Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The possible involvement of tachykinin neurokinin-1 and neurokinin-2 receptors in the activation of various micturition-related reflexes was assessed by the intrathecal administration of selective neurokinin-1 or neurokinin-2 receptor antagonists at lumbosacral spinal cord level in urethane-anaesthetized rats. The effect of the glutamate N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovaleric acid, was also investigated for comparison. The effect of antagonists was investigated on: (i) the chemonociceptive vesicovesical reflex activated by topical application of capsaicin onto the urinary bladder; (ii) the distension-induced micturition reflex produced by transvesical filling with saline; (iii) distension-induced rhythmic bladder contractions in isovolumetric conditions (urethra-ligated rats); and (iv) the somatovesical excitatory reflex caused by noxious perineal pinching. The neurokinin-2 receptor selective antagonists MEN 10,376 and SR 48,968 were ineffective in the three models in all doses tested. Selective neurokinin-1 receptor antagonists blocked the chemonociceptive reflex produced by topical application of capsaicin with the rank order of potency (lowest effective dose in brackets): GR 82,334 (1 nmol/rat) > RP 67,580 (10 nmol/rat) > (+/-)CP 96,345 (100 nmol/rat). Unlike GR 82,334, RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) were also effective on the distension-induced micturition reflex elicited by transvesical filling. Similarly, distension-induced rhythmic contractions were inhibited by RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) whereas the effect of GR 82,334 was not significant. RP 68,651, the enantiomer of RP 67,580 devoid of neurokinin-1 receptor blocking activity, was inactive in both models. 2-Amino-5-phosphonovateric acid (250 nmol/rat) blocked the three types of vesicoexcitatory reflexes. Intravenous administration of (+/-)CP 96,345, RP 67,580 or 2-amino-5-phosphonovateric acid at the same doses proven effective after the intrathecal route, had no effect on distension-induced rhythmic contractions. To ascertain whether the effect of neurokinin-1 receptor antagonists or 2-amino-5-phosphonovaleric acid may be related to a blockade of tachykinins released from capsaicin-sensitive primary afferent neurons, the effect of RP 67,580 was investigated on the distension-evoked micturition reflex in capsaicin-pretreated rats. Capsaicin pretreatment (50 mg/kg, subcutaneously, four days before) increased bladder capacity. RP 67,580 was no longer effective in capsaicin-pretreated rats. In contrast, 2-amino-5-phosphonovateric acid produced a further increase in bladder capacity in capsaicin-pretreated rats. We conclude that tachykinin neurokinin-1 but not neurokinin-2 receptors are involved in the activation of vesicoexcitatory micturition-related reflexes in the rat spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Evidence for a role of tachykinins as sensory transmitters in the activation of micturition reflex. 810 62

A large body of recent evidence suggests that a number of inhibitory and excitatory neuropeptides and amino acids may participate in the episodic secretion of hypothalamic LHRH and pituitary LH in castrated rats. However, the precise functional relationships among these messenger molecules in the control of LH secretion remain to be ascertained. The aim of this study was to test the hypothesis that inhibition of LH release by an opioid [beta-endorphin (beta END)], cytokine [interleukin-1 beta (IL-1 beta)], or tachykinin [neuropeptide-K (NPK)] is a result of diminished excitatory amino acid (EAA) signaling. Adult male rats were castrated and received an intracerebroventricular cannula in the third ventricle for administration of beta END (10 micrograms/rat), NPK (2.5 nmol/rat), or IL-1 beta (100 ng/rat) 2 weeks postcastration. One day before the experiments, rats received an intraatrial cannula for frequent blood sampling and for iv injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 5 mg/kg) at 30-min intervals. Blood samples for LH measurements were withdrawn immediately before and 10 min after each NMDA injection. The results show that intracerebroventricular beta END, IL-1 beta, or NPK inhibited LH release. Multiple injections of NMDA did not alter the existing pattern of LH secretion in castrated control rats. However, similar NMDA injections completely prevented the decrease in LH release by beta END, IL-1 beta, or NPK. Plasma LH levels in these rats remained within the range seen in untreated control rats throughout the 120-min duration of the experiment, and NMDA injections at 30-min intervals evoked pulses of LH that resembled those seen normally in castrated rats. The blockade of the inhibitory effects of the three peptides by NMDA and previous knowledge of hypothalamic sites of NMDA action suggest that EAA systems may represent a common pathway down-stream in the hypothalamic LHRH-regulating circuitry to mediate diminution of LH release by inhibitory peptides. Further, their inhibitory influence may be exerted either directly at the level of LHRH neurons and/or by diminution in EAA efflux, leading to suppression of LHRH and LH release.
 ...
PMID:Evidence that luteinizing hormone suppression in response to inhibitory neuropeptides, beta-endorphin, interleukin-1 beta, and neuropeptide-K, may involve excitatory amino acids. 831 64

Tumor necrosis factor (TNF) has been implicated in the pathophysiology of a number of inflammatory diseases of the lung. Using the TNF receptor fusion protein, Ro 45-2081, our study investigated the involvement of TNF in allergic inflammatory responses in the airways of sensitized guinea pigs and Brown-Norway rats. Sensitized guinea pigs exhibited an enhanced airway reactivity to substance P (1-10 micrograms/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by Ro 45-2081 (3 mg/kg, i.p.). Treatment with Ro 45-2081 (1-3 mg/kg, i.p.) dose-dependently inhibited (P < .05) the accumulation of neutrophils and total cells in bronchoalveolar lavage fluid in sensitized guinea pigs examined at 6 and 24 hr postchallenge. Ro 45-2081 (3 mg/kg, i.p.) also significantly (P < .05) reduced the number of eosinophils in bronchoalveolar lavage at both time points whereas a lower dose (1 mg/kg, i.p.) had no effect. Ro 45-2081 (1 or 3 mg/kg, i.p.) abolished antigen-induced microvascular leakage (quantified by tissue content of Evans blue dye) in the trachea and main bronchi in sensitized guinea pigs. In the Brown-Norway rat, Ro 45-2081 (1-3 mg/kg, i.p.) caused a dose-dependent inhibition of neutrophil and eosinophil infiltration into bronchoalveolar lavage fluid at 24 hr after antigen challenge. In both guinea pig and Brown-Norway rat models, treatment with dexamethasone (30 mg/kg, i.p., for guinea pig and 0.3 mg/kg, i.p., for Brown-Norway rat) produced virtually identical results to those obtained with Ro 45-2081. The ability of Ro 45-2081 to inhibit antigen-induced responses in sensitized animals suggests that TNF is a mediator of allergic inflammation in the lung.
 ...
PMID:Pharmacological evidence for tumor necrosis factor as a mediator of allergic inflammation in the airways. 876 39

In this study, Freund's adjuvant-induced monoarthritis in the rat hind paw was used to induce chronic pain and inflammation. In order to compare the basal outflow, electrically-evoked release and total content of calcitonin gene-related peptide like immunoreactivity (CGRP-LI) with previously reported changes in substance P (SP-LI), the lumbar enlargement of monoarthitic (complete Freund's adjuvant-treated, CFA rat) and control (incomplete Freund's adjuvant-treated, IFA rat) spinal cords were used. During the 4-wk period after injection, neither the basal nor the evoked release of CGRP-LI from CFA cords differed from controls. By contrast, we have previously reported that SP-LI release from CFA rat spinal cords was significantly higher than from controls, 21 days after inoculation with Freund's adjuvant. Electrically-evoked CGRP-LI release from 21-day CFA rat spinal cord slices was not modified by superfusion with a GABAB antagonist, CGP 36742 (100 microM) which could greatly increase SP-LI release. However, the release of both peptides was significantly increased to the same extent in IFA and normal tissue but to a lesser extent in CFA cords, by superfusion with the opioid antagonist naloxone (1 microM). In conclusion, CGRP-LI, unlike SP-LI, did not appear to be susceptible to any changes in the lumbar enlargement of the rat spinal cord during inflammation of the hind paw. In addition, CGRP-LI release was increased by antagonism of opiate but not GABAB receptors, suggesting that during chronic inflammation of one hind paw, the GABAB ergic system, unlike the opioid system, might be activated to selectively inhibit the enhanced SP-LI release but not CGRP-LI release which is not changed.
 ...
PMID:Calcitonin gene-related peptide content, basal outflow and electrically-evoked release from monoarthritic rat spinal cord in vitro. 888 Aug 59

Vascular cell responses in inflammation are affected by several neuropeptides of perivascular nerve fibers. Secretoneurin is a 33-amino acid peptide that is coreleased from these nerve endings with other proinflammatory neuropeptides, eg, substance P and calcitonin gene-related peptide. Furthermore, secretoneurin has been shown to be chemotactic for human skin fibroblasts and human blood monocytes in vitro and in vivo. An action on cellular components of the vascular wall is not yet reported. We therefore investigated in vitro effects of this novel sensory neuropeptide on endothelial cells. Secretoneurin exerted a potent and reversible inhibitory effect both on endothelial cell growth under low serum conditions (1% fetal calf serum) and endothelial cell growth factor-activated endothelial cell proliferation. We show in the present study that secretoneurin exerts this effect on aortic (rat) and pulmonary artery (bovine) endothelial cells, as well as venous (human umbilical vein) endothelium. Endothelial cell chemotaxis was tested by means of three different migration assays employing nitrocellulose and polycarbonate micropore filters. Secretoneurin consistently exhibited potent chemoattractant activity. The effective concentrations for the observed effects were in the picomolar range. The combination of chemotactic and antiproliferative effects on endothelial cells suggests that secretoneurin may act as a regulatory factor of vascular cell functions.
 ...
PMID:Inhibition of proliferation and stimulation of migration of endothelial cells by secretoneurin in vitro. 915 58

This study investigates the role of tachykinin NK1 and NK2 receptors in motor responses induced by the intravesical instillation of capsaicin in urethane-anaesthetized rats. SR 140,333 (1 micromol/kg, i.v.), a nonpeptide NK1 receptor antagonist, abolished urinary bladder contractions induced by the selective NK1 receptor agonist [Sar9]SP-sulfone (0.1-100 nmol/kg, i.v.) without affecting those induced by the NK2 receptor agonist [betaAla8]NKA(4-10). MEN 11,420 (100 nmol/kg, i.v.), a cyclic peptide NK2 receptor antagonist, abolished bladder contractions induced by [betaAla8]NKA(4-10) (0.3-300 nmol/kg, i.v.) without modifying those induced by [Sar9]SP-sulfone. Intravesical instillation of capsaicin (6 nmol/0.6 ml/rat) produced a motor response consisting in a primary contraction followed by a series of high amplitude phasic contractions. The intravesical instillation of saline (0.6 ml/rat) produced a primary contraction of lower amplitude with respect to that induced by capsaicin and the total area under the curve was also lower in saline-instilled rats, however the number and the amplitude of phasic contractions was similar to that induced by capsaicin. MEN 11,420 (100 nmol/kg, i.v.) did not modify motor responses induced by the intravesical administration of saline. In contrast, in capsaicin-instilled rats, MEN 11,420 (100 nmol/kg, i.v.) reduced the primary contraction, the area under the curve and also the number of phasic contractions. SR 140,333 (1 micromol/kg, i.v.) reduced the primary contraction but not other parameters. The combination of SR 140,333 (1 micromol/kg, i.v.) and MEN 11,420 (100 nmol/kg, i.v.) produced an additive inhibitory effect on the primary contraction but not a further inhibition on other parameters with respect to that observed with MEN 11,420 alone. In hexamethonium (110 micromol/kg, i.v.)-pretreated animals the intravesical instillation of capsaicin produced a tonic contraction having greater amplitude and area than that induced by saline. MEN 11,420, but not SR 140,333, significantly reduced the bladder response to capsaicin in hexamethonium-pretreated rats. Again, the combined administration of MEN 11,420 and SR 140,333 did not produce further inhibitory effect in comparison to MEN 11,420 alone. It is concluded that the motor responses induced by the intravesical instillation of capsaicin are mediated by the activation of peripheral tachykinin NK2 receptors.
 ...
PMID:MEN 11,420, a peptide tachykinin NK2 receptor antagonist, reduces motor responses induced by the intravesical administration of capsaicin in vivo. 927 23

To reveal possible involvement of NK-1 substance P receptors and N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the production of inflammatory hyperalgesia, we examined the effects of intrathecal injections of antagonists at those receptors on the nociceptive threshold of inflammatory hyperalgesic rats in the paw-pressure test. Intrathecal injections of the NK-1 antagonist CP-96,345 (0.3-3 nmol/rat), the NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-APV, 1-10 nmol/rat), and the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1-10 nmol/rat) dose-dependently suppressed adjuvant- and carrageenin-induced hyperalgesia, without effect on the nociceptive threshold of non-inflamed paws. Furthermore, to estimate whether inflammatory hyperalgesia is accompanied with an alteration of the responsiveness to substance P and excitatory amino acids, we examined the effects of injections of complete Freund's adjuvant (intradermal) and carrageenin (subcutaneous) on the aversive responses to intrathecal substance P and excitatory amino acid agonists. Both injections significantly potentiated the aversive behaviors elicited by intrathecal injections of excitatory amino acid agonists, NMDA (1 nmol/rat), a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA, 1 nmol/rat) and kainate (1 nmol/rat), but not those by substance P. The present results suggest that the enhancement of synaptic transmission mediated by substance P and excitatory amino acids in the spinal dorsal horn is at least partly involved in the production of inflammatory hyperalgesia, and that such a hyperalgesia is accompanied with the enhanced responsiveness to excitatory amino acids through NMDA and non-NMDA receptors, but not with changes in responsiveness to substance P.
 ...
PMID:Involvement of spinal substance P and excitatory amino acids in inflammatory hyperalgesia in rats. 951

An electromyographic (EMG) study was carried out in 51 anesthetized rats to assess if neurokinin, NK-1 and NK-2, receptor mechanisms and tachykinins were involved in the increased jaw muscle activity which can be reflexly evoked by injection of the small-fiber excitant and inflammatory irritant mustard oil (MO) into the temporomandibular joint (TMJ) region. A baseline level of EMG activity was recorded bilaterally for 20 min from digastric (DIG) and masseter (MASS) muscles and then each animal was treated with NK-1 or NK-2 antagonist or vehicle. In one series of experiments either the NK-1 antagonist CP-99,994 (20 microg approximately 54 nmol), the NK-2 antagonist MEN-10,376 (10 microg approximately 9 nmol or 20 microg approximately 18 nmol) or vehicle (control) was administrated into the lateral ventricle (i.c.v.); in another series the NK-1 antagonist (4 mg/kg approximately 3-4 micromol/rat) or vehicle (control) was given intravenously (i.v.). After 10 min, MO (20 microl, 20%) was applied to one TMJ (first injection) and 45 min later, MO was applied to the opposite TMJ (second injection). Pretreatment with neurokinin antagonists had little effect on the incidence of the MO-evoked EMG responses but did significantly reduce the EMG magnitude and duration. In the animals pretreated with NK-1 antagonist only the responses to the second MO injection was significantly affected whereas NK-2 pretreatment reduced the EMG responses to both MO injections to the TMJ. The systematic depression of the MO-evoked EMG responses by the NK-2 antagonist suggests that neurokinin A may be involved in the EMG responses. Since the NK-1 antagonist produced no systematic changes in responses elicited by the first MO injection, substance P does not seem to be associated directly with the initiation or maintenance of the EMG responses but may be involved if a 'central sensitization' has been induced by the first MO injection to the TMJ.
 ...
PMID:Involvement of NK-1 and NK-2 tachykinin receptor mechanisms in jaw muscle activity reflexly evoked by inflammatory irritant application to the rat temporomandibular joint. 958 57

Thymic epithelium, including nurse cells (TEC/TNC), as well as other thymic stromal cells (macrophages and dentritic cells), express a repertoire of polypeptide belonging to various neuroendocrine protein families (such as the neurophypophysial, tachykinin, neurotensin and insulin families). A hierarchy of dominance exists in the organization of the thymic repertoire of neuroendocrine precursors. Oxytocin (OT) is more expressed in the TEC/TNC than vasopressin (VP); insulin-like growth factor 2 (IGF-2) thymic expression predominates over IGF-1, and much more over (pro)insulin. Thus, OT was proposed to be the self antigen of the neurohypophysial family, and IGF-2 the self antigen precursor of the insulin family. The dual role of the thymus in T-cell life and death is recapitulated at the level of the thymic neuroendocrine protein repertoire. Indeed, thymic polypeptides behave as accessory signals involved in T-cell development and positive selection according to the cryptocrine model of signaling. Moreover, thymic neuroendocrine polypeptides are the source of self antigens presented by thymic MHC molecules to developing pre-T cells. This presentation might induce the negative selection of T cells bearing a randomly rearranged antigen receptor (TCR) oriented against neuroendocrine families. Using an animal model of autoimmune type 1 diabetes (BB rat), we have shown a defect in intrathymic expression of the self antigen of the insulin family (IGF-2) and in IGF-2-mediated T-cell education to recognize and tolerate the insulin family. Altogether these studies have enlightened the crucial role played by the thymus in the induction of the central self tolerance of neuroendocrine families. The tolerogenic properties of thymic self peptides could be used in a novel type of vaccination for the prevention of autoimmune diseases.
 ...
PMID:The thymic repertoire of neuroendocrine-related self antigens: biological role in T-cell selection and pharmacological implications. 987 42

The inhibitory action of the natural selective tachykinin NK3 receptor agonist, PG-KII, (pGlu-Pro-Asn-Pro-Asp-Glu-Phe-Val-Gly-Leu-Met-NH2), on colonic propulsion was studied in rats after central administration. Intracerebroventricular injection of PG-KII (0.1, 1, 10 and 100 ng/rat) produced a dose-related inhibition of colonic propulsion, measured as the increase in the mean expulsion time of a 5-mm glass bead placed in the distal colon. At the same doses as PG-KII, the selective tachykinin NK3 receptor agonist, senktide, (succ-[Asp6-MePhe8] substance P-(6-11)), induced a similar dose-related inhibition. Conversely, substance P (0.1, 1 and 10 microg/rat), a tachykinin NK1-preferring receptor agonist, had weaker antipropulsive effects, neurokinin A (0.1, 1 and 10 microg/rat), a tachykinin NK2-preferring receptor agonist, at the highest dose used only slightly inhibited colonic propulsion and neurokinin B (0.1, 1 and 10 microg/rat), a tachykinin NK3-preferring receptor agonist, left propulsion unchanged. Pretreatment with the selective tachykinin NK3 receptor antagonist, 3-indolycarbonyl-Hyp-Phg-N(me)-Bzl, referred as to R820 (6.2 microg/rat), prevented PG-KII-induced colonic antipropulsion, whereas the tachykinin NK1 receptor antagonist, (S)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pi peridin-3-yl] ethyl)-4-phenyl-1-azoniabicyclo[2.2.2] octane chloride, referred to as SR 140,333 (1 microg/rat), and the tachykinin NK2 receptor antagonist, ([Tyr5,D-Trp6,8,9, Arg10] neurokinin A-(4-10)), referred to as Men 10,376 (5 microg/rat), left it unchanged. These findings show that of the tachykinins tested, PG-KII and senktide are the most potent central inhibitors of colonic propulsion in the rat, suggesting that the central tachykinin NK3 receptor system plays an inhibitory role in modulating colonic transit. As well as confirming the selectivity of PG-KII for tachykinin NK3 receptors, we show that PG-KII provides useful information about the physiological role of central tachykinin NK3 receptors and that glass bead expulsion test is a reliable non-invasive in vivo method for evaluating the tachykinin NK3 receptor selectivity of new synthetic or natural tachykinins.
 ...
PMID:Central tachykinin NK3 receptors in the inhibitory action on the rat colonic propulsion of a new tachykinin, PG-KII. 1044 91


<< Previous 1 2 3 4 5 6 Next >>