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 antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin).
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PMID:Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors. 750 56

This study investigated whether activation of serotonin1A [5-hydroxytryptamine (5-HT)1A] receptors in the dorsal horn of the spinal cord attenuates the reflex pressor response to static contraction and passive muscle stretch. In addition, we determined if the attenuation of the response to contraction is mediated by inhibiting substance P (SP) release in the dorsal horn. Static contractions of the triceps surae muscle of chloralose-anesthetized cats were induced by stimulating the cut L7 and S1 ventral roots. Microdialysis (10 mM) of a selective 5-HT1A agonist [8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT)] into the L7 dorsal horn region produced a reversible attenuation of the reflex pressor response to a 1-min contraction (in mmHg: control = 36 +/- 3; 8-OH-DPAT = 17 +/- 3; recovery = 31 +/- 8; P = 0.013; n = 6) or passive stretch (in mmHg: control = 36 +/- 6; 8-OH-DPAT = 15 +/- 2; recovery = 32 +/- 6; P = 0.002; n = 6). However, a 5-HT1B agonist, 1-[3-(trifluoromethyl)-phenyl]piperazine, had no effect on the reflex pressor response. During 5-min contractions (n = 8), 8-OH-DPAT (10 mM) also blunted the pressor response but had no effect on the levels of SP-like immunoreactivity (in fmol/100 microliters: control = 0.492 +/- 0.026; 8-OH-DPAT = 0.501 +/- 0.034). These results suggest that activation of 5-HT1A receptors in the dorsal horn attenuates the reflex pressor response to contraction through a mechanism other than inhibition of SP release.
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PMID:Modulation of reflex pressor response to contraction and effect on substance P release by spinal 5-HT1A receptors. 753 69

Neurogenic oedema formation in the rat hind paw skin induced by electrical stimulation of the saphenous nerve and measured by extravasation of [125I]-albumin, was inhibited by the 5-HT1B receptor agonist, CP-93,129, and the novel tryptamine analogue, CP-122,288. Significant inhibition of up to 66% of control was observed with CP-122,288 (2 x 10(-14) - 2 x 10(-7) mol kg-1) and CP-93,129 (5 x 10(-7) - 5 x 10(-6) mol kg-1), with the minimum effective dose for CP-122,288 being about 10(7) fold less than that for CP-93,129. Oedema formation induced by the intradermal administration of exogenous mediators (substance P and histamine) in rat dorsal skin was not inhibited by CP-122,288 (2 x 10(-10) mol kg-1). These results suggest that CP-122,288 is a potent inhibitor of neurogenic inflammation in rat skin and that the effect may be due to a prejunctional inhibition of neuropeptide release.
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PMID:Effect of a 5-HT1 receptor agonist, CP-122,288, on oedema formation induced by stimulation of the rat saphenous nerve. 764 62

The modulatory effect of spinal serotonin (5-HT)1 receptors on nociception was studied in mice. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, putative 5-HT1A agonists, m-trifluoromethylphenyl-piperazine (TFMPP) and 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo(1,2-1a)quinoxaline (CGS 12066B), 5-HT1B agonists, and 5-carboxamidotryptamine (5-CT), a mixed 5-HT1A and 5HT1B agonist, were used. Intrathecal administration of 8-OH-DPAT, buspirone and 5-CT (1-12 nmol/mouse) significantly facilitated the tail-flick reflex, whereas TFMPP and CGS 12066B prolonged tail-flick latency. When administered i.t. after s.c. pretreatment (25 min) with morphine sulfate, 8-OH-DPAT, buspirone and 5-CT shifted the morphine sulfate dose-response curve 3- to 5-fold to the right. Spiperone, propranolol and pindolol (mixed 5-HT1A and 5-HT1B antagonists) effectively reversed both the tail-flick facilitation and the antagonistic effect on morphine sulfate-induced antinociception produced by 8-OH-DPAT and 5-CT. In addition, simultaneous i.t. administration of 8-OH-DPAT with substance P or N-methyl-D-aspartic acid decreased biting but increased scratching behavior, an effect which is also blocked by the 5-HT1 antagonists. These results confirm and extend other reports on the facilitory role of 5-HT1A receptor subtype on nociceptive responses and support the involvement of 5-HT1B receptor subtype in the antinociceptive action of serotonin.
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PMID:Differential roles of 5-hydroxytryptamine1A and 5-hydroxytryptamine1B receptor subtypes in modulating spinal nociceptive transmission in mice. 768 14

The intrathecal (i.th., T8-10) administration in conscious rats of the 5-hydroxytryptamine (5-HT)1A agonist 8-OH-DPAT (10 nmol), and to a lesser extent the 5-HT1B agonist CGS 12066B (6 nmol), resulted in a blood pressure reduction and a bradycardia. These responses were prevented by the i.th. pretreatment with substance P (SP) (6.5 nmol) and enhanced following pretreatment with the non-peptide SP antagonist CP-96,345 (10 nmol). The partial 5-HT1A agonist 8-MeO-CLEPAT (10 nmol) had by itself small cardiovascular effects. Following the pretreatment with SP, 8-MeO-CLEPAT caused a pressor response and a tachycardia whereas the opposite effects were observed following pretreatment with the SP antagonist. These results support the notion of a functional interaction between serotonergic and SP mechanisms at the level of the preganglionic sympathetic nerves in the spinal cord.
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PMID:Cardiovascular effects of intrathecal administration of agents active at 5-hydroxytryptamine1-receptors in the rat: modulation by substance P and a substance P antagonist. 769 86

Substance P (SP) nerve terminals innervate the intermediolateral cell column (IML) of the thoracic spinal cord, where SP coexists with serotonin (5-HT), neurokinin A (NKA) and thyrotropin-releasing hormone (TRH). Neither the depolarization-induced release of SP nor the presence of other neurochemicals in the regulation of SP release has been directly studied in this system. In the present study, basal and K(+)-stimulated release of SP from the microdissected intermediate area (including the IML, intercalated nucleus and central autonomic nucleus) of the rat thoracic spinal cord, and the regulation of SP release by presynaptic autoreceptors and by coexisting neurochemicals (5-HT, NKA and TRH) were studied using an in vitro superfusion system. Potassium evoked a concentration- and extracellular Ca(2+)-dependent release of SP. In rats pretreated with the serotoninergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), both SP content and the absolute amount of SP released were decreased. However, the fraction of the remaining tissue content of SP released by K+ depolarization was not changed subsequent to 5,7-DHT treatment. Moreover, 5-HT, 5-HT1B agonists (CGS-12066B and RU 24969) and a 5-HT3 agonist (2-methyl-5-HT) did not alter the K(+)-evoked release of SP. These data demonstrate that SP is released from the intermediate area of the rat thoracic spinal cord and some of the SP released comes from serotoninergic nerve terminals. Although 5-HT coexists with SP in the IML, neither endogenous 5-HT nor 5-HT receptor ligands appear to regulate the release of SP. Other colocalized neuropeptides (NKA and TRH) are not involved in the regulation of SP release because neither NKA, a NK2 agonist (GR 64349) nor a TRH analog (MK-771) changed the K(+)-evoked release of SP. A neurokinin-1 (NK1) antagonist (GR 82334) dose-dependently (10(-9)-10(-7) M) increased the K(+)-stimulated release of SP. These data suggest the presence of presynaptic inhibitory NK1 autoreceptors. Whereas, NK1 agonists, [GR 73632 (10(-9)-10(-6) M) and [Sar9, Met (O2)11]SP (10(-8)-10(-6) M)], increased the basal and K(+)-stimulated release of SP, the excitatory effects of GR 73632 were not blocked by the NK1 antagonist. Moreover, GR 73632 increased the efflus of SP to a greater extent in the absence of peptidase inhibitors. Thus, the effect of NK1 agonists on the release of SP may be related to an inhibition of peptide degradation rather than activation of NK1 autoreceptors.
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PMID:Characterization of substance P release from the intermediate area of rat thoracic spinal cord. 885 11

The possible presynaptic action of the anti-migraine drug sumatriptan on primary afferent fibres containing substance P and/or calcitonin gene-related peptide was investigated on superfused rat horizontal spinal cord slices with attached dorsal roots. Electrical stimulation of dorsal roots triggered a significant overflow of both peptides; this could be reduced by sumatriptan in a concentration-dependent manner. As expected from the involvement of 5-HT1B/1.D beta receptors, methiothepin, (-)tertatolol and GR 127,935, but not WAY 100,635, prevented the inhibitors effect of sumatriptan. These data support the idea that the anti-migraine action of sumatriptan may involve, at least in part, a presynaptic inhibitory control of nociceptive (trigeminovascular) substance P- and/or calcitonin gene-related peptide-containing sensory fibres.
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PMID:Sumatriptan inhibits the release of CGRP and substance P from the rat spinal cord. 890 6

The cholinergic system exerts an important modulatory effect on hippocampal functions. Presynaptic inhibition of hippocampal and neocortical acetylcholine (ACh) release by serotonin (5-HT) has been reported in both rat and human brain. There is some controversy, however, concerning the 5-HT receptor which mediates the inhibitory effects of 5-HT. Using slices of the hippocampal formation of rat prelabelled with [3H]-overflow ([3H]-choline, superfused and depolarized electrically (2 min, 3 Hz, 2 ms, 24 mA) or by K+ (20 mM) we observed that 5-HT inhibits hippocampal and entorhinal [3H]-overflow ([3H]-ACh release) by 5-HT1B receptors located on cholinergic terminals. However, this inhibition requires the functional elimination of substance P/gamma-aminobutyric acid (SP/GABA) interneurons which express 5-HT2A receptors as shown by in situ hybridisation histochemistry. Activation of these somadendritically located 5-HT2a receptors facilitates SP release. SP, in turn, stimulates hippocampal [3H]-ACh release through NK1 receptors present on cholinergic terminals. These findings suggest close links between cholinergic afferents, SP interneurons and 5-HT2 receptors. A loss of cholinergic afferents and 5-HT2 receptors, along with a reduction in substance P-immunoreactive neurons, have been observed in the brains of patients suffering from Alzheimer's disease, suggesting the concept that these three alterations reflect a disruption of a functional unit. The present findings might help to explain early pathological changes in Alzheimer's disease.
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PMID:Modulation of cortical acetylcholine release by serotonin: the role of substance P interneurons. 893 61

In 1996, our knowledge of acute antimigraine therapy expanded in three major areas. First, large surveys have confirmed the remarkable efficacy profile of sumatriptan in clinical practice. No satisfying clinical, pharmacokinetic or genetic explanations were found for its major shortcomings: nonresponders, headache recurrence and noncardiac chest symptoms. Second, the novel 5-HT1B/D agonists zolmitriptan (311C90), rizatriptan (MK-462), eletriptan (UK-116,044), avitriptan (BMS-180048) and alniditan (R091274) were all proved superior to placebo for attack treatment, but their advantages over sumatriptan are yet to be analysed in more detail. A higher lipophilicity explains (except for alniditan) their greater oral bioavailability and better central nervous system penetration. A central action now proved experimentally in animals and in humans for 5-HT1B/D agonists such as zolmitriptan may be advantageous for the antimigraine efficacy, but it could also increase sedation. Third, an endothelin (Ro470203, bosentan) and a neurokinin 1 (RPR100893) receptor antagonist were found to be ineffective in migraine. Both compounds are potent inhibitors of neurogenic plasma extravasation in rat dura mater, which might suggest that this pharmacological property does not necessarily predict efficacy in aborting migraine attacks.
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PMID:Acute migraine therapy: the newer drugs. 922 32

1. Primary afferent nerve fibers control cutaneous blood flow and vascular permeability by releasing vasoactive peptides. These vascular reactions and the additional recruitment of leukocytes are commonly embodied in the term neurogenic inflammation. 2. Calcitonin gene-related peptide (CGRP) acting via CGRP1 receptors is the principal transmitter of neurogenic dilatation of arterioles whereas substance P (SP) and neurokinin A (NKA) acting via NK1 receptors mediate the increase in venular permeability. 3. Neurogenic vasodilatation and plasma protein leakage play a role in inflammation because many inflammatory and immune mediators including interleukin-1 beta, nitric oxide, prostanoids, protons, bradykinin, histamine, and 5-hydroxytryptamine can stimulate peptidergic afferent nerve fibers or enhance their excitability. 4. Neurogenic inflammatory reactions can be suppressed by alpha 2-adrenoceptor agonists, histamine acting via H1 receptors, 5-hydroxytryptamine acting via 5-HT1B receptors, opioid peptides, and somatostatin through prejunctional inhibition of peptide release from vasoactive afferent nerve fibers. CGRP, SP, and NKA receptor antagonists are powerful pharmacological tools to inhibit neurogenic inflammation at the postjunctional level. 5. Imbalance between the facilitatory and inhibitory influences on afferent nerve activity has a bearing on chronic inflammatory disease. Impaired nerve function represents a deficit in skin homeostasis while neuronal overactivity is a factor in allergic and hyperreactive disorders of the skin.
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PMID:Neurogenic vasodilatation and plasma leakage in the skin. 945 75


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