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)

Noradrenaline- and peptide-containing nerve fibres project into the bone marrow and terminate in association with stromal cells and within the parenchyma. Peptidergic nerve terminals are also associated with antigen-processing and -presenting cells throughout the body and have been shown to be important in leucocyte trafficking and wound healing, as well as haemopoiesis. Here, we tested the in vivo effects of deleting the peripheral neuropeptide network on haemopoiesis and also investigated whether the target cell population for these substances was myeloid progenitor cells (colony-forming unit-granulocyte/macrophage, CFU-GM). Deletion of the neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP) by capsaicin abrogates normal blood cell production. These neuropeptides produced significant stimulation of colony formation from unfractionated bone marrow and elicited production of soluble factors capable of stimulating highly enriched CFU-GM. CGRP also had a direct stimulatory effect on highly enriched CFU-GM. Noradrenaline elicited factors that inhibited colony formation and had no direct effect on CFU-GM. We conclude that the neuropeptides form the positive arm of a neural control system and that noradrenaline acts as a negative regulator.
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PMID:Neuropeptide control of bone marrow neutrophil production is mediated by both direct and indirect effects on CFU-GM. 1065 37

Vasomotor responses to various agonists were studied on isolated circular segments of human epicardial coronary arteries from three different age groups; 23-38 years, 40-58 years and 63-86 years. Noradrenaline had no or only weak contractile effect on coronary arteries from younger patients but induced contraction of all artery segments from older patients. The Emax value was significantly (P<0.0001) higher in arteries from the oldest group compared to each of the two younger age groups, whereas the potency was similar in all three groups. Linear regression analysis of noradrenaline-induced contraction in individual patients revealed a significantly positive age-correlation (correlation coefficient 0.67, P<0.0001). Contraction induced by endothelin-1 and relaxation induced by substance P, calcitonin gene-related peptide and vasoactive intestinal peptide on arteries precontracted with U46619 showed no significant differences in maximum responses and potencies between the three age groups, and no significant linear age-correlation. These data demonstrate a large variability in contractile responses to noradrenaline with contractions seen mostly in coronary arteries from older patients. It thus seems that sympathetic activation could contribute to coronary ischaemia in some patients.
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PMID:Influence of ageing on vasomotor responses of human epicardial coronary arteries. 1081 52

Ventricular septal (150-200 microm) arteries were isolated from the hearts of six-week-old CD-1 mice and mounted on a pressure myograph. Equilibration of the vessels at 70 mm Hg for 60 min resulted in the development of spontaneous myogenic tone. Maximum tone observed in these vessels greatly exceeded that previously reported in septal arteries from rats. Inhibition of endothelin ET(A) and endothelin ET(B) receptors with bosentan (1 and 10 microM) reduced basal tone. Endothelin release required intact endothelial cells. The alpha(1)-adrenceptor selective agonists phenylephrine and methoxamine did not cause change in coronary tone, while the alpha(2)-adrenceptor selective agonists 6-allyl-2-amino5,6,7, 8-tetrahydro-4H-thiazolo-[4,5-d]azepin-dihydrochloride (BHT 920) and clonidine produced vasodilatation. Noradrenaline (1 nM-10 microM) induced a concentration-dependent vasodilatation, which was inhibited by concurrent treatment with yohimbine (10 microM) and propranolol (20 microM). Vasodilatation due to BHT 920 was abolished with vessel denudation, indicating the endothelial location of alpha(2)-adrenoceptors. Acetylcholine (1 nM-10 microM) caused an endothelium dependent vasodilatation; inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine methyl ester attenuated this response. The endothelium-dependent vasodilators bradykinin and substance P produced no vasomotor effect in mouse coronary arteries. Differences between human and murine responses may impact on the relevance of the mouse coronary artery for use as a potential model of human coronary vessel diseases.
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PMID:Endothelial and myogenic regulation of coronary artery tone in the mouse. 1113 53

Nerve fibers project into the bone marrow and terminate in association with stromal cells. Nerve terminals are also associated with antigen-processing and -presenting cells throughout the body and have been shown to be important in leukocyte trafficking and wound healing as well as hemopoiesis. Here we show that neuropeptide input to the bone marrow is vital to normal granulopoiesis and that deletion of the neuropeptides, substance P, and calcitonin gene-related peptide (CGRP), with the neurotoxin, capsaicin, abrogates normal blood cell production. Norepinephrine, neurokinins a and 2, and vasoactive intestinal peptide all have inhibitory effects on in vitro CFU-GM colony formation. Substance P, neurokinin 1, nerve growth factor, and CGRP have stimulatory effects on CFU-GM. Furthermore, in vitro experiments show that, apart from CGRP, all the neuroactive substances we tested operate through effects on accessory cells, stimulating the release of regulatory molecules that have a direct effect on purified CFU-GM.
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PMID:Neuropeptide control of bone marrow neutrophil production. A key axis for neuroimmunomodulation. 1126 70

Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants. Lesions of noradrenergic neurons, however, result in either normal or reduced pain behavior and variable changes in morphine antinociception, undermining the proposed association between noradrenaline (NA) deficiency and chronic pain (hyperalgesia). We used mice lacking the gene coding for dopamine beta-hydroxylase, the enzyme responsible for synthesis of NA from dopamine, to reexamine the consequences of a lack of NA on pain behavior. Here, we show that absence of NA in the central nervous system results in a substance P-mediated chronic hyperalgesia (decreased nociceptive threshold) to thermal, but not mechanical, stimuli and decreased efficacy of morphine. Contrary to studies that show substance P-mediated hyperalgesia requires intense stimuli, we found that even a mild stimulus is sufficient to evoke substance P-dependent hyperalgesia in the NA-deficient mice. Restoring central NA normalized both the nociceptive threshold and morphine efficacy, which is consistent with a tonic inhibitory effect of NA on nociceptive transmission. Unexpectedly, however, antagonists to the substance P receptor (the NK1 receptor) could achieve the same effect as NA replacement. We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation.
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PMID:The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline. 1180 10

SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], a new nonpeptide tachykinin neurokinin 1 (NK1) receptor antagonist, was evaluated against the neurochemical, electrophysiological, and behavioral effects provoked by direct activation of brain tachykinin NK1 receptors or by stress in guinea pigs. SSR240600 (0.1-10 mg/kg i.p. or p.o.) antagonized the excitatory effect of i.c.v. infusion of [Sar(9),Met(O2)(11)]substance P (SP) on the release of acetylcholine in the striatum of anesthetized and awake guinea pigs. This antagonistic action was still observed after repeated administration of SSR240600 (5 days, 10 mg/kg p.o., once a day). SSR240600 (10 mg/kg i.p.) inhibited the phosphorylation of the cAMP response element-binding protein in various brain regions induced by i.c.v. administration of [Sar9,Met(O2)(11)]SP. In slice preparations, neuronal firing of the locus coeruleus (LC) neurons elicited by the application of [Sar9,Met(O2)(11)]SP was suppressed by SSR240600 at 100 nM. Norepinephrine release in the prefrontal cortex, elicited either by an intra-LC application of [Sar9,Met(O2)(11)]SP or by an i.c.v administration of corticotropin-releasing factor, was reduced by SSR240600 (0.3-1 mg/kg and 1-10 mg/kg i.p., respectively). SSR240600 (1-10 mg/kg i.p.) inhibited vocalizations induced in adult guinea pigs by an i.c.v. administration of the NK1 receptor agonist, GR73632 [D-Ala-[L-Pro9,Me-Leu8]substance P(7-11)]. Furthermore, SSR240600 (1-10 mg/kg i.p.) inhibited distress vocalizations produced in guinea pig pups by maternal separation. SSR240600 also reduced maternal separation-induced increase in the number of neurons displaying NK1 receptor internalization in the amygdala. Finally, SSR240600 counteracted the increase in body temperature induced by isolation stress. In conclusion, SSR240600 is able to antagonize various NK1 receptor-mediated as well as stress-mediated effects in the guinea pig.
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PMID:SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin 1 receptor: II. Neurochemical and behavioral characterization. 1243 42

1. Motor innervation in the canine rectoanal region was examined in isolated strips of the circular muscle layer. Contractile responses to electrical field stimulation began at lower frequencies and were more persistent in the internal anal sphincter (IAS) than in the rectum. 2. Motor innervation to the IAS was almost exclusively sympathetic, since it was blocked by guanethidine (Guan 3 microM) while the response in the proximal rectum was approximately 50% muscarinic, and sensitive to the M(3) selective antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP, 0.1 microM) and 50% tachykinergic, and sensitive to the neurokinin 2 (NK(2)) receptor antagonist GR 94800 (1 microM). From IAS to rectum there was a gradual shift in the relative contribution of intrinsic and extrinsic neural innervation. 3. Responses to exogenously applied transmitters exhibited a similar pattern to that observed with motor innervation. Norepinephrine (NE) was most potent in the IAS and acetylcholine (ACh) and NK-A were most potent in the proximal rectum. The responses were inhibited by prazosin, 4-DAMP and GR 94800 respectively. 4. A gradient in the density of adrenergic alpha(1), muscarinic and NK(2) receptors also existed from IAS to rectum as determined by measuring the binding of [(3)H]-prazosin, [(3)H]-quinuclidinyl benzilate ([(3)H]-QNB and [(3)H]-SR-48968 to smooth muscle membranes. 5. In summary, these data suggest that the shift in motor innervation in the rectoanal region is achieved in part by changes in receptor populations available for activation by sympathetic and enteric motor neurons.
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PMID:Excitatory motor innervation in the canine rectoanal region: role of changing receptor populations. 1246 42

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA). To test whether the ERSNA-induced increases in ARNA involved norepinephrine activating alpha-adrenoceptors on the renal sensory nerves, we examined the effects of renal pelvic administration of the alpha(1)- and alpha(2)-adrenoceptor antagonists prazosin and rauwolscine on the ARNA responses to reflex increases in ERSNA (placing the rat's tail in 49 degrees C water) and renal pelvic perfusion with norepinephrine in anesthetized rats. Hot tail increased ERSNA and ARNA, 6,930 +/- 900 and 4,870 +/- 670%.s (area under the curve ARNA vs. time). Renal pelvic perfusion with norepinephrine increased ARNA 1,870 +/- 210%.s. Immunohistochemical studies showed that the sympathetic and sensory nerves were closely related in the pelvic wall. Renal pelvic perfusion with prazosin blocked and rauwolscine enhanced the ARNA responses to reflex increases in ERSNA and norepinephrine. Studies in a denervated renal pelvic wall preparation showed that norepinephrine increased substance P release, from 8 +/- 1 to 16 +/- 1 pg/min, and PGE(2) release, from 77 +/- 11 to 161 +/- 23 pg/min, suggesting a role for PGE(2) in the norepinephrine-induced activation of renal sensory nerves. Prazosin and indomethacin reduced and rauwolscine enhanced the norepinephrine-induced increases in substance P and PGE(2). PGE(2) enhanced the norepinephrine-induced activation of renal sensory nerves by stimulation of EP4 receptors. Interaction between ERSNA and ARNA is modulated by norepinephrine, which increases and decreases the activation of the renal sensory nerves by stimulating alpha(1)- and alpha(2)-adrenoceptors, respectively, on the renal pelvic sensory nerve fibers. Norepinephrine-induced activation of the sensory nerves is dependent on renal pelvic synthesis/release of PGE(2).
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PMID:Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE2-dependent activation of alpha1- and alpha2-adrenoceptors on renal sensory nerve fibers. 1769 65

There is now considerable neurobiological evidence on the pathogenesis and pathophysiology of depression. Nevertheless the underlying pathophysiology is far from fully elucidated. Norepinephrine and serotonin deficit hypotheses have been known for quite a long time. Other theories also claim a dysfunction of the dopaminergic and GABA-ergic system in depression, an altered expression of neuropeptides (e.g. of substance P), and neuroimmunologic and neuroendocrinologic mechanisms such as an overdrive of the hypothalamic-pituitary adrenal system. The neurotrophin hypothesis suggests that decreased production of neurotrophic factors and impaired neurogenesis are crucial for the pathophysiology of depression. These upcoming pathophysiological concepts have also initiated novel treatment approaches whose clinical utility still has to be demonstrated.
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PMID:[New insights into the pathogenesis and pathophysiology of depression]. 1796 Mar 53

Neurokinin A and B are putative inflammatory mediators. We assessed their ability to alter prenodal lymphatic resistance. Intralymphatic neurokinin A (3.0 x 10(-6), 3.0 x 10(-5) and 3.0 x 10(-4) mol l(-1)) significantly constricted lymphatics at the two highest doses. Preliminary experiments suggested that neurokinin B might dilate lymphatics. To test this, lymphatic pressure was increased by norepinephrine (3.1 x 10(-6) mol l(-1)). Neurokinin B (2.7 x 10(-4) mol l(-1)) was then infused intralymphatically during norepinephrine infusion. Norepinephrine increased perfusion pressure from 5.6 +/- 0.6 mmHg to 12.1 +/- 1.4 mmHg. Subsequent infusion of neurokinin B significantly decreased lymphatic perfusion pressure from 11.9 +/- 1.3 mmHg to 9.9 +/- 1.1 mmHg. These data indicate that neurokinin A and B can alter lymphatic resistance and are consistent with the hypothesis that lymph vessel function may be subject to modulation by neurokinins.
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PMID:Neuropeptide modulation of lymphatic smooth muscle tone in the canine forelimb. 1847 67


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