Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.
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PMID:Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. 138 26

N-([(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl)-L-phenylalanine benzyl ester (RB101) is the first systemically active prodrug generating through a biologically dependent cleavage of the disulfide bond the potent (S)2-amino-1-mercapto-4-methylthio butane (aminopeptidase N) (IC50 = 11 nM) and N-[(R,S)-2-mercapto-methyl-1-oxo-3-phenylpropyl]-L-phenylalanine (neutral endopeptidase) (IC50 = 2 nM) inhibitors (aminopeptidase N). RB101 easily crosses the blood-brain barrier, as shown by the observed complete inhibition of cerebral endopeptidase 24.11 after i.v. injection in mice. The prodrug induces strong, dose-dependent antinociceptive responses in mice after i.v., i.p. or s.c. administration, in the hot plate (ED50 = 9 mg/kg) and phenylbenzoquinone-induced writhing (ED50-3.25 mg/kg) tests in mice, which are currently used in analgesics screening. RB101 is also active in the tail-flick and tail-electric stimulation tests in rats. In contrast, under disulfide forms, the above selective aminopeptidase N or endopeptidase 24.11 inhibitors are inactive after i.v. administration and their association 3 times less potent than RB101 alone. In all the tests used, the pain-alleviating effect of RB101 was suppressed by naloxone, but, except for the tail-flick and the motor response to tail-electric stimulation, not by the delta-selective antagonist naltrindole. The preferential involvement of mu opioid receptors in the analgesic effects of endogenous enkephalins, whose extracellular levels are increased by the two RB101-generated inhibitors, is suggested by the similar apparent pA2 values for RB101-naloxone (pA2: 7.53 +/- 0.046) and DAMGO (mu-selective ligand)-naloxone (pA2: 7.38 +/- 0.049).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats. 156 Mar 64

The link between endogenous opioid peptides and the genetic predisposition to preferentially consume ethanol was examined in alcohol preferring C57BL/6J mice compared with the alcohol nonpreferring DBA/2 mice. Concentrations of Met-enkephalin pentapeptide or precursor in various brain regions of potential relevance were not different between the two strains. C57BL/6J mice had a significantly lower pain threshold that could be increased by a selective mu-receptor opioid agonist [D-Ala2, MePhe4, Met(O)5-ol]-enkephalin. Treatment with this drug also decreased ethanol consumption in C57BL/6J mice. Increasing the synaptic half-life of endogenous enkephalins by the enkephalinase inhibitor kelatorphan also decreased ethanol consumption. Assay of endogenous enkephalin degrading activity showed increased enkephalinase activity in striatal issue of C57BL/6J compared with DBA/2 tissue. These results suggest that a relative lack of enkephalin peptides trans-synaptically, possibly resulting from enhanced enkephalin degradation may contribute to increase alcohol consumption in C57BL/6J mice.
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PMID:Endogenous opioids are involved in the genetically determined high preference for ethanol consumption. 165 11

Characterization of the distribution of the peptide-degrading enzyme neutral endopeptidase-24.11 (E.C. 3.4.24.11; NEP; enkephalinase) in the rat brainstem was examined by means of a unique fluorescent histochemical method. Enzyme staining was completely blocked by three potent NEP inhibitors (thiorphan, phosphoramidon, and JHF-26) at a concentration of 50 nM, supporting the specificity of this method to visualize sites of NEP activity selectively. At all levels of the brainstem, NEP was localized to cell bodies, cell processes or terminal-like fields and was localized to more than 90 distinct nuclei or subnuclei. In the mesencephalon these included the central gray, cuneiform n., dorsal and lateral tegmental n., inferior colliculus, interpeduncular n., lateral and medial geniculate n., central linear raphe n., mesencephalic n. of the trigeminal nerve, mammillary nuclei, occulomotor n., red n., superior colliculus, ventral n. of the lateral lemniscus, substantia nigra-ventral tegmental area, and the zona incerta. In the pons, NEP staining was restricted to fewer regions or nuclei, including the dorsal and ventral cochlear n., facial n., motor trigeminal n., principal sensory trigeminal n., parabrachial nuclei, pontine n., the oral and caudal pontine reticular n., pontine olivary nuclei, several pontine tegmental nuclei, pontine raphe nuclei, and the trapezoid n. In the cerebellum, staining was localized largely to the granule cell layer of the cerebellar cortex. Scattered staining was observed in the molecular cell layer. The medulla contained extensive NEP staining localized to nuclei that included the ambiguous n., dorsal motor n. of the vagus, hypoglossal n., inferior olivary n., prepositus hypoglossus n., solitary tract n., nuclei of the spinal tract of the trigeminal n., and the lateral, medial, and superior vestibular nuclei. Nuclei of the medullary reticular formation that were also richly stained for NEP included the raphe magnus n., raphe obscurus n., raphe pallidus n., dorsal, lateral, and ventral reticular nuclei of the medulla, and the gigantocellular, lateral paragigantocellular, linear, paramedian and parvicellular reticular nuclei. The widespread distribution of NEP in the brainstem suggests the existence of a number of functional systems, including the pathways involved in the mechanisms of pain and analgesia, which are potential targets of NEP inhibitors. In most regions, the distribution of NEP closely overlapped with that reported for the enkephalins, and showed a more restricted overlap with the reported distribution of substance P.
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PMID:Fluorescent histochemical localization of neutral endopeptidase-24.11 (enkephalinase) in the rat brainstem. 169 88

In unanaesthetized acupuncture-sensitive rabbit d-phenylalanine injection didn't change the EP in response to tooth pulp electrostimulation, but prolonged the analgetic effect of auriculo-acupuncture stimulation 15 Hz expressed by decreasing of the amplitude of N1P2 component EP. In acupuncture-resistant rabbit d-phenylalanine injection induced analgetic effect which was enhanced and prolonged by auriculo-acupuncture stimulation. It's suggested that the recovery of pain sensibility after acupuncture analgesia is determined by enkephalinase's mechanism activation which is activated permanently in acupuncture-resistant rabbits.
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PMID:[Action of an enkephalinase blocker on the effect of acupuncture in acupuncture sensitive and resistant rabbits]. 177 10

Enkephalinase (endopeptidase 24.11) is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. The enzyme was quantified in synovial fluid obtained from 36 swollen joints. Its concentration correlated with the synovial fluid cell count, mainly the polymorphonuclear cells and lymphocytes, and with the erythrocyte sedimentation rate. No statistically significant difference in enkephalinase levels was demonstrated between the groups of patients with rheumatoid arthritis, seronegative spondylarthropathy, microcrystalline arthritis, or osteoarthritis. The presence of enkephalinase in the synovial fluid could reflect the intensity of the inflammatory process, or it could represent a physiologic regulator of inflammation and pain within the joint.
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PMID:Enkephalinase: a physiologic neuroimmunomodulator detected in the synovial fluid. 185 79

The analgesic and acute central nervous system (CNS) side effect potential of the enkephalinase inhibitor SCH 32615 (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenyl-alanine-beta-alanine) were evaluated after IV administration to mice, rats and squirrel monkeys. In mice, SCH 32615 caused dose-related suppression of acetic acid-induced writhing (minimal effective dose, MED = 3 mg/kg IV). In rats, SCH 32615 produced dose-related increases in the response latencies in the yeast inflamed-paw test (MED = 10 mg/kg IV). In squirrel monkeys, using a new hot-water bath tail-flick test, SCH 32615 significantly prolonged the escape latencies (MED = 100 mg/kg IV). These results in primates are the first data showing an analgesic action of an enkephalinase inhibitor in a reflex model of pain. When measured for its CNS side effect potential, SCH 32615 had no significant effects in rats (up to 100 times its analgesically active doses) or in monkeys (up to three times). In the mouse, at doses 100 times its minimal effective dose, SCH 32615 produced brief convulsions; these lasted only a minute, resolved quickly, and did not cause lethality. In contrast, in rats and squirrel monkeys, the standard opioid analgesic morphine produced profound CNS side effects; this was particularly notable in monkeys, in which morphine's maximal analgesic effects were associated with near lethal respiratory depression. These data demonstrate that SCH 32615 produces selective analgesic actions and that its acute side effect liability is less than that seen with a clinically used standard.
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PMID:Analgesic and acute central nervous system side effects of the intravenously administered enkephalinase inhibitor SCH 32615. 201 47

Transplants of adrenal medullary tissue or isolated chromaffin cells into the spinal cord subarachnoid space has been shown to reduce pain sensitivity in rats. This analgesia probably results from the release of neuroactive substances, particularly opioid peptides, from the transplanted cells since it is induced by nicotinic stimulation of chromaffin cell receptors, and can be blocked by naloxone. However, this analgesia is short-lived, most likely due to the rapid hydrolysis of opioid peptides. The purpose of this study was to determine whether protection of opioid peptide hydrolysis by the potent enkephalinase inhibitor kelatorphan could prolong this analgesia. Results indicated that the intrathecal injection of kelatorphan in animals with either adrenal medullary or chromaffin cell implants significantly prolonged nicotine-stimulated analgesia. Pretreatment with naloxone completely eliminated this analgesia. These results suggest that it may be possible to induce long-term reductions in pain sensitivity using enkephalinase inhibitors following the transplantation of opioid peptide-producing cells into the CNS.
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PMID:Prolonged analgesia by enkephalinase inhibition in rats with spinal cord adrenal medullary transplants. 236 94

The metallopeptidase enkephalinase known to participate in the inactivation of endogenous enkephalins and, possibly, other neuropeptides such as tachykinins, was visualized by autoradiography using a [125I]iodinated monoclonal antibody. A detailed mapping of the enzyme in rat brain and spinal cord was established on 10-micron serial sections prepared in a frontal plane as well as a few sections in a sagittal plane. On adjacent sections, and for the purpose of comparison, substance P-like and enkephalin-like immunoreactivities were also visualized by autoradiography using a 125I-monoclonal antibody and a polyclonal antibody detected by a secondary 125I-anti-rabbit antibody respectively. Histological structures were identified on adjacent Nissl-stained sections. Using the highly sensitive 125I-probe, enkephalinase immunoreactivity was found to be distributed in a markedly heterogeneous manner in all areas of the central nervous system. Immunoreactivity was undetectable in white matter areas, for example the corpus callosum or fornix, and had a laminar pattern in, for example, the cerebral cortex or hippocampal formation. Hence, although immunodetection was not performed at the cellular level, a major neuronal localization of the peptidase is suggested. The latter is consistent with the detection of a strong immunoreactivity in a pathway linking the striatum to the globus pallidum, the entopeduncular nucleus and the substantia nigra, as well as with a series of biochemical and lesion data. The strong immunoreactivity also present in choroid plexuses and ependymal cells as well as in the intermediate lobe and in scattered cells of the anterior lobe of the pituitary suggests that populations of glial and endocrine cells also express the peptidase. The highest density of enkephalinase immunoreactivity was observed in basal ganglia and limbic areas (caudate putamen, globus pallidus, nucleus accumbens, olfactory tubercles) as well as in areas involved in pain control mechanisms (superficial layers of the spinal nucleus of the trigeminal nerve or of the dorsal horn of the spinal cord) which also display the highest immunoreactivities for both enkephalins and substance P (except in globus pallidus for the latter). These localizations account for the opioid-like analgesic and motor effects of enkephalinase inhibitors inasmuch as a selective or predominant participation of the peptidase in enkephalin inactivation is assumed. A number of other areas appear richly endowed in both enkephalinase and enkephalins whereas substance P is hardly detectable. This is particularly the case for the olfactory bulb, bed nucleus of the accessory olfactory tract, the cerebellum (where enkephalinase mainly occurs in the molecular layer) and the hippocampal formation (namely in the molecular layer of the dentate gyrus).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Detailed immunoautoradiographic mapping of enkephalinase (EC 3.4.24.11) in rat central nervous system: comparison with enkephalins and substance P. 247 16

The possible changes in neutral endopeptidase EC 3.4.24.11 ("enkephalinase", NEP), mu and delta opioid binding sites, were investigated using in vitro quantitative radioautography in various regions of the central nervous system of the Freund's adjuvant-induced arthritic rat, a model of chronic pain. Enkephalinase was labeled by a specific tritiated inhibitor, [3H]N-[(2RS)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]glycine ([3H]HACBO-Gly), while mu and delta opioid binding sites were selectively labelled with [3H]Tyr-D-Ala-Gly-(Me)Phe-Gly-ol ([3H]DAGO) and [3H]Tyr-D-Thr-Gly-Phe-Leu-Thr ([3H]DTLFT), respectively. As compared to controls, no significant modifications were found in NEP, mu or delta binding sites at both supraspinal and spinal levels of arthritic rats. These results suggest that the enhanced efficiency of exogenous opioids or endogenous enkephalins, reported to occur in this model of chronic inflammatory pain, are not directly related to changes in mu and delta opioid binding sites or steady state levels of NEP.
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PMID:Lack of significant changes in mu, delta opioid binding sites and neutral endopeptidase EC 3.4.24.11 in the brain and spinal cord of arthritic rats. 255 47


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