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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that morphine produces a concentration-dependent multiphasic modulation (inhibitions and facilitations) of substance P (SP) release from trigeminal nucleus caudalis slices by activation of distinct populations of mu-, delta- and kappa-opioid receptors. In the present study, we have examined a wide range of morphine concentrations on K(+)-evoked SP release from dissociated rat dorsal root ganglion (DRG) neurons in culture. SP immunoreactivity was measured in the release buffer. Morphine produced a biphasic effect on K(+)-evoked SP release without affecting basal release. A concentration of 30 nM morphine facilitated SP release while a concentration of 1 microM suppressed release. Higher concentrations of morphine (10-30 microM) did not alter SP release. The facilitatory effect evoked by 30 nM morphine was abolished by opioid-receptor blockade with naloxone (30 nM) and the inhibitory effect produced by 1 microM morphine tended to be reversed. We conclude that an intact neuronal circuitry is not required for morphine to produce an opioid receptor mediated biphasic modulation of SP released from unmyelinated primary afferents. It is plausible that the dose-dependent biphasic effects of opioid agonists may also produce biphasic effects on nociception.
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PMID:Morphine produces a biphasic modulation of substance P release from cultured dorsal root ganglion neurons. 747 8

Substance P- and opioid peptide-immunoreactive nerve terminals functionally interact in the spinal cord as two opposing systems in the regulation of the nociceptive pathway. In order to determine how SP-ergic system adapts to chronic opioid receptor blockade, the effects of naltrexone on SP level, SP receptor and the second messenger system coupled to the SP receptor were examined in the rat spinal cord. Male Sprague-Dawley rats were treated with naltrexone or vehicle for seven days by constant minipump infusion. Animals were sacrificed on day 8, spinal cords rapidly removed, segmentally sectioned and used to determine SP and inositol 1,4,5-trisphosphate [ins(1,4,5)P3] tissue contents, and to examine the regulation of their respective receptors in in vitro receptor binding assays. Following chronic naltrexone treatment, SP content in the lumbosacral segment of the spinal cord was increased by 53% over matched control values. The binding capacity (Bmax) of SP receptors, determined using [125I]BHSP, in lumbosacral synaptosomal membranes was significantly increased by 92%, but the binding affinity (Kd) remained unchanged. In addition, the concentration of [Sar9, Met(O2)11]SP, an NK-1 receptor-specific agonist, required to inhibit half of [125I]BHSP binding (IC50) in lumbosacral synaptosomal membranes was significantly decreased, but the IC50s for SP, the endogenous ligand for the SP receptor, and [Pro7]NK B, an NK-3 receptor-specific agonist, were unaltered by chronic blockade of opioid receptors. The data suggest that although naltrexone does not directly interact with tachykinin receptors, it acts indirectly on SP-ergic neurons to cause a change in the apparent affinity of NK-1 receptor (as reflected by a change in IC50 value). Formation of cellular ins(1,4,5)P3 in the lumbosacral cord, quantified by a highly sensitive and selective radioreceptor assay, was significantly increased by 34% relative to matched controls. A time course study indicated that increases in ins(1,4,5)P3 contents over the time studied corresponded qualitatively with increases in SP level in the lumbosacral cord. With [3H]ins(1,4,5)P3 as a ligand, Scatchard analyses of the concentration dependent saturation curves showed that the density of intracellular ins(1,4,5)P3 receptors was also increased by 119%, with no change in binding affinity. The data suggest that ins(1,4,5)P3 formation, possibly coupled to functional SP receptor activation, and ins(1,4,5)P3 receptors, which mediate ins(1,4,5)P3-induced alterations in intracellular Ca2+ flux, are increased in the lumbosacral cord by chronic blockade of opioid receptors. Taken together, the data support the concept of a role for endogenous opioids in the regulation of SP receptor activity in the spinal cord.
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PMID:Modulation of substance P-ergic system in the rat spinal cord by an opioid antagonist. 751 75

The effect of endogenous opioid receptor stimulation on the central cardiovascular and behavioral actions of substance P (SP) was examined in conscious rats. SP (55 pmol) injected intracerebroventricularly (i.c.v.) elicited increases in mean arterial pressure, heart rate, and stereotyped behavioral activation such as exploring and grooming, which were considered to be parts of the cardiovascular defense reaction. Intravenous (i.v.) pretreatment with morphine (2.5 and 5.0 mg/kg) attenuated the cardiovascular and behavioral responses produced by SP i.c.v. dose-dependently. The i.v. pretreatment with naloxone (10 mg/kg) had no effect on the central SP-induced response. Pressor responses elicited by i.c.v. injection of corticotropin-releasing factor or angiotensin II were also attenuated by pretreatment with i.v. morphine (5.0 mg/kg). Our results showed that endogenous opioid receptor stimulation antagonizes the central cardiovascular and behavioral actions of SP. Morphine may not influence the primary site of action of SP but does influence the central neural pathway which conveys the SP-induced sympathetic activation signal.
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PMID:Inhibition by morphine of the cardiovascular and behavioral responses evoked by centrally administered substance P in conscious rats. 751 72

Substance P, a putative neurotransmitter or neuromodulator of nociception or pain in the spinal cord, exhibits both antinociceptive and hyperalgesic properties. Investigators have shown that the N-terminal metabolite of substance P, substance P(1-7), produces naloxone-reversible antinociception when given supraspinally and systemically in mice and hyperalgesia when injected intrathecally in rats. The goal of our investigation was to identify the receptors mediating these actions of substance P(1-7) at the initial site of release of substance P, i.e. in the spinal cord. Thirty minutes after intrathecal injection, substance P(1-7) produced naloxone-reversible antinociception in a dose-dependent manner in the abdominal stretch assay. When administered with naloxone, substance P(1-7) produced hyperalgesia 5 and 10 min after injection, which was inhibited by dizocilpine (MK-801), a phencyclidine ligand and non-competitive antagonist of N-methyl-D-aspartate. Antinociception was inhibited by the mu-selective opioid antagonist beta-funaltrexamine, but not by the mu 1-selective opioid antagonist naloxonazine or the delta-selective antagonist naltrindole, indicating a mu 2-opioid receptor-mediated effect. These findings suggest that the N-terminal portion of substance P may modulate nociception or pain, as demonstrated in the acetic acid abdominal stretch (writhing) assay, via activation of two different receptor systems. Substance P(1-7)-induced hyperalgesia is mediated by a phencyclidine-sensitive mechanism and antinociception involves activity at mu-opioid, most likely mu 2, receptors.
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PMID:Activity at phencyclidine and mu opioid sites mediates the hyperalgesic and antinociceptive properties of the N-terminus of substance P in a model of visceral pain. 752 Oct 22

Expression of neuropeptide messenger RNAs in striatal neurons was studied in post mortem human brain tissue by the use of in situ hybridization histochemistry. Clusters of cells expressing high levels of prodynorphin messenger RNA, and less strikingly, preprotachykinin messenger RNA, were prominent in the caudate nucleus and were present but less pronounced in the putamen. Proenkephalin and prosomatostatin messenger RNA-containing cells were more homogeneously distributed throughout the striatum, though the latter were much sparser. The four neuropeptide messenger RNA patterns in the nucleus accumbens were rather homogeneous compared with the dorsal striatum. Of these, prodynorphin messenger RNA showed a higher level of expression per cell in the nucleus accumbens relative to the dorsal striatum. The relationship of neuropeptide-containing cell clusters to the striosomal organization was characterized by looking at the register of these markers with patterns of low acetylcholinesterase activity and dense mu opiate receptor binding. In the caudate and putamen, clusters of cells expressing high levels of dynorphin and preprotachykinin messenger RNAs were clearly in register with the striosomes. The accumbens was defined by high prodynorphin messenger RNA levels, both low and high levels of acetylcholinesterase staining, and very low to absent mu opiate receptor binding. The distribution of high-expressing prodynorphin messenger RNA-containing cells--to the patch compartment and throughout the entire ventral striatum/nucleus accumbens region--defines the limbic domain of the neostriatum and suggests particular relevance to human striatal organization and function, because the distribution of this opioid neuropeptide is considerably more compartmentalized in human than in non-human species.
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PMID:The human neostriatum shows compartmentalization of neuropeptide gene expression in dorsal and ventral regions: an in situ hybridization histochemical analysis. 753 7

Coexistence of the mRNA for each subtype of opioid receptor (OPR) with the mRNA for preprotachykinin A (PPTA), a precursor protein of substance P (SP), in the rat dorsal root ganglia was examined by double in situ hybridization technique. About 90% and 30% of PPTA mRNA-positive neurons expressed mu- and kappa-OPR mRNAs at high level, respectively. However, only about 3% of PPTA mRNA-positive neurons expressed delta-OPR mRNA at high level. These results suggest that mu- and kappa-OPRs exist on most of and a part of the primary afferent terminals containing SP, respectively. On the other hand, among the neurons which highly expressed mu-, delta- or kappa-OPR mRNA, PPTA mRNA was not expressed in about 58%, 95% or 24% of those neurons, respectively. These findings suggest the possibility that OPRs co-exist with other neurotransmitters and/or neuromodulators than SP in the primary afferent neurons.
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PMID:Double in situ hybridization study on coexistence of mu-, delta- and kappa-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia. 754 48

The modulation of the release of substance P (SP) from sensory primary afferents by activation of kappa opioid receptors is not only equivocal, but also contradictory. Thus, in the present study, we have determined the effect of nanomolar concentrations of the highly selective kappa opioid receptor agonist trans-(+)-3,4-dichloro-N-methyl-N-[2-91- (pyrrolidinyl)cyclohexyl]benzacetamide methane sulphonate (U50488H), as well as micromolar concentrations of moderately mu-selective agonist morphine, on K(+)-evoked SP release from rat trigeminal nucleus caudalis slices. U50488H (10-30 nM) and morphine (10-30 microM) increased K(+)-evoked SP release without stimulating basal SP release. Both U50488H and morphine concentration-response curves were biphasic because the highest and the lowest concentrations of U50488H (100 nM) and morphine (3 microM) tested, respectively, inhibited SP release. Enhancement of K(+)-evoked SP release induced by 30 nM U50488H and 30 microM morphine was blocked by the opioid receptor antagonists naloxone (30 nM; nontype selective) and norbinaltorphimine (3 nM; kappa selective), but not by N,N diallyl Tyr-Aib-Aib-Phe-Leu (0.3 microM; delta selective), naloxonazine (1 nM; mu 1 selective) or beta-funaltrexamine (20 nM; mu selective). These findings indicate that activation of at least one population of kappa opioid receptors increases the release of SP from trigeminal nucleus caudalis. Excitatory presynaptic kappa opioid receptors on SP-containing primary afferents may be involved in the hyperalgesia of inflammatory processes, the "anti-analgesic" effect of dynorphin and the paradoxical "analgesia" produced by low doses of naloxone.
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PMID:Activation of kappa opioid receptors by U50488H and morphine enhances the release of substance P from rat trigeminal nucleus slices. 767 33

The effects of cold water swim stress (CWSS) on the nociceptive responses to i.t. administered substance P (SP) and somatostatin (SST) were examined. Male ICR mice, weighing about 30 g, were forced to swim in water at 20 degrees C for 3 min. In unstressed mice, i.t. injection of SP (0.1 nmol) and SST (1 nmol), respectively, produced nociceptive-related behaviors. Although CWSS had no effect on the intensity of the SP-induced nociceptive responses, CWSS significantly reduced the intensity of the SST-induced nociceptive responses. The effect of CWSS on the SST-induced nociceptive responses was blocked by naloxone (5 mg/kg, s.c.) and naltrindole (1 mg/kg, s.c.), a selective delta-opioid receptor antagonist, but not by beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist. These results indicate that CWSS may selectively reduce the SST-induced nociceptive responses primarily through delta-opioid receptors.
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PMID:Cold water swim stress inhibits the nociceptive responses to intrathecally administered somatostatin, but not substance P. 768 27

1. Effects of the alpha 2-adrenoceptor agonists, UK14304 and clonidine, the 5-HT1 receptor agonist, sumatriptan and the kappa-opioid receptor agonist, GR103545, on sensory neurotransmission in histamine-contracted guinea-pig isolated pulmonary artery (GPPA) have been studied. 2. Electrical field stimulation (EFS) induced frequency-dependent relaxations of histamine-contracted GPPA, which were attenuated by tetrodotoxin and capsaicin pretreatment but not by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). 3. Substance P (0.3 microM) induced relaxations which were subject to rapid tachyphylaxis. Neither the NK1 receptor antagonist, (+/-)-CP 96,345, nor desensitization to substance P had any effect of EFS-induced relaxations of histamine-contracted GPPA. 4. Calcitonin gene-related peptide (CGRP; 3 and 30 nM) induced concentration-dependent relaxations of histamine-contracted GPPA. The putative CGRP receptor antagonist, CGRP8-37 (1 microM), markedly attenuated EFS-induced relaxations as well as relaxations induced by a low concentration of CGRP. 5. Sumatriptan (0.1 and 1 microM) and the selective kappa-opioid receptor agonist, GR103545 (10 and 100 nM) had no effect on EFS-induced relaxations of histamine-contracted GPPA. In contrast, the alpha 2-adrenoceptor agonists UK14304 (1-100 nM) and clonidine (300 nM) attenuated responses to EFS, the attenuation of UK14304 (100 nM) being reversed by yohimbine (300 nM). 6. It is concluded that in GPPA, where a presynaptic inhibition of sensory neurotransmission by alpha 2-adrenoceptor activation could be shown, there was no evidence for such modulation by either sumatriptan-sensitive 5-HT1 receptors or kappa-opioid receptors.
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PMID:Sensory nerve-mediated relaxation of guinea-pig isolated pulmonary artery: prejunctional modulation by alpha 2-adrenoceptor agonists but not sumatriptan. 768 95

1. The non-peptide neurokinin NK1-receptor antagonist, RP 67580 (3aR, 7aR), a perhydroisoindolone derivative, powerfully reduced plasma extravasation in rat hind paw skin induced by local application of xylene (ID50 = 0.03 mg kg-1, i.v.) or capsaicin (ID50 = 0.06 mg kg-1, i.v.), or by i.v. injection of exogenous substance P (SP) or septide ([pGlu6,Pro9]SP(6-11)) (ID50 = 0.04-0.05 mg kg-1, i.v.). RP 67580 (1 mg kg-1, i.v.) also abolished capsaicin-induced nasal fluid hypersecretion (by 82 +/- 5%). These effects were found to be stereospecific, the enantiomer, RP 68651 (3aS, 7aS), being inactive at 1 mg kg-1, i.v. 2. In rats neonatally treated with capsaicin (50 mg kg-1, s.c.), plasma extravasation induced by SP was significantly increased (by 43 +/- 7%). RP 67580 (1 mg kg-1, i.v.) completely inhibited the SP-induced plasma extravasation in capsaicin neonatally treated-animals, as it did in control animals. This result suggests that RP 67580 acts at the postsynaptic level for the inhibition of plasma extravasation. 3. Opioid receptor agonists, mu-(morphine) and kappa-(PD-117302) at 10 mg kg-1, s.c., in contrast to NK1-receptor antagonists, did not inhibit plasma extravasation induced by exogenous SP. They were, however, partially effective against plasma extravasation induced by electrical nerve stimulation (74 +/- 4% and 48 +/- 9% inhibition at 10 mg kg-1, s.c. of morphine and PD-117302, respectively, compared to 90 +/- 3% inhibition obtained with RP 67580, 3 mg kg-1, s.c.). These results indicate the presynaptic action of opioid receptor agonists, in contrast to the postsynaptic action of NK1-receptor antagonists for the inhibition of plasma extravasation.4. Ligature of the saphenous nerve distal to the point of electrical stimulation, local application of lignocaine to the saphenous nerve, neonatal capsaicin pretreatment, and colchicine at very low doses(120 microg kg-1 day-1 given for 3 days) were found to prevent plasma extravasation elicited by electrical nerve stimulation.5. The foregoing results demonstrate that the non-peptide NK1-receptor antagonist, RP67580, is a potent inhibitor of plasma extravasation induced in skin by NK1-receptor agonists, by local application of chemical irritants (capsaicin or xylene) or by electrical nerve stimulation. Moreover, opioid receptor agonists and colchicine inhibit plasma extravasation induced by electrical nerve stimulation but not that elicited by exogenous SP. Therefore, it is possible to inhibit neurogenic inflammation either at the presynaptic level with opioid receptor agonists and colchicine, or at the postsynaptic level withNK1-receptor antagonists, and that the new non-peptide NK1-receptor antagonists may have a great potential for alleviation of inflammation in various pathological syndromes in man.
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PMID:A non-peptide NK1-receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically. 768 5


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