA induced by acute injection of amphetamine (1.25 and 2.5 mg/kg, i.p.), whereas scopolamine blocked amphetamine-stimulated striatal preproenkephalin expression. Pretreatment with oxotremorine (0.25 mg/kg, s.c.) significantly attenuated amphetamine (1.25 and 2.5 mg/kg, i.p.)-stimulated striatal preprodynorphin and, to a lesser degree, substance P messenger RNA expression. Oxotremorine tended to increase amphetamine-stimulated preproenkephalin messenger RNA expression, but the effect did not reach statistical significance. In addition, scopolamine increased spontaneous, and enhanced amphetamine-stimulated, behavioral activity, whereas oxotremorine attenuated amphetamine-stimulated behaviors. These data support the concept that cholinergic transmission, via interaction with muscarinic receptors, inhibits basal and D1 receptor-stimulated striatonigral dynorphin/substance P gene expression and facilitates striatopallidal enkephalin gene expression.
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PMID:Muscarinic receptors regulate striatal neuropeptide gene expression in normal and amphetamine-treated rats. 892 22

In chronically cannulated rats, microinjection of a competitive metabotropic glutamate receptor (mGluR) antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (MCPG), into the dorsal striatum at doses of 0.4, 2 and 10 micrograms/1 microliter did not affect basal levels of preprodynorphin, substance P and preproenkephalin mRNAs in the dorsal striatum as revealed by quantitative in situ hybridization. However, intrastriatal MCPG (0.08, 0.4 and 2 micrograms/1 microliter) dose-dependently attenuated increases in the three mRNA expression induced by acute amphetamine injection (2 mg/kg, i.p.). MCPG had no significant effect on spontaneous, and amphetamine-stimulated, behavioral activities. These data indicate that activation of MCPG-sensitive mGluRs is necessary for upregulation of striatal neuropeptide mRNA expression in response to amphetamine exposure. However, the mGluR activity is not implicated in maintaining basal levels of the peptide gene expression in the striatum.
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PMID:Intrastriatal injection of the metabotropic glutamate receptor antagonist MCPG attenuates acute amphetamine-stimulated neuropeptide mRNA expression in rat striatum. 893 69

Systemic administration of the muscarinic receptor antagonist, scopolamine, augments, whereas the muscarinic receptor agonist, oxotremorine, attenuates behaviors (locomotion and stereotypies) and preprodynorphin (PPD) and substance P (SP) gene expression in striatonigral neurons induced by the indirect dopamine receptor agonist, amphetamine (AMPH). In contrast, systemic scopolamine blocks, whereas oxotremorine augments, AMPH-stimulated preproenkephalin (PPE) gene expression in striatopallidal neurons. This study investigated the site of action of these effects by administering scopolamine and oxotremorine directly into the striatum and assessing the expression of neuropeptide mRNAs with quantitative in situ hybridization. Unilateral injection of scopolamine into the dorsal striatum augmented, and oxotremorine attenuated, AMPH (2.5 mg/kg, i.p.)-stimulated behaviors. Intrastriatal scopolamine at a concentration of 62 mM, but not 6.2 mM, increased basal levels of PPD and SP mRNAs in the dorsal striatum. In addition, both 6.2 and 62 mM scopolamine significantly augmented AMPH-stimulated PPD and SP mRNA levels. Intrastriatal infusion of 1.6 or 8.1 mM oxotremorine did not alter basal levels of striatal PPD and SP mRNAs. However, both concentrations of oxotremorine completely blocked AMPH-stimulated SP mRNA and oxotremorine at 8.1 mM blocked AMPH-stimulated PPD mRNA. In contrast, PPE induction by AMPH was blocked by 62, but not 6.2, mM scopolamine. Both concentrations of oxotremorine tended to augment basal and AMPH-stimulated PPE mRNA in the dorsal striatum but the trend was not significant. These data demonstrate an inhibition of striatonigral, and facilitation of striatopallidal, gene expression through activation of local striatal muscarinic receptors, which is consistent with the changes seen after systemic administration of muscarinic agents. Therefore, muscarinic cholinergic regulation of basal and stimulated expression of neuropeptide mRNA is processed within the striatum.
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PMID:Intrastriatal injection of a muscarinic receptor agonist and antagonist regulates striatal neuropeptide mRNA expression in normal and amphetamine-treated rats. 906 45

Neuropeptide and immediate early gene expression in striatonigral neurons of the normosensitive striatum is induced by mixed D1/D2 receptor agonists and indirect dopamine agonists, such as cocaine and amphetamine. Both D1 and D2 receptor antagonists block these events. In contrast, the partial D1 agonist, SKF-38393, does not evoke striatonigral gene expression in intact rats. These findings have contributed to the idea that both D1 and D2 receptors must be stimulated to evoke gene expression in striatonigral neurons. How these "D1/D2 interactions" are accomplished is unclear in light of the controversy over whether striatonigral neurons express both D1 and D2 receptors. This study addresses these issues by demonstrating that in intact rats 1) a full D1 receptor agonist, SKF-82958, induced behavioral activity and preprodynorphin (PPD) and substance P (SP) gene expression in medium spiny neurons in the dorsal, and especially, in the ventral striatum, 2) either a D1 antagonist, SCH-23390, or a D2 antagonist, eticlopride, blocked these effects, 3) the muscarinic antagonist, scopolamine, augmented PPD and SP mRNA expression induced by SKF-82958 and prevented the ability of eticlopride to block SKF-82958-induced PPD and SP mRNAs and 4) the SKF-82958-induced increase in preproenkephalin mRNA in striatopallidal neurons was blocked by SCH-23390 or scopolamine but not by eticlopride. These data indicate that endogenous acetylcholine attenuates D1 receptor-stimulated PPD/SP gene expression in medium spiny neurons, mediates D1 receptor-stimulated preproenkephalin gene expression in striatopallidal neurons and contributes to D2 receptor involvement in D1-stimulated PPD/SP gene expression.
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PMID:The full D1 dopamine receptor agonist SKF-82958 induces neuropeptide mRNA in the normosensitive striatum of rats: regulation of D1/D2 interactions by muscarinic receptors. 915 8

Caffeine is a widely consumed substance that elicits psychomotor stimulant effects and also displays addictive properties. In order to assess the effect of caffeine on striatal neuropeptide mRNA expression, male rats were injected (i.p.) with caffeine at 20, 40 or 80 mg/kg of body weight twice daily for 9 consecutive days. Preproenkephalin (PPE), preprotachykinin A (PPT-A) and preprodynorphin (PPD) mRNA levels were determined in coronal sections of brain tissue by in situ hybridization histochemistry. PPE mRNA levels were increased by chronic caffeine in all subdivisions of the striatum at 80 mg/kg (dorsolateral caudate-putamen (dlCPu), +139%; dorsomedial CPu (dmCPu), +42%; ventrolateral CPu (vlCPu), +102%; ventromedial CPu (vmCPu), +20%; and anterior CPu (aCPu), +75% relative to vehicle-injected controls that were normalized to 0% change). Similarly, PPD mRNA expression was increased in all aspects of the striatum at 80 mg/kg (dlCPu, dmCPu, vlCPu, vmCPu and aCPu, +98%, +25%, +104%, +9% and +85%, respectively). In contrast to PPE mRNA, PPD mRNA was increased +117% above control in the nucleus accumbens (NAc) at 20 mg/kg of caffeine. PPT-A mRNA expression was not significantly affected by caffeine treatment in the CPu or NAc. The data demonstrate that repeated exposure to caffeine selectively increases opioid neuropeptide mRNA expression in the striatum and the NAc of the rat brain by a dopamine-independent mechanism.
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PMID:Concurrent elevation of the levels of expression of striatal preproenkephalin and preprodynorphin mRNA in the rat brain by chronic treatment with caffeine. 928 Jan 60

Specific antibodies were produced against C-terminal portions of rat preprodynorphin (PPD), preproenkephalin (PPE), and preprotachykinin A (PPT). PPD, PPE, and PPT C-terminal immunoreactivity was observed in many cell bodies of medium-sized neurons in the rat neostriatum (caudate-putamen). Intense PPE immunoreactivity was found in neuropil of the globus pallidus, whereas intense to moderate PPD and PPT immunoreactivity was distributed in neuropil of the substantia nigra and the entopeduncular nucleus. A double-immunofluorescence analysis revealed that PPE-immunoreactive neostriatal neurons rarely showed immunoreactivity for PPD (<1%) or PPT (<2%). In contrast, more than 95% of PPD-immunoreactive neostriatal neurons showed PPT immunoreactivity, and vice versa. No PPD-, PPE-, or PPT-immunoreactive neostriatal neurons showed immunoreactivity for the markers of neostriatal intrinsic neurons, such as calretinin, choline acetyltransferase, parvalbumin, or somatostatin. When tetramethylrhodamine-dextran amine (TMR-DA) was injected into the substantia nigra, almost all neurons that were labeled retrogradely with TMR-DA showed immunoreactivity for PPD (98%) or PPT (99%), but very few of them exhibited PPE immunoreactivity (1%). After injection of TMR-DA into the globus pallidus, 86%, 17%, and 10% of the retrogradely labeled neurons showed immunoreactivity for PPE, PPD, and PPT, respectively. These results support the notion that the neostriatal projection neurons are divided into at least two groups: The projection neurons of one group contain enkephalins and send projection fibers almost exclusively to the globus pallidus, and the others contain tachykinins and dynorphins/Leu-enkephalin and send projection fibers mainly to the substantia nigra.
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PMID:Preprodynorphin-, preproenkephalin-, and preprotachykinin-expressing neurons in the rat neostriatum: an analysis by immunocytochemistry and retrograde tracing. 929 49

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