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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A perifused preparation of guinea pig myenteric nerve varicosities (synaptosomes) was used to determine the characteristics of evoked tachykinin release and the inhibition of such release by adenosine analogues. Release of substance P-like immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) was evoked by elevated extracellular [K+] in a reversible and repeatable manner. This release was completely abolished in the absence of extracellular Ca2+. Perifusion in the presence of 5'-N-ethylcarboxamidoadenosine (NECA), a nonselective A1/A2 adenosine receptor agonist, decreased K(+)-evoked release of SP-LI and NKA-LI compared with that in the absence of the nucleoside. Similar decrements in peptide release were obtained with N6-cyclopentyl adenosine (CPA), a selective A1 agonist, and 2-[p-(2-carboxyethyl)]phenethylamino-5'-N-ethyl-carboxamidoadenosi ne (CGS 21680), a selective A2 agonist. Response to all nucleosides was graded. Potency order of adenosine analogues was CPA greater than NECA much greater than CGS 21680. Inhibition due to the nucleosides was diminished in the presence of the highly selective A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) while perifusion in the presence of DPCPX alone did not alter evoked release of either peptide. These findings provide direct measurements of inhibitory effects of adenine nucleosides on the release, from enteric nerve endings, of endogenous neuromediators SP and NKA. The findings also directly demonstrate the presence of functional adenosine receptors of the A1 subtype on enteric nerve endings coupled negatively to release of tachykinins. The presence of A2 receptors on enteric nerve endings is neither supported nor excluded.
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PMID:Adenosine A1 receptors mediate inhibition of tachykinin release from perifused enteric nerve endings. 137 85

Intrathecal administration of substance P at the lower thoracic spinal level has an antinociceptive effect on reaction time in the tail-flick test; this response is blocked by naloxone i.v. but not by i.v. administration of opiate antagonists which do not cross the blood-brain barrier. As morphine-induced analgesia is blocked by adenosine antagonists, to determine whether this substance P-induced, opioid-mediated antinociception also includes a purine link, the adenosine receptor antagonist, caffeine, was given systemically 10 min prior to substance P administration. In control rats pretreated with saline, substance P (6.5 nmol) produced an increase in reaction time to about 160% of preadministration values at one min after intrathecal injection. The effect could also be observed at 6 min after this injection. Pretreatment with 16 or with 32 mg/kg of caffeine i.p. blocked the response to substance P, and produced a hyperalgesia similar to that reported in studies at the lumbo-sacral spinal level. These results indicate that the adrenal opioid-induced antinociception observed upon intrathecal administration of substance P at the lower thoracic level occurs via an adenosine link. This is the first demonstration of a purine link in the expression of antinociceptive effects of an endogenously released opioid.
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PMID:Adenosine receptor link in an adrenal opioid-induced antinociception in the rat tail-flick test. 137 72

The mechanism of action of xanthines in asthma remains controversial. Since sensory innervation may play a role in the pathogenesis of asthma, we investigated whether xanthines were capable of reducing the contractile response of the bronchi to nerve stimulation. In guinea-pig bronchi in vitro, electrical field stimulation (EFS: 40 V, 16 Hz, 0.2 ms during 10 s) induces a rapid cholinergic contraction followed by a long-lasting contraction due to a local release of neuropeptides from C-fibre endings. We measured isometric neuronally-mediated contractions of bronchial smooth muscle and studied the effects of increasing concentrations of two xanthine derivatives, theophylline, an antagonist of adenosine receptors, and enprofylline, which has no effect on adenosine receptors. Both enprofylline (1-50 microM) and theophylline (10-100 microM) inhibited, in a concentration-dependent manner, the peptidergic contraction, an effect which was more marked with enprofylline than theophylline (EC50 = 9.6 +/- 0.7 microM and 62.0 +/- 4.7 microM, respectively). Conversely, the cholinergic response was unaffected. Contractions induced by exogenous substance P (0.03-3 microM) were also unaffected by theophylline and enprofylline at the above mentioned EC50s. Our results suggest that concentrations of theophylline, similar to those used therapeutically, reduce the release of sensory neuropeptides from C-fibre endings. This effect is unrelated to adenosine receptor blockade, since enprofylline had a similar inhibitory effect.
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PMID:Modulation by theophylline and enprofylline of the excitatory non-cholinergic transmission in guinea-pig bronchi. 148 66

Adenosine receptors capable of modulating tachykininergic transmission were characterized in functional studies using both field-stimulated and cholecystokinin octapeptide-stimulated contractile responses of atropinized guinea pig longitudinal muscle-myenteric plexus preparations. These tetrodotoxin-sensitive responses, which were mediated by release of one or more tachykinins, were inhibited by adenosine analogs in a concentration-dependent manner. The rank order of potencies of the analogs as inhibitors of the responses to cholecystokinin octapeptide was N6-cyclopentyladenosine greater than 5'-N-ethylcarboxamidoadenosine much greater than 2-phenylaminoadenosine (CV 1808). Schild analysis of the antagonism of the presynaptic inhibitory effects of 5'-N-ethylcarbocamidoadenosine and N6-cyclopentyladenosine on cholecystokinin octapeptide-stimulated responses using the A1 selective antagonists 1,3-dipropyl-8-(4-sulfophenyl)xanthine and 1,3-dipropyl-8-(cyclopentyl)xanthine yielded linear isoboles with unit slopes indicating competitive antagonism. The affinity of the antagonists for the receptor site(s) involved in inhibition of tachykininergic transmission was similar to those established previously for cholinergic transmission. The rank order of potency of adenosine analogs as inhibitors of the field-stimulated responses was such that N6-cyclopentyladenosine = 5'-ethylcarboxamidoadenosine. Reverse-phase high-performance liquid chromatography analysis performed on lysates of isolated myenteric nerve endings demonstrated the presence of substance P and neurokinin-A. Neurokinin-B was undetectable. These studies indicate that adenosine receptor(s) on myenteric nerve endings are coupled negatively to tachykinin release and that they are probably identical to those involved in the modulation of acetylcholine release.
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PMID:Adenosine receptors are coupled negatively to release of tachykinin(s) from enteric nerve endings. 169 84

1. The effects of a number of purine analogues were examined on the rat isolated colon muscularis mucosae. Adenosine, adenosine 5'-monophosphate (AMP), adenosine 5'-diphosphate (ADP), adenosine 5'-triphosphate (ATP), 2-methylthioATP (MeSATP), adenosine 5'-(2-fluorodiphosphate) (ADP beta F), adenosine 5'-(beta, gamma-methylene)triphosphonate (AMPPCP) and adenosine 5'-(alpha, beta-methylene)triphosphonate (AMPCPP) each contracted the muscularis mucosae in the concentration range 1-100 microM. 2. MeSATP was the most potent purine agonist, with a threshold concentration for contraction of 0.05 microM and an EC50 of approximately 0.3 microM, and AMPCPP was less potent than ATP. The enantiomer of AMPPCP, L-AMPPCP, was inactive at concentrations up to 100 microM. 3. The adenosine receptor antagonist 8-(p-sulphophenyl)theophylline (8-SPT, 50 microM) produced approximately 50 fold shifts of the dose-response curves to adenosine, AMP and AMPPCP, whereas those to ATP, MeSATP and substance P (SP) were unaffected. Intermediate shifts were observed for the dose-response curves to ADP, ADP beta F and AMPCPP. With a lower concentration of 8-SPT (10 microM) a dose ratio of approximately 11 was observed for the inhibition of the effects of both adenosine and AMPPCP. 4. ATP was rapidly degraded by the tissue to ADP, AMP and adenosine, ADP beta F was more slowly degraded to AMP and adenosine, and no significant degradation of AMPPCP was detected during 20 min incubation. 5. The results are consistent with the existence in the rat colon muscularis mucosae of a mixed population of purine receptors of P2Y and P1 types. The colon thus contains the first documented incidence of a P2Y-receptor mediating contraction. The powerful inhibition by the P1-purinoceptor antagonist 8-SPT of the effects of AMPPCP suggests that its action in this tissue is mediated by Pl-purinoceptors, although 8-SPT was more potent here than has previously been demonstrated.
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PMID:A study of the purinoceptors mediating contraction in the rat colon. 169 98

Isolated myenteric nerve varicosities prepared from the myenteric plexus of the guinea pig ileum were investigated as a suitable model system with which to study the release of several neuropeptide-like immunoreactivities (-LI). Basal release of substance P-LI, neurokinin A-LI, Leu-enkephalin-LI and Met-enkephalin-LI was determined, and clear depolarization-induced release of the enkephalin-LI's and neurokinin A-LI was obtained using this preparation, providing further support for their roles as putative mediators in the enteric nervous system. Evoked-release of these peptides was dependent on the presence in the incubation mixture of certain antagonists to known endogenous neuronal mediators. In the absence of such antagonists, no unequivocal evidence of release was seen. Clear evoked release of Leu-enkephalin-LI occurred only in the presence of the adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX), atropine and naloxone. Release of Met-enkephalin-LI occurred in the presence of either atropine or naloxone. The release of neurokinin A-LI was evident in the presence of DPSPX. These findings suggest the existence of either distinct subpopulations of nerve varicosities or distinct neuronal pools containing each peptide and that these peptides may be under differential regulation by endogenous inhibitory mediators. It is concluded that, under suitable conditions, isolated myenteric nerve varicosities provide a useful model system for the study of release, and the modulation of release, of endogenous neuropeptides.
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PMID:Neuropeptide release from isolated myenteric nerve endings derived from the guinea pig myenteric plexus. 170 15

Excitatory amino acid (EAA)-induced cell death in the striatum is dependent upon intact glutamatergic afferents arising from the cerebral cortex. Through a mechanism possibly related to inhibition of glutamate release, adenosine receptor agonists attenuate EAA induced toxicity in the rat striatum. In the present study, we examined whether 2-chloroadenosine (2CLA), a stable adenosine analog, protects against toxicity induced by kainate (KA), quisqualate (QUIS), N-methyl-D-aspartate (NMDA), and ibotenate (IBO). In vivo intrastriatal injections of 2CLA (50 nmol) with each EAA tested provided a partial but significant protective effect versus injection of the EAA alone, as measured by striatal concentrations of gamma-aminobutyric acid (GABA) and substance P-like immunoreactivity (SP-LI). These results show that 2CLA attenuates both NMDA- and non-NMDA-mediated neuronal cell death.
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PMID:2-Chloroadenosine attenuates NMDA, kainate, and quisqualate toxicity. 192 33

A "functionalized congener" approach to adenosine receptor antagonists has provided a means to synthesize highly potent peptide conjugates of 1,3-dialkylxanthines. The antagonist XAC, such a functionalized xanthine amine congener, has been attached to a segment derived from the neurotransmitter peptide substance P (SP) to form a binary drug that binds to both receptors with Ki values of 35 nM (central A1-adenosine) and 300 nM (striatal SP). Coupling of the functionalized adenosine agonist N6-[p-(carboxymethyl)phenyl]adenosine to an SP C-terminal peptide also resulted in a binary drug that binds to both receptors. The demonstration that the biochemical properties of two unrelated drugs, both of which act through binding at extracellular receptors, may be combined in the same molecule suggests a novel strategy for drug design. In principle, a combined effect of the two different substances that produce the same final effect (e.g., hypotension by adenosine agonists and by SP analogues) might occur in vivo. Adenosine analogues have analgesic properties, and the binary drug derived from substance P and adenosine agonists or antagonists might provide useful tools for probing interrelationships of SP pathways and sites for the antinociceptive action of adenosine.
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PMID:Binary drugs: conjugates of purines and a peptide that bind to both adenosine and substance P receptors. 244 Oct 57

Adenosine agonists administered systemically, intracerebroventricularly and intrathecally have been demonstrated to induce antinociception. Results from studies utilizing intrathecal administration of adenosine or adenosine analogs, in particular, suggest that endogenous adenosine may inhibit the transmission of nociceptive impulses at spinal sites. The present investigations were performed to extend our understanding of the role of adenosine in antinociception by examining the effect of adenosine agonists on behavior induced by two putative spinal nociceptive neurotransmitters, substance P and N-methyl-D-aspartate. Coadministration of each of several adenosine agonists with substance P or N-methyl-D-aspartate intrathecally significantly decreased the intensity of behaviors induced by putative nociceptive neurotransmitters in mice. Adenosine agonist-mediated inhibition was antagonized by theophylline supporting adenosine agonist interactions with cell membrane surface adenosine receptors. Rank order potencies were determined for several adenosine analogs with varying selectivity for A1 and A2 adenosine receptor subtypes. However, rank order potencies did not correlate well with rank order potencies reported previously for adenosine receptor subtypes in biochemical assays. The results of these investigations demonstrate that adenosine inhibits behavior induced by nociceptive neurotransmitters interacting with spinal substance P or N-methyl-D-aspartate receptors. Furthermore, observations provide additional support for endogenous antinociceptive pathways that utilize adenosine at spinal sites.
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PMID:Behavior induced by putative nociceptive neurotransmitters is inhibited by adenosine or adenosine analogs coadministered intrathecally. 245 77

Previous investigations find that morphine administered i.c.v. induces antinociception directly at supraspinal sites and indirectly via activation of descending spinal systems. Independent experimentation suggests substance P and N-methyl-D-aspartate (NMDA) administered intrathecally (i.t.) can act as putative pain neurotransmitters to stimulate afferent pathways mediating nociception. The present studies were designed to determine whether a functional link exists between these observations. Mice were administered morphine i.c.v. 15 min before i.t. injections of substance P or NMDA. Additional investigations utilized coadministration of substance P or NMDA i.t. with one of several antagonists. Morphine administered i.c.v. inhibited both substance P- and NMDA-induced behavior in a dose-dependent manner. Coadministration of noradrenergic or adenosine receptor antagonists with substance P or NMDA i.t. dose-dependently reversed morphine (i.c.v.)-mediated inhibition. Methysergide injected i.t. caused significant, but only partially effective, antagonism of the effects of morphine (i.c.v.). Naloxone coadministered i.t. was effective in reversing morphine (i.c.v.)-mediated inhibition of NMDA-induced behavior, but ineffective in the substance P assay. These data demonstrate a functional link between activation of descending systems mediating antinociception by morphine (i.c.v.) and inhibition of putative pain neurotransmitters by spinally active antinociceptive agents. The potential involvement of serotonergic and opioid spinal systems is not clear, but noradrenergic and adenosine spinal pathways appear to play an important role in the indirect actions of morphine (i.c.v.). Differences in the inhibition of NMDA- and substance P-induced behavior also provide evidence for the presence of substance P and NMDA receptors in separate afferent pathways transmitting nociceptive stimuli.
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PMID:Morphine (intracerebroventricular) activates spinal systems to inhibit behavior induced by putative pain neurotransmitters. 248 Oct 30


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