Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetorphan, a parenterally active enkephalinase inhibitor, induced dose-dependently a naloxone-reversible analgesia on the hot-plate jump test in DBA/2J (DBA2) mice but was devoid of effects in C57BL/6J (C57) mice. By contrast, acetorphan increased locomotion in both strains; however, the DBA2 strain was much more sensitive than C57 mice to the locomotor stimulant effect. The increased locomotion was antagonized by naloxone in both strains. These data suggest that endogenous enkephalins modulate nociception and locomotion in the two inbred strains differently.
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PMID:Role of endogenous enkephalins in locomotion and nociception studied with peptidase inhibitors in two inbred strains of mice (C57BL/6J and DBA/2J). 271 68

In several pain models, tricyclic antidepressants (TCAs) have been shown to reduce nociception. In the present study, we evaluated the antinociceptive effect of metapramine (META) in 4 nociception tests: (1) the hot plate test; (2) the phenylbenzoquinone-induced writhing; (3) the tail flick test; and (4) the test of electrical stimulation of the tail. We further analysed, using META and clomipramine (CLOM), the eventual role of endogenous opioids in analgesia induced by TCAs. The analgesic effects of META and CLOM in the hot plate test and in the test of electrical stimulation of the tail were reversed by naloxone. On the other hand, we failed to demonstrate a potentiation of META- or CLOM-induced analgesia by acetorphan, an inhibitor of 'enkephalinase.' We also failed to show a potentiation of Met5-enkephalin intracerebroventricularly injected by the two TCAs. Moreover, the administration of the enzymatic inhibitor or of Met5-enkephalin led to a slight decrease of the analgesic effect of the TCAs. These results (1) indicate that in our 4 pain tests, META clearly reduces nociception and (2) provide evidence that the involvement of endogenous enkephalins in the analgesia induced by TCAs is improbable.
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PMID:Analgesic effects of metapramine and evidence against the involvement of endogenous enkephalins in the analgesia induced by tricyclic antidepressants. 282 90

We have shown that a number of compounds which inhibit the degradation of met-enkephalin can produce naloxone-reversible analgesia in mice. These compounds also potentiate the analgesia produced by acupuncture, foot shock, and transcutaneous nerve stimulation in animals and humans. The potency of their effectiveness as analgesics or potentiators parallels their potency as inhibitors of mouse brain enkephalinase. D-Phenylalanine (DPA), one of these enkephalinase inhibitors, has been used successfully for the management of chronic intractable pain in humans and to potentiate the treatment of many painful conditions by acupuncture. Other aspects of pharmacology of DPA will be discussed, including its effects on the cardio-vascular system, behavior, and lack of development of tolerance and dependence when used chronically in animals and humans.
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PMID:Pharmacology of enkephalinase inhibitors: animal and human studies. 286 74

Actinonin which has been found to be an inhibitor of aminopeptidase M (EC 3.4.11.2) also inhibited enkephalinase A (EC 3.4.24.11) and enkephalin aminopeptidase which were partially purified from the corpus striatum membrane of guinea-pig brain. The IC50 values were 5.6 microM for enkephalinase A and 0.39 microM for enkephalin aminopeptidase. Actinonin also inhibited with an IC50 value of 1.1 microM dipeptidyl aminopeptidase tested on whole brain homogenate of rats in the presence of thiorphan and bestatin. Analgesia was assessed by measuring the tail-flick latency of mice. The analgesic effect of [Met5]enkephalin injected intracisternally (i.cist., 50 micrograms) was potentiated by an intraperitoneal (i.p., 100 and 300 mg/kg) as well as an i.cist. (25 micrograms) injection of actinonin. Actinonin was found to inhibit all three enzymes of enkephalin metabolism and, when given peripherally, to potentiate enkephalin analgesia.
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PMID:Composite effects of actinonin when inhibiting enkephalin-degrading enzymes. 288 48

Endogenous opioid peptides, by modulating the release of sympathetic transmitters, may play a role in the pathogenesis of migraine and related headaches which are considered hypernociceptive syndromes. Hypoendorphinaemia has been demonstrated in migraine attack. Captopril, a drug able to potentiate morphine analgesia in rats and inhibit enkephalinase in animals and in man, improves the clinical course of migraine. In the present research the cerebrospinal fluid and plasma beta-endorphin (beta-EP) levels have been evaluated following a single oral dose of captopril. The drug increased plasma beta-EP levels in migraine sufferers, and these data may be relevant in the mechanism of action of this drug in migraine and related headaches.
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PMID:Hypernociceptive syndromes and pharmacological inhibition of endogenous opioid degradation. 294 84

With the aim of producing an analgesia physiologically induced by endogenous opioids, several series of inhibitors of the degradation enzymes of enkephalins have been synthetized by using as a model, at the atomic level, the active site of thermolysin, a bacterial endopeptidase similar to enkephalinase. Thiorphan and retro-thiorphan are very potent inhibitors of enkephalinase (KI = 2 nM), but the retro compound is more selective, as it is unable to recognise the angiotensin conversion enzyme. Recently, a series of inhibitors containing a bidentate group were found to be capable of inhibiting the three metallopeptidases which break down the enkephalins. One of these compounds, kelatorphan, totally protects, in vitro and in vivo, Met-enkephalin from enzymatic degradation. Kelatorphan is the first complete inhibitor of enkephalin metabolism and is the only compound to possess an analgesic activity greater than that of a mixture of thiorphan and bestatin (non-specific aminopeptidase inhibitor). A tritiated derivative of kelatorphan has been used to visualise the enkephalinase in the rat brain by means of autoradiography. The enzyme has a heterogeneous distribution with a particularly high concentration in the nigro-striatal system.
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PMID:[Enkephalinase inhibitors and molecular study of the differences between active sites of enkephalinase and angiotensin-converting enzyme]. 299 52

The neutral endopeptidase EC 3.4.24.11, also designated enkephalinase, has been visualized by in vitro autoradiography using the tritiated inhibitor [3H]-N-[(2RS)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl] glycine, ([3H]HACBO-Gly). Specific binding of [3H]HACBO-Gly (Kd = 0.4 +/- 0.05 nM) corresponding to 85% of the total binding to brain slices was inhibited by 1 microM thiorphan, a selective inhibitor of enkephalinase, but remained unchanged in the presence of captopril, a selective inhibitor of angiotensin-converting enzyme. Very high levels of [3H]HACBO-Gly binding were found in the choroid plexus and the substantia nigra. High levels were present in the caudate putamen, globus pallidus, nucleus accumbens, olfactory tubercle, and in the substantia gelatinosa of the spinal cord. Moderate densities were found in parts of the amygdala, the periaqueductal gray matter, the interpeduncular nucleus, and the molecular layer of the cerebellum. The distribution of enkephalinase was compared to that of mu and delta opioid receptors, selectively labeled with [3H]Tyr-D-Ala-Gly-MePhe-glycinol and [3H]Tyr-D-Thr-Gly-Phe-Leu-Thr, respectively. In the caudate putamen, [3H]HACBO-Gly binding overlapped the clustered mu sites but appeared more closely related to the diffusely distributed delta sites. High levels of enkephalinase and mu opioid binding sites were present at the level of the periaqueductal gray matter and in the substantia gelatinosa of the spinal cord, regions where only sparse delta opioid receptors could be detected. The association of enkephalinase with delta and mu opioid receptors in these areas is consistent with the observed role of the enzyme in regulating the effects of opioid peptides in striatal dopamine release and analgesia, respectively. Except for the choroid plexus and the cerebellum, the close similarity observed in numerous rat brain areas between the distribution of enkephalinase and that of mu and/or delta opioid binding sites could account for most of the pharmacological effects elicited by enkephalinase inhibitors.
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PMID:Autoradiographic comparison of the distribution of the neutral endopeptidase "enkephalinase" and of mu and delta opioid receptors in rat brain. 300 54

The research on endogenous opioid is only a decade old but the considerable number and the variety of studies devoted to this subject suggest that these neuropeptides might play a pivotal role in various biological functions. The most abundant opioid peptides enkephalins are synthesized as large precursors. They bind to several classes of receptors as mu and delta types and are degraded by specific enzymes (aminopeptidase M, enkephalinase, dipeptidylaminopeptidase) belonging to the group of metallopeptidases. The analysis of the functions of the enkephalinergic system can now be investigated by using recently designed selective mu (DAGO, TRIMU 5), delta (DTLET, DEPDPE), kappa (U 50, 488) agonists or antagonists (ICI 174, 864 for the delta type) and kelatorphan a complete inhibitor of enkephalin metabolism. The former probes were obtained by a rational approach based on the conformational adaptability of the endogenous peptides while inhibitors of enkephalin degrading enzymes were designed by taking into account crystallographic data on metallopeptidases. mu and delta receptors present distinct distributions in the brain. Enkephalinase visualized by autoradiography seems to be closely associated with opioid receptors. Pain control could be insured in brain structures by mu receptor-stimulation whereas both mu and delta types might be involved at the level of the spinal cord. In both cases, a "physiological" analgesia is produced by kelatorphan.
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PMID:[The pharmacology of various classes of cerebral opioid receptors]. 302 30

Both the MAO-B inhibitor deprenyl (2.5-10 mg/kg, ip, 60 min prior) and the MAO-B substrate beta-phenylethylamine (PEA, 40 micrograms, icv) potentiated the analgesic action of the enkephalinase inhibitor phosphoramidon (250 micrograms, icv) in animals allowed normal sleep. The enhancing effect of PEA on phosphoramidon analgesia was further potentiated by deprenyl (5 mg/kg, ip) pretreatment. Deprenyl (5 mg/kg, ip) or PEA (40 micrograms, iv) given alone did not induce analgesia in animals allowed undisturbed sleep. REM sleep deprivation (REMSD) decreased the basal pain threshold and abolished the analgesic effect of phosphoramidon. The administration of deprenyl and/or PEA failed to restore the analgesic effect of phosphoramidon in REM sleep deprived animals. The results indicate that excess PEA has a stimulatory effect on the analgesic activity of endogenously released enkephalins in rats allowed undisturbed sleep but not in REM sleep deprived animals. It is suggested that the failure of phosphoramidon to induce analgesia after REMSD, is probably due to a functional insufficiency of an enkephalinergic system.
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PMID:An analgesic effect of enkephalinase inhibition is modulated by monoamine oxidase-B and REM sleep deprivations. 309 Apr 52

SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine] was synthesized as a p.o. active prodrug enkephalinase inhibitor. In vivo, it is de-esterified to SCH 32615 (N-[L-(-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine), the active constituent. In vitro, the Ki for SCH 32615 to block the degradation of Met5-enkephalin by isolated enkephalinase is 19.5 +/- 0.9 nM. In contrast, SCH 32615 did not inhibit aminopeptidase or diaminopeptidase III degradation of Met5-enkephalin up to 10 microM and did not affect angiotensin converting enzyme up to 10 microM. In vivo, p.o. administered SCH 34826 potentiated the analgesic effects of D-Ala2-Met5-enkephalinamide in mice (ED50 = 5.3 mg/kg p.o.) and rats [minimal effective dose (MED) = 1 mg/kg p.o.]; SCH 32615 had no effect up to 30 mg/kg p.o., but was active parenterally (ED50 in mice = 1.4 ng/kg sc). Direct, naloxone-reversible analgesic effects of SCH 34826 were demonstrated in the mouse low temperature hot-plate test (MED = 30 mg/kg p.o.), the mouse acetic acid-induced writhing test (MED = 30 mg/kg p.o.), the rat stress-induced analgesia test (MED = 10 mg/kg p.o.) and the modified rat yeast-paw test (MED = 100 mg/kg p.o.). Using the rat D-Ala2-Met5-enkephalinamide potentiation test the duration of action of SCH 34826 was at least 4 hs. No respiratory or gastrointestinal side effects of any consequence were noted at doses up to 100 times those active in the D-Ala2-Met-5-enkephalinamide potentiation test.
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PMID:Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. 316 88


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