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)

Several neuropeptides play a key role in the transfer (substance P, calcitonin gene-related peptide, etc) and control (enkephalins, cholecystokinin, etc) of nociceptive messages from primary afferent fibres to spino-thalamic neurones in the dorsal horn of the spinal cord. This first relay in nociceptive pathways has been shown to be a major target for opioids such as analgesic drugs, and the effects of exogenous (mainly morphine) and endogenous opioids on the release of neuropeptides within the dorsal horn are reviewed here for a better understanding of the cellular mechanisms responsible for their antinociceptive action. Complex modulations of the in vitro (from tissue slices) and in vivo (in halothane-anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid) release of substance P and calcitonin gene-related peptide by opioids have been reported, depending on the opioid receptor (mu, delta, kappa, and their subtypes) stimulated by these compounds. In particular, the inhibition by delta agonists of substance P release from primary afferent fibres, and that by the concomitant stimulation of mu and kappa receptors of the release of calcitonin gene-related peptide are very probably involved in the analgesic action of specific opioids and morphine at the level of the spinal cord. Furthermore, the negative modulation (through presynaptic opioid autoreceptors) by delta and mu agonists of the spinal release of met-enkephalin, and the complex inhibitory/excitatory influence of delta, mu and kappa receptor ligands on the release of cholecystokinin within the dorsal horn very likely also contribute to the antinociceptive action of these drugs and morphine. The reviewed data strongly support the existence of functional interactions between mu and kappa receptors within the spinal cord, and their key role in the analgesic action of non specific opiates (acting on mu, delta and kappa receptors) such as morphine.
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PMID:Opioidergic control of the spinal release of neuropeptides. Possible significance for the analgesic effects of opioids. 785 37

Opioid peptides and opioid receptors, particularly the delta receptor, are abundant in the striatum where they contribute to the neuronal interactions, and are involved in various behavioral effects. The recent cloning of the delta-opioid receptor now allows the identification of the striatal neurons that express it, and that are direct targets of endogenous opioid peptides such as enkephalins. In this context, we have used in situ hybridization histochemistry to determine the distribution of the delta-opioid receptor messenger RNA in the forebrain, and especially the phenotype of the neurons expressing the delta-opioid receptor gene in the striatum. We show that the topgraphy of the neurons containing the delta-opioid receptor messenger RNA is similar to the topography of the neurons containing the choline acetyltransferase messenger RNA in the mouse forebrain. Comparison of adjacent serial sections demonstrates that the delta-opioid receptor gene is indeed expressed exclusively in cholinergic interneurons in the striatum. As these neurons also selectively express the substance P receptor gene, our data suggest that the striatal cholinergic interneurons are a common link in the interactions between the two striatal efferent populations, namely enkephalin and substance P neurons.
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PMID:Delta-opioid receptor gene expression in the mouse forebrain: localization in cholinergic neurons of the striatum. 787 Feb 94

1. The pharmacological properties of the novel diarylacetamide kappa-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting kappa agonist) and ICI 204448 (a peripherally-selective kappa agonist). 2. EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (kappa:mu:delta:sigma binding ratio 1:536:125: > 1,786) to kappa-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for kappa-opioid receptors (rabbit vas deferens preparation). 3. Systemically-applied [14C]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands and kidneys. Considerably less radioactivity is detected in the whole brain, and this radioactivity is concentrated in the region of the cerebral ventricles in the choroid plexuses. EMD 61753 penetrates only poorly into the CNS. 4. EMD 61753 was weakly effective in pharmacological tests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30 mg kg-1, s.c., (doses of 0.1, 1.0 and 10 mg kg-1, s.c., and 1.0, 10 and 100 mg kg-1, p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg-1, s.c., and 100 mg kg-1, p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an ID50 value of 453 mg kg-1, s.c. 5. EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 1.9 mg kg-1, s.c., and 10.4 mg kg-1, p.o.; 2nd phase ID50 0.26 mg kg-1, s.c., and 3.5 mg kg-1, p.o.) and rodent abdominal constriction test (ID50 mouse 1.75 mg kg-1, s.c., and 8.4 mg kg-1, p.o.; ID50 rat 3.2 mg kg-1, s.c., and 250 mg kg-1, p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (ID50 0.08 mg kg-1, s.c., and 6.9 mg kg-1, p.o., after remedial application, and 0.2 mg kg-1, s.c., and 3.1 mg kg-1, p.o., after prophylactic application) and naloxone-reversible antinociception. The antinociceptive action of systemically-applied (50 mg kg-1, p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection of the K-opioid antagonist norbinaltorphimine (100 Lg) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally.6. Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose-dependently inhibited by systemically-applied EMD 61753 (ID13 values 3.7 mg kg-1, s.c., and 35.8 mg kg-1, p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 microg). Extravasation elicited by the intraplantar application of substance P (10 microg) was not influenced by the administration of EMD 61753.7. EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg-1, s.c., and 10 mg kg-1, p.o., and in saline-loaded rats at doses of and above 10 mg kg-1, s.c.,and 30mgkg-1, p.o.8. The prostaglandin-mediated fall in mean arterial blood pressure elicited in anaesthetized rats by i.v.application of arachidonic acid was not inhibited by prior treatment with EMD 61753 (10mg kg-1,p.o.). Thus, a blockade of prostaglandin synthesis via inhibition of cyclo-oxygenase activity does not contribute to the in vivo effects of EMD 61753 and its metabolites.9 The present experiments therefore indicate that EMD 61753 is a potent, selective and orally-effective full ic-opioid receptor agonist which has a limited ability to penetrate the blood-brain barrier and elicit centrally-mediated sedation, putative aversion, diuresis, and antinociception. The inhibitory actions of systemically-applied EMD 61753 against hyperalgesic pressure nociception and neurogenic inflammation are mediated peripherally, probably by opioid receptors on the endings of sensory nerve fibres.
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PMID:A pharmacological profile of the novel, peripherally-selective kappa-opioid receptor agonist, EMD 61753. 788 87

The antitussive effects of SR 48968, a non-peptide tachykinin NK2 receptor antagonist, were investigated on citric acid-induced cough in the unanesthetized guinea-pig and compared with the effects of codeine. SR 48968 (0.01-0.3 mg/kg i.p.) inhibited in a dose-dependent manner the number of coughs induced by inhalation of an aqueous solution of citric acid with an ED50 of 0.1 mg/kg (0.17 mumol/kg). Under similar conditions, the codeine ED50 was 8 mg/kg (27 mumol/kg). Naloxone, an opioid receptor antagonist, abolished the effects of codeine but did not modify the effects of SR 48968. These data suggest that NK2 receptor stimulation might play an important role in the regulation of the cough reflex and that SR 48968 could be a potential antitussive agent.
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PMID:Antitussive effect of SR 48968, a non-peptide tachykinin NK2 receptor antagonist. 811 16

In the present work we have studied the postnatal development of functional dopamine, opioid and tachykinin receptors, which regulate cholinergic activity in the neostriatum. The release of endogenous acetylcholine from rat striatal slices was measured using a chemiluminescent method. We have observed that the inhibition mediated by dopamine through D2 receptors was not detectable until postnatal day 10, whereas the inhibition mediated by opioid receptors was detectable at postnatal day 15 for delta-receptors ([D-Pen2,D-Pen5]-enkephalin) and at postnatal day 21 for mu-receptors ([D-Ala2,Gly(ol)5]-enkephalin). Excitatory effect mediated by tachykinins through NK1 ([Sar9,Met(O2)11]- Substance P), NK2 ([Nle10]-Neurokinin A4-10), or NK3 (senktide) receptors was already detectable at postnatal day 5. In order to examine the influence of dopamine in the development of tachykinin and opioid systems in the neostriatum, we induced dopamine deficiency by intraventricular injection of 6-hydroxydopamine at postnatal day 3. We observed an increase in senktide-evoked acetylcholine release at postnatal day 30. The effect produced by [Sar9,Met(O2)11]-Substance P and [Nle10]-Neurokinin A4-10 was not modified. Furthermore, at postnatal day 35, we could observed that the two opioid receptor agonists have no effect. Our results show that dopamine, tachykinins and opioids are already able to mediate the modulation of acetylcholine release in early stages of development with a different pattern of postnatal development. Furthermore, the integrity of a dopaminergic system plays an important role in the functional development of the neostriatal cholinergic neurons which are differentially modulated by opioids or tachykinins.
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PMID:Postnatal development of functional dopamine, opioid and tachykinin receptors that regulate acetylcholine release from rat neostriatal slices. Effect of 6-hydroxydopamine lesion. 813 28

In this article, first, the different stages of acquisition and processing of nociceptive information from peripheral receptor to brain are reviewed and the plastic changes that accompany tissue injury are underlined. For instance, the subclassification of peripheral receptors in nociceptors and non-nociceptors (e.g., mechanoreceptors, thermoreceptors) must be understood in the light of peripheral sensitization. This phenomenon is the probable explanation for primary hyperalgesia, the decrease in pain threshold at the site of injury. The observation that substance P enhances N-methyl-D-aspartate (NMDA)-elicited responses suggests that these two receptors may operate in concert to prolong and amplify the afferent input generated by peripheral tissue injury. Such afferent barrage induces a state of central sensitization. Second, the major problems in the management of cancer pain, i.e. the development of tolerance to opioids and opioid-insensitive pain, are discussed. The loss of drug effect observed after chronic exposure of the opioid receptor (tolerance) may be the consequence of the down-regulation or desensitization phenomenon (where the total number of receptors coupled to the second messenger is reduced). The agonist dose-response begins to shift to the right. The dramatic analgesic improvement obtained with subanaesthetic doses of ketamine, an NMDA receptor antagonist, in those of our cancer patients who have become resistant to morphine is intriguing. As shown for tolerance, insensitivity to opioids may represent a rightward shift in the opioid dose-response curve and the analgesic effect of ketamine the reversal of that shift.
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PMID:Pain management: physiopathology, future research and endpoints. 814 5

Since opioids can influence the release of acetylcholine, substance P and a number of other neurotransmitters that have been implicated in the pathogenesis of Alzheimer's disease (AD), it is of interest to assess opioid receptor levels in AD. We have examined mu, delta and kappa opioid receptor binding parameters, binding sensitivity to a GTP analog and distribution in amygdala, frontal cortex and putamen of AD brain. Control brains were matched according to age, sex, post-mortem interval and storage time. Kd values and GTP analog binding sensitivity did not differ in AD and control brains. Bmax values for mu ([3H]DAMGE) sites also appeared unaffected by in vitro binding assays. In contrast, kappa ([3H]U69593) and delta ([3H]DSLET) opioid receptor levels, were significantly changed. In AD amygdala kappa Bmax values increased from control levels of 123 +/- 12 to 168 +/- 13 fmol/mg protein, whereas densities of kappa and delta sites were decreased from 94 +/- 8 to 48 +/- 8 and 102 +/- 3.6 to 69 +/- 8.5 fmol/mg protein, respectively, in putamen. Autoradiography revealed corresponding differences in the distribution of kappa opioid receptors. The findings indicate that the kappa binding site, which is quantitatively the major opioid receptor class in human brain, undergoes marked changes in AD amygdala and putamen.
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PMID:Opioid receptor density changes in Alzheimer amygdala and putamen. 814 29

Neutral endopeptidase 24.11 (NEP; "enkephalinase") may inactivate a number of centrally active neuropeptides including the enkephalins and substance P. In most areas of the central nervous system, the cell types which express NEP activity are not known. The hypoglossal nucleus (N.XII) was selected as a model system to characterize the cytochemical localization of NEP. The effect of hypoglossal nerve axotomy upon the distribution of NEP activity in the hypoglossal nucleus was compared to the effect upon cholinergic markers, the mu opiate receptor, and the enkephalins. By use of a fluorescence histochemical method, NEP was localized at all levels of N.XII to the soma and proximal processes of the majority of the apparent motor neurons in the nucleus. Fluorescent double-labeling studies revealed the presence of numerous enkephalinergic varicosities which localized to the neuropil surrounding NEP-stained motor neurons. To determine whether NEP was synthesized by these motor neurons, 18 rats received a unilateral transection of the hypoglossal nerve. A pronounced decrease in NEP staining in N.XII was observed on the operated side as early as 3 days following axotomy. This decrease persisted at all levels of the nucleus for about 5 weeks. By 7 weeks, the staining between the control and operated sides was indistinguishable. By contrast, there was no apparent change in the density or distribution of enkephalin-immunoreactive varicosities in five animals examined 6 to 32 days following axotomy. Radioligand binding of [3H]DAMGO to the mu-opiate receptor in N.XII was studied in 20 animals by quantitative autoradiography at 2, 6, and 11 days after axotomy. No significant changes in the level of radioligand binding to the mu-receptor were detected in response to axotomy. In contrast to the opiate system, the cholinergic enzymes choline acetyltransferase, acetylcholinesterase, and pseudocholinesterase showed a coordinate decrease in motor neuron-associated staining on the operated side of N.XII at 3, 6, and 11 days following axotomy which paralleled the decrease in NEP staining. By contrast, the lysosomal enzyme marker, acid phosphatase, showed a pronounced increase in staining on the operated side. The results of this study are consistent with the synthesis of NEP by cholinergic N.XII motor neurons and indicates that the enkephalins and NEP in N.XII are closely associated, but derive from separate neuronal populations. The widespread overlap in the distribution of NEP-stained motor neurons and enkephalinergic varicosities in N.XII provides additional anatomical support for a potential role for NEP in the inactivation of centrally active enkephalins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential response of neutral endopeptidase 24.11 ("enkephalinase"), and cholinergic and opioidergic markers to hypoglossal axotomy. 820 Oct 16

Extravasation elicited in rat skin by antidromic electrical stimulation of the saphenous nerve was dose dependently inhibited by the intravenous (i.v.) application of the mu-opioid receptor agonists, morphine and [D-Ala2,Me-Phe4,Gly-ol5]enkephalin (DAGO), and the kappa-opioid receptor agonists (-)-U 50488H, (-)-ICI 197067 and ICI 204448. This inhibition was antagonised by naloxone, and the lack of action of (+)-U 50488H (5 mg/kg) indicated that the kappa effect was stereoselective. The delta-opioid receptor agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE), and the sigma-receptor agonist, (+)-SKF 10047, had no effect on neurogenic extravasation at a dose of 5 mg/kg. Opiate-induced changes in cutaneous blood flow were not important for opiate inhibition since extravasation produced by exogenous substance P (the putative neurotransmitter) was not influenced by the opiates. An indirect opiate action via the adrenal glands was excluded since the effectiveness of DAGO, (-)-ICI 197067 and ICI 204448 was unchanged after adrenalectomy. Finally, the cutaneous locus of the opiate effect was shown by blocking the activity of systemically applied DAGO and ICI 204448 with naloxone injected into paw. These results indicate that specific mu-opioid and kappa-opioid, but not delta-opioid and sigma receptor agonists, inhibit neurogenic plasma extravasation in rat skin, probably via opioid receptors on peripheral terminals of sensory C-fibres.
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PMID:Mu- and kappa-opioid receptor agonists produce peripheral inhibition of neurogenic plasma extravasation in rat skin. 839 50

The presence of mu-opioid receptor-like immunoreactivity (MOR-LI) on axon terminals was confirmed by light and electron microscopy within the superficial layers of the medullary and spinal dorsal horns of the rat. By means of double-immunofluorescence histochemistry, co-localization of MOR-LI and substance P (SP)-LI was occasionally observed in axon terminals within the superficial layers of the dorsal horns.
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PMID:Co-localization of mu-opioid receptor-like and substance P-like immunoreactivities in axon terminals within the superficial layers of the medullary and spinal dorsal horns of the rat. 857 93


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