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 effects of haloperidol and clozapine on tachykinin tissue levels, preprotachykinin-A messenger RNA, spontaneous and potassium-evoked tachykinin release, dopamine D2 receptors, and [125I]Bolton-Hunter-substance P binding sites in the striato-nigral system were examined. Chronic administration (10 days) of the dopamine receptor antagonist haloperidol (2 mg/kg i.p.) significantly decreased tissue levels of substance P like-immunoreactivity and neurokinin A like-immunoreactivity in the striatum and the substantia nigra. The corresponding preprotachykinin-A mRNA was decreased in the striatum. Haloperidol did not affect the potassium-evoked tachykinin release in the substantia nigra but significantly increased the spontaneous release. Haloperidol increased the number of D2-receptors but left [125I]Bolton-Hunter-substance P binding sites, representing neurokinin 1 (NK-1) receptors, as determined by competition experiments with selective ligands, unchanged. Clozapine (30 mg/kg, i.m.) did not influence nigral and striatal tachykinin tissue levels, preprotachykinin-A mRNA and potassium-evoked release or spontaneous efflux in the substantia nigra, or D2-receptors and [125I]Bolton-Hunter-substance P binding sites. The present data indicate that neuroleptics influence the striato-nigral tachykinin system in different ways. Tachykinins may, therefore, contribute to the therapeutic and/or untoward effects of certain neuroleptic drugs.
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PMID:Effects of haloperidol and clozapine on preprotachykinin-A messenger RNA, tachykinin tissue levels, release and neurokinin-1 receptors in the striato-nigral system. 169 86

1. Whole-cell patch-clamp recordings were made from pairs of neurones in cell cultures of rat myenteric neurones. In some pairs, action potentials evoked in the first neurone evoked a slow excitatory postsynaptic potential (EPSP) in the second neurone. 2. Action potentials at a frequency of at least 5 Hz were required to evoked slow EPSPs. In one group of cells, the slow EPSP followed a series of nicotinic fast EPSPs; in another group, fast EPSPs did not precede the slow EPSP. 3. The slow EPSPs were 2-16 mV in amplitude and were accompanied by decreased resting potassium conductance. 4. Most (17/28) neurones in which action potentials evoked only slow EPSPs in a follower cell contained substance P (SP)-like immunoreactivity; they were not immunoreactive for 5-hydroxytryptamine (0/15) or vasoactive intestinal peptide (0/22). 5. Postsynaptic responses to SP, neurokinin A and a synthetic tachykinin [( pGlu6, Pro9]SP6-11) mimicked the slow EPSPs. The non-tachykinin peptide vasoactive intestinal polypeptide (VIP), which was not found in neurones that evoked only slow EPSPs, also mimicked the slow EPSPs. Responsiveness to SP decreased significantly during slow EPSPs. 6. Desensitization to either SP or VIP reduced or prevented the slow EPSPs and also responses to each other. Two proposed antagonists of SP receptors, [D-Arg1, D-Pro2,D-Trp7,9,Leu11]substance P and [D-Arg1,D-Trp7,9,Leu11]substance P, did not affect the slow EPSPs significantly. 7. Antisera against SP reversibly blocked or reduced slow EPSPs evoked by eight of thirteen presynaptic neurones that evoked slow EPSPs without evoking fast EPSPs. All eight of the presynaptic neurones that evoked anti-SP-sensitive slow EPSPs contained SP-like immunoreactivity. None of the presynaptic neurones that evoked anti-SP-insensitive slow EPSPs contained detectable SP-like immunoreactivity. Normal sera and anti-VIP antisera did not alter the slow EPSPs detectably. 8. It is concluded that subsets of myenteric neurones release an SP-like transmitter to evoke slow EPSPs. These neurones appear to lack a 'classical' neurotransmitter that evokes fast EPSPs.
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PMID:Substance P mediates synaptic transmission between rat myenteric neurones in cell culture. 170 Jan 7

1. Whole-cell recording was used to investigate the effects of substance P on cultured neurones from the rat nucleus basalis. 2. Brief applications of substance P produced a reduction, about 1 min in duration, of resting membrane conductance. The concentration producing a half-maximal effect was approximately 40 nM, with the continuous presence of substance P resulting in desensitization of the response. 3. The control current-voltage relation exhibited inward rectification over the voltage range -70 to -150 mV, and hyperpolarization produced a time-dependent decrease of current (inactivation). 4. The substance P-sensitive current, obtained by subtracting the current during the presence of the tachykinin from the control current, showed no time-dependent inactivation, though its current-voltage relation also revealed inward rectification, with the reversal potential being approximately equal to the potassium equilibrium potential, Vk. 5. The relation between the substance P-sensitive chord conductance and voltage could be fitted by a Boltzmann equation, with changes in [K+]o shifting this relation along the voltage axis roughly in parallel with the shift in Vk. The maximum conductance was proportional to [( K+]o). 6. Cs+ (0.1 mM) blocked the substance P-sensitive current in a voltage-dependent manner, with an equivalent valency for Cs+ of 1.9. Barium blockage of the substance P-sensitive current was less voltage dependent. 7. Replacement of external Na+ by tetramethylammonium (TMA+) ions reduced the substance P-sensitive current by only 18%. 8. These results indicate that substance P inhibits potassium channels with inward rectifier properties very similar to those of skeletal muscle. 9. Application of sodium nitroprusside did not alter the effect of substance P, suggesting that cyclic GMP plays no role in the channel modulation.
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PMID:Modulation of inwardly rectifying channels by substance P in cholinergic neurones from rat brain in culture. 170 Jan 8

Adenosine agonists produce antinociception when injected directly onto the spinal cord of rats and mice. One mechanism to account for this effect could be inhibition of neurotransmitter release from nociceptive sensory neurons. Consequently, we studied whether these agents could inhibit the potassium stimulated release of one such transmitter, substance P, from rat spinal cord slices. A 2 cm section of lumbar spinal cord was dissected from male Sprague-Dawley rats, chopped into 0.5 x 0.5 mm sections and perfused at 37 degrees C with a modified Krebs bicarbonate buffer containing either 3.5 mM, 30 mM, or 50 mM KCl in the presence and absence of various adenosine analogs. Perfusates, collected every 2 min, were assayed for substance P by radioimmunoassay. Exposure of tissue to 50 mM KCl produced an approximate three-fold increase in the release of substance P over basal release. This increase in release was calcium dependent. Perfusion of spinal cord tissues with either adenosine (10(-3) M). N6-cyclohexyladenosine (10(-5) M or 5 x 10(-5) M), 5'-N-ethylcarboxamide adenosine (10(-5) M) or L-N6-phenylisopropyladenosine (10(-5) M) did not significantly alter basal or potassium-stimulated release of SP when compared to controls. In contrast to the adenosine agonists, exposure of the spinal cord tissue to 10(-5) M morphine significantly reduced the potassium-stimulated release of substance P. Pretreatment of the slices with 10(-5) M theophylline or 8-phenyl-theophylline did not significantly attenuate the inhibition of substance P release produced by morphine. Theophylline alone (10(-5) M) had no significant effect on either basal or potassium-stimulated release of SP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine analogs do not inhibit the potassium-stimulated release of substance P from rat spinal cord slices. 170 22

Peptides have recently been found to function as neuromodulators or neuromediators within nociceptive pathways at central and peripheral sites. More complex and varied in their chemistry compared to "classical" low molecular weight monoamine neurotransmitters, peptides may nonetheless co-exist with these within a single neuron. The biological activity of a peptide results from an "address" segment that permits receptor binding and a "message" segment that initiates reactions within the cell. Opioid peptides (endorphins) are derived from three precursors and act by altering ionic fluxes of potassium or calcium across cell membranes. Nonopioid peptides active in nociception include calcitonin and its gene-related peptide C.G.R.P., bradykinin, substance P, somatostatin, cholecystokinin, and corticotropin-releasing hormone, among others. Ongoing investigations show significant responses of several peptide systems in experimental models relevant to vascular pain. Although the creation of novel peptide analogues has therapeutic promise, their present clinical use must be cautious in light of reports of neurotoxicity after intraspinal application of some of these compounds in animal models.
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PMID:Neuropeptides and pain. 170 17

The effects of calcitonin gene-related peptide (CGRP) on acetylcholine (ACh) release from myenteric plexus neurons in primary culture were investigated. CGRP (10(-12) to 10(-6) M) produced a dose-dependent increase in [3H]ACh release. The ACh release caused by CGRP was significantly inhibited (74 +/- 24%) by preincubation with dideoxyadenosine but was increased more than threefold by preincubation with theophylline. Incubation of myenteric plexus neurons with CGRP (10(-8) M) in the presence of diltiazem (10(-5) M) or in a calcium-free medium markedly reduced [3H]ACh release. CGRP potentiated [3H]ACh release stimulated by potassium or substance P but not by cholecystokinin octapeptide or forskolin. The results demonstrate that CGRP cause release of ACh from guinea pig myenteric plexus neurons and suggest that the peptide acts through an adenosine 3',5'-cyclic monophosphate-dependent mechanism that involves neuronal calcium channels.
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PMID:Stimulation of acetylcholine release in myenteric plexus by calcitonin gene-related peptide. 170 74

1. Intracellular recordings were made from neurones of the guinea-pig gall-bladder in vitro. Intracellular injection of horseradish peroxidase revealed a simple structure, consisting of a soma and a single process, but no discernible dendritic arborization. 2. The resting membrane potential was -50.5 +/- 0.4 mV and the input resistance was 80 M omega. 3. Gall-bladder neurones spiked only once at the onset of depolarizing current pulses. Action potentials were blocked by tetrodotoxin, but a Ca2(+)-dependent spike could be elicited in the presence of tetrodotoxin and tetraethylammonium. 4. Action potential after-hyperpolarizations had a duration of 172 +/- 3.7 ms and reversed at a membrane potential of -93 mV; this reversal potential was linearly related to the logarithm of the external potassium concentration. The initial phase of the after-hyperpolarization was inhibited by tetraethylammonium (1-10 mM) and was not affected by 3,4-diaminopyridine. The late phase of the after-hyperpolarization was blocked by apamin (10 nM) or curare (500 microM). Both the early and late phases of the after-hyperpolarization were inhibited when the preparation was perfused with a calcium-free, high-magnesium solution. The calcium-free, high-magnesium solution had no effect on the membrane potential or input resistance of these cells. 5. Fast excitatory synaptic responses and antidromic responses were elicited in gall-bladder neurones by focal stimulation of fibre tracts. High-frequency fibre tract stimulation often resulted in prolonged, calcium-dependent, depolarizations that were associated with a decrease in input resistance. 6. 5-Hydroxytryptamine and substance P caused depolarizations that were associated with a decrease in input resistance. Bethanechol caused hyperpolarizations that were associated with a decrease in input resistance and which were blocked by atropine.
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PMID:Intracellular recording from neurones of the guinea-pig gall-bladder. 170 71

We studied smooth muscle strips from rabbit distal colon to determine age-related changes in length-tension properties and agonist-mediated contraction. Strips from newborn (1-d-old) and weanling (11-wk-old) rabbits were oriented to measure isometric tension in longitudinal muscle. Active tension comprised 47 +/- 4 and 75 +/- 5% of the total tension in the newborn and weanling, respectively. Total and active tensions in the weanling were greater than in the newborn (p less than 0.001). Although the potencies for bethanechol were similar, the maximal response was nearly 9-fold greater in weanlings (6900 +/- 292 mN/cm2) versus newborns (753 +/- 112 mN/cm2), p less than 0.001. Maximal stress increased with age for bethanechol, high extracellular potassium, substance P, neurokinin A, cholecystokinin octapeptide, bombesin, and serotonin. ED50 for bethanechol, substance P, neurokinin A, and bombesin did not change with age. Serotonin was 12 times more potent in newborns versus weanlings (p less than 0.05). In contrast, cholecystokinin octapeptide was five times less potent in newborns (18.6 nM versus 3.4 nM, respectively, p less than 0.05). Substance P-induced contractions were inhibited partially by atropine. We conclude that length-tension properties of longitudinal colonic smooth muscle differ, and responses to agonists increase with age.
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PMID:Developmental changes in agonist-mediated colonic smooth muscle contraction in the rabbit. 170 95

1. In the present study, the levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) in human cardiopulmonary tissue were determined in combination with studies on CGRP-LI release from the left anterior descending coronary artery (LAD) and functional effects of CGRP on coronary arterial tone. 2. The highest levels of CGRP-LI were found in the LAD followed in declining order by the bronchus, right atrium, pulmonary artery, lung and left ventricle. 3. Exposure to capsaicin evoked a clear-cut increase in CGRP-LI outflow, suggesting release from isolated large specimen of the LAD. This release was Ca2(+)-dependent and was markedly attenuated by incubation with the mitochondrial Ca2(+)-inhibitor, ruthenium red. Exposure to potassium also released CGRP-LI in a Ca2(+)-dependent fashion from the LAD. 4. In functional experiments on human epicardial coronary arteries with an inner diameter of 0.4 to 0.8 mm, human CGRP alpha and beta relaxed the potassium-precontracted arteries equipotently. Substance P (SP) also relaxed these precontracted arteries but the relaxation could be prevented by incubation with methylene blue, an inhibitor of endothelium derived relaxing factor (EDRF)-mechanisms, which did not influence the effect of CGRP. 5. Capsaicin evoked a ruthenium red-sensitive relaxation of the potassium-precontracted arteries. However, ruthenium red did not affect the relaxations induced by CGRP or SP. Furthermore, the capsaicin effect was not influenced by methylene blue. 6. It is concluded that CGRP-LI is present in human cardiopulmonary tissue and can be released upon exposure to high concentrations of capsaicin as well as potassium. CGRP causes relaxation of arteries independently of EDRF activation and closely resembles the vasodilator effects of capsaicin. This supports the view that the coronary vasodilatation observed upon sensory nerve activation is mediated by CGRP. Ruthenium red inhibits capsaicin-induced CGRP-LI release and functional effects and may thus serve as an experimental tool in evaluating the function of capsaicin-evoked stimulation of peripheral nerve terminals.
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PMID:Calcitonin gene-related peptide and human epicardial coronary arteries: presence, release and vasodilator effects. 170 13

In bullfrog sympathetic neurons, luteinizing hormone-releasing hormone, muscarine, and substance P act as agonists at specific membrane receptors to decrease a potassium current, IM. The receptors are coupled to guanine nucleotide-binding proteins (G-proteins). Whole-cell recordings of IM were made from isolated bullfrog sympathetic neurons to examine the effects of intracellularly applied guanosine-5'-O-(2-thiodiphosphate) (GDP beta S) on agonist inhibition of IM. Successive responses to a given agonist were decreased in the presence of GDP beta s. Subsequent responses to the other agonists were then measured to determine the degree of overlap of the effect of GDP beta S for the different agonists. GDP beta S selectively inhibited successive responses to one agonist such that a subsequent application of a different agonist was still effective. If GDP beta S acts at the level of the G-protein, this suggests that each receptor is coupled to a separate population of G-proteins. Alternatively, GDP beta S may act at the receptor level to block receptor coupling to IM.
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PMID:Selectivity of the effects of guanosine-5'-O-(2-thiodiphosphate) on agonist inhibition of the M-current in amphibian sympathetic neurons. 171 78


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