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)

Bacterial lipopolysaccharide (LPS) and corticotropin releasing hormone (CRH) plus arginine vasopressin (AVP) induce immunoassayable (1-13)ACTH (alpha MSH) from mononuclear leukocytes. We studied the ability of LPS and CRH + AVP to in vitro stimulate native ACTH (not alpha MSH) and substance P (SP) production and thymidine incorporation in human mononuclear leukocytes. Neither CRH + AVP nor LPS stimulated detectable amounts of intracellular or extracellular ACTH (less than 15 pg/8 x 10(6) cells or total medium) or SP (less than 50 pg/8 x 10(6) cells or total medium) at 1, 2, 3 or 4 days of incubation. LPS, but not CRF + AVP, increased the amount of 3H-thymidine incorporation over controls. This data questions the importance of an immunoadrenal axis and the synthesis of SP by mononuclear leukocytes.
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PMID:Corticotropin releasing hormone and arginine vasopressin stimulation of ACTH and substance P in human mononuclear leukocytes. 169 18

Substance P is one of a series of tachykinins which is present throughout the central nervous system, and has potent effects on neuroendocrine function. Recent studies have suggested that it inhibits pituitary-adrenal activity at a site above the level of the pituitary. We have therefore used a well-validated rat hypothalamic incubation system to investigate the effects of substance P on the release of the principal corticotrophin-releasing hormone, CRH-41. Substance P caused a dose-dependent inhibition of the 28-mM KCl-stimulated release of CRH-41, with a maximum effect at 100 nM (P less than 0.01). This effect was attenuated by 10 microM of the substance P antagonist (D-Pro2,-D-Trp7,9)-substance P. No statistically significant effect of substance K was seen at 1 or 100 nM. Substance P, at a dose of 100 nM, did not alter the 28-mM KCl-stimulated release of CRH-41 from isolated median eminences in vitro. It is concluded that substance P is a potent inhibitor of the stimulated release of CRH-41, probably acting at a site within the hypothalamic paraventricular nucleus.
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PMID:Inhibition of CRH-41 release by substance P, but not substance K, from the rat hypothalamus in vitro. 170 6

Male rats were exposed to severe 14 day immobilization stress. Body weight, body temperature, food and water intake, behavioral parameters, and serum corticosterone levels were measured during and after the stress period. On the 7th day after cessation of stress the experimental animals together with the control rats were taken to immunocytochemical analysis involving morphometry and microdensitometry of tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), various neuropeptide, and glucocorticoid receptor (GR) immunoreactivities (IRs) in a large number of regions of the central nervous system. In addition, adrenocorticotropic hormone (ACTH) IR was analyzed in the pituitary gland. Seven days following cessation of the chronic stress food intake, total locomotion and forward locomotion had been restored to normal. Serum corticosterone levels appeared to remain increased even 6 days following cessation of the chronic immobilization stress, probably caused by increased release of ACTH. Paraventricular corticotropin releasing hormone (CRF) IR was negatively correlated with the pituitary ACTH IR, indicating that the increase in ACTH release was produced by an increased release of CRF from the hypothalamus. The major immunocytochemical change observed 7 days after cessation of stress was a disappearance of 5-HT IR in the 5-HT cell groups B1, B2, B3, and B7. 5-HT IR in nerve terminals was only affected in the dorsal horn, where 5-HT IR was increased in the substantia gelatinosa. GR IR was found to be significantly increased in monoaminergic cell groups: serotoninergic B7, dopaminergic A12, and noradrenergic A1, A2, and A6. A trend for a reduction of TH IR was observed in nigral DA cells associated with significant reductions in TH IR in striatal DA nerve terminals. Finally, increases in 5-HT and substance P (SP) IR were found in the nerve terminals of the substantia gelatinosa of the cervical spinal cord in the stress group. In the present experimental model evidence has been obtained for a maintained activation of the hypothalamic-pituitary-adrenal axis as evaluated 7 days after cessation of severe chronic immobilization stress. The reduction of 5-HT IR in various 5-HT cell groups indicates a reduction of 5-HT synthesis, which may also be associated with reduced 5-HT release from the nerve terminals, since no depletion was observed in terminal regions and in one case an increase in 5-HT IR was noted (substantia gelatinosa).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chronic immobilization stress: evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male rat. 276 Jun 6

Recombinant human interleukin-1 beta (IL-1 beta) significantly increased prostaglandin E2 (PGE2) in a dose-dependent manner in rat astrocyte culture. The minimum effective dose of IL-1 beta was 10(-10)M. IL-1 alpha also increased PGE2, but at a higher concentration. The minimum effective dose of IL-1 alpha was 10(-8)M, indicating it to be 100-fold less effective than IL-1 beta. On the other hand neither IL-1 beta nor IL-1 alpha increased PGE2 production by neuron cultures at any concentration tested. PGE2 response to IL-1 beta was suppressed by simultaneous addition of CRH, somatostatin-14 and LHRH, while these neuropeptides alone did not alter the basal PGE2 levels. Substance P, vasoactive intestinal polypeptide and alpha-MSH altered neither basal nor IL-1 beta-induced increase in PGE2 levels. Angiotensin II (AII) alone also increased PGE2 in cultured astrocytes. Combined addition of AII and IL-1 beta induced a synergistic effect in increasing PGE2 levels. The direct action of IL-1 beta on astrocyte culture suggests that astrocytes may be the target cells for IL-1 beta in the central nervous system. In view of the essential role of central PGE2 in IL-1 beta-induced CRH/ACTH release, these findings suggest the presence of a sophisticated regulatory network in the immune-neuroendocrine interaction.
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PMID:Interleukin-1 beta increases prostaglandin E2 in rat astrocyte cultures: modulatory effect of neuropeptides. 278 13

Neurotensin (NT) differentially altered ethanol-induced anesthesia as measured by duration of loss of righting response or by blood ethanol levels producing loss of righting response in mice (LS and SS) which were selectively bred for differences in response to ethanol. At doses of 5-500 ng i.c.v., NT increased ethanol sensitivity in SS mice, but not in LS mice, as measured by blood ethanol concentrations at loss of righting response. At higher doses, 0.5-10 micrograms i.c.v., NT enhanced the sensitivity of both SS and LS mice to ethanol-induced anesthesia. The hypothermic effect of ethanol determined at loss of righting response was not altered in either LS or SS mice at low doses of NT, but at higher doses NT enhanced ethanol-induced hypothermia in both lines of mice. The altered anesthetic sensitivity was specific for ethanol in that NT did not alter pentobarbital-induced sleep time in either LS or SS mice and halothane anesthesia was altered slightly only in LS mice. NT analogues, N-acetyl-NT8-13, and [D-Trp11]-NT but not NT1-8 enhanced the anesthetic action of ethanol in SS mice. Bombesin, cholecystokinin sulfate, substance P, [D-Trp8, D-Cys14]-somatostatin and corticotropin releasing hormone (CRF) were not effective in enhancing ethanol-induced anesthesia in LS or SS mice. CRF appeared to decrease ethanol sensitivity in LS but not in SS mice. Beta-Endorphin (beta-END) markedly increased the ethanol sensitivity of SS and to a lesser extent of LS mice at relatively high doses, e.g. 0.5-1.0 micrograms i.c.v. The results of the present study indicate that differences in brain sensitivity of LS and SS mice to ethanol may be mediated by genetic differences in NT systems. Likewise, NT, and probably beta-endorphin, may interact with other neurochemical processes that are involved in the mechanism of ethanol-induced anesthesia and that differ genetically in LS and SS mice.
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PMID:Neurotensin selectively alters ethanol-induced anesthesia in LS/Ibg and SS/Ibg lines of mice. 294 96

Stress is known to precipitate or worsen a number of disorders, such as migraines, in which mast cells are suspected of being involved by releasing vasoactive, nociceptive, and proinflammatory mediators. However, no functional association has been demonstrated yet between a migraine trigger and brain mast cell activation. Nontraumatic immobilization (restrain) stress has been shown to stimulate the hypothalamic-pituitary-adrenal axis and to cause redistribution of immune cells. Here, restrain stress caused degranulation in 70% of rat dura mast cells within 30 min, as shown both by light and electron microscopy. These morphologic findings were accompanied by cerebrospinal fluid elevation of rat mast cell protease I, but not II, indicating secretion from connective tissue type mast cells. Mast cell activation due to stress was abolished in animals that had been treated neonatally with capsaicin, indicating that neuropeptides in sensory nerve endings are involved in this response. Complete inhibition was also achieved by pretreating the animals ip with polyclonal antiserum to CRH. Mast cells in the dura were localized close to nerve processes containing substance P, but no CRH-positive fibers were identified even though these were found close to mast cells in the median eminence. This is the first time that stress is shown to activate intracranial mast cells; apparently through the sequential action of CRH and sensory neuropeptides. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders such as migraines, which are induced or exacerbated by stress.
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PMID:Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect. 758 32

Neuropeptide K (NPK), a member of the kassinin-like tachykinin family, is contained in the rat hypothalamus and is known to stimulate pituitary ACTH release. The intraperitoneal bolus administration of NPK dose-dependently enhanced corticosterone blood level not only in intact rats, but also in hypophysectomized/ACTH replaced animals. NPK did not affect corticosterone secretion of dispersed rat adrenocortical cells; however, it concentration-dependently raised basal corticosterone production by decapsulated adrenal quarters (including both cortical and medullary tissues). Minimal and maximal effective concentrations were 10(-9) and 10(-8) M, respectively. 10(-8) M NPK potentiated corticosterone response of adrenal quarters elicited by 10(-12) M ACTH, but not that evoked by higher concentrations of ACTH. The direct corticosterone secretagogue effect of 10(-8) M NPK is annulled by 10(-6) M alpha-helical-CRH or corticotropin-inhibiting peptide, competitive inhibitors of CRH and ACTH, respectively. In light of these findings, the hypothesis is advanced that NPK exerts a direct stimulatory action on adrenocortical secretion and that the mechanism underlying this effect of NPK may involve the activation of the intra-medullary CRH/ACTH system.
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PMID:Neuropeptide K enhances glucocorticoid release by acting directly on the rat adrenal gland: the possible involvement of zona medullaris. 783 90

1. Gamma-aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone, stimulates the release of CRH, and so of ACTH and cortisol, while alprazolam, an indirect GABAA agonist, blocks naloxone-induced ACTH and cortisol secretion. Sodium valproate (SV) inhibits ACTH release in response to CRH, metyrapone and substance P. We hypothesized that, if this action is GABAA-mediated, SV should also inhibit naloxone-stimulated ACTH release. 2. We studied five healthy volunteers in randomized, double-blind, placebo-controlled afternoon studies with SV 400 mg, given 180 min before i.v. naloxone 125 micrograms/kg bodyweight. Plasma concentrations of ACTH, cortisol and SV were measured at intervals during the experiments. 3. SV had no effect on the mean integrated ACTH and cortisol responses to naloxone; ACTH: 165 +/- 21 versus 284 +/- 40 pmol.min per L, P = 0.08; cortisol: 10.5 +/- 1.9 versus 12.8 +/- 1.2 nmol.min per L-3, P = 0.14, placebo/nal versus SV/nal respectively. Basal ACTH and cortisol levels were also not significantly altered by SV (P > 0.30). Mean SV levels were not significantly different between SV/nal and SV/placebo studies (P > 0.50). 4. In conclusion, SV had no effect on naloxone-induced ACTH and cortisol release in normal humans at the dose and plasma drug concentrations studied. This contrasts with the potent inhibitory effect of alprazolam, and suggests that the effect of SV on the human hypothalamic-pituitary-adrenal axis may not be through a GABAA-mediated mechanism. Alternatively, higher plasma SV levels or more sustained exposure to SV may be necessary to inhibit hypothalamic secretion of CRH.
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PMID:Effect of sodium valproate on naloxone-stimulated ACTH and cortisol release in humans. 858 96

Tachykinins are a family of peptides that are able to modulate the activity of the hypothalamo-pituitary CRH-ACTH system. Mammalian tachykinins include neurokinin A (NKA), neurokinin B (NKB), neuropeptide K (NPK), and substance P (SP). We investigated by RIA the effects of tachykinins on the release of CRH and ACTH by rat adrenal medulla in vitro. NKA and NPK concentration-dependently enhanced the release of both CRH and ACTH, NPK being more active than NKA. NKB exerted only a minor stimulatory action exclusively on CRH release, and SP was ineffective. The stimulatory effect of both NKA and NPK on ACTH release was blocked by the CRH receptor antagonist alpha-helical-CRH, thereby suggesting that the increase in ACTH secretion is consequent to the stimulation of CRH release. These findings indicate that NKA and NPK are stimulators not only of the central (hypothalamo-pituitary), but also of the peripheral (intramedullary) branch of the CRH-ACTH system.
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PMID:Neuropeptide K and neurokinin A stimulate CRH and ACTH release by rat adrenal medulla in vitro. 921 Jan 65

Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings. Mast cells are activated by electrical nerve stimulation and millimolar concentrations of neuropeptides, such as substance P (SP). Moreover, acute psychological stress induces CRH-dependent mast cell degranulation. Intradermal administration of rat/human CRH (0.1-10 microM) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion. The effect of CRH on Evans blue extravasation was stronger than equimolar concentrations of the mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH, which does not interact with its receptors (CRHR), had no biological activity. Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR. The stimulatory effect of CRH, like that of compound 48/80 on skin vasodilation, could not be elicited in the mast cell deficient W/Wv mice but was present in their +/+ controls, as well as in C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice. Treatment of rats neonatally with capsaicin had no effect on either Evans blue extravasation or mast cell degranulation, indicating that the effect of exogenous CRH in the skin was not secondary to or dependent on the release of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue extravasation and mast cell degranulation was inhibited by the mast cell stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory molecule somatostatin. To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation. The possibility that nitric oxide might also be involved was tested using pretreatment with a nitric oxide synthase inhibitor that, however, increased the effect of CRH. These findings indicate that CRH activates skin mast cells at least via a CRHR1-dependent mechanism leading to vasodilation and increased vascular permeability. The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.
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PMID:Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. 942 40


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